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Salehi Nowbandegani P, Wohns AW, Ballard JL, Lander ES, Bloemendal A, Neale BM, O'Connor LJ. Extremely sparse models of linkage disequilibrium in ancestrally diverse association studies. Nat Genet 2023; 55:1494-1502. [PMID: 37640881 DOI: 10.1038/s41588-023-01487-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 07/24/2023] [Indexed: 08/31/2023]
Abstract
Linkage disequilibrium (LD) is the correlation among nearby genetic variants. In genetic association studies, LD is often modeled using large correlation matrices, but this approach is inefficient, especially in ancestrally diverse studies. In the present study, we introduce LD graphical models (LDGMs), which are an extremely sparse and efficient representation of LD. LDGMs are derived from genome-wide genealogies; statistical relationships among alleles in the LDGM correspond to genealogical relationships among haplotypes. We published LDGMs and ancestry-specific LDGM precision matrices for 18 million common variants (minor allele frequency >1%) in five ancestry groups, validated their accuracy and demonstrated order-of-magnitude improvements in runtime for commonly used LD matrix computations. We implemented an extremely fast multiancestry polygenic prediction method, BLUPx-ldgm, which performs better than a similar method based on the reference LD correlation matrix. LDGMs will enable sophisticated methods that scale to ancestrally diverse genetic association data across millions of variants and individuals.
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Affiliation(s)
- Pouria Salehi Nowbandegani
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
| | - Anthony Wilder Wohns
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
- Stanford University School of Medicine, Stanford, CA, USA.
| | - Jenna L Ballard
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Graduate Group in Genomics and Computational Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Eric S Lander
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biology, MIT, Cambridge, MA, USA
- Department of Systems Biology, Harvard Medical School, Boston, MA, USA
| | - Alex Bloemendal
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Benjamin M Neale
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Luke J O'Connor
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
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The association of gene polymorphisms with milk production and mastitis resistance phenotypic traits in dairy cattle. ANNALS OF ANIMAL SCIENCE 2023. [DOI: 10.2478/aoas-2022-0091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Abstract
The aim of this study was to evaluate the association between gene polymorphisms (SNPs) and mastitis indicators and their relationship with milk production profitability in dairy herd.A functional analysis was also performed of five genes containing the studied SNPs and those located close by. DNA was isolated from the hair bulb of 320 dairy cows kept in three herds and SNP-microarray analysis was performed. The data on 299 cows was subjected to final statistical analysis using AI-REML method with one-trait repeatability test-day animal model and pedigree information using the DMU4 package. Five from 35 SNPs significantly associated with mastitis indicators or production traits and located within a gene or no more than 500,000 nucleotides from the gene were selected for the functional and economic analysis. A questionnaire was also developed to collect associated economic data of 219 cows from three herds, such as the value of milk production and direct costs incurred over three years; this allowed the gross margin, direct profitability index and direct costs incurred to produce one liter of milk to be determined, among others. None of the five studied SNPs were related to protein content. The rs110785912(T/A), found near CXCR4, and rs136813430(T/C), located in the TLR4 gene exon, were associated with lnSCC, while rs110455063(C/G), located near IGFI, was associated with milk yield, fat and total solid contents. rs109421300(T/C), associated with fat/protein content ratio, as well as fat and total solid content, is located in the DGAT1 gene intron. rs41587003(A/C), located in the DLG2 gene intron, was associated with lactose content. The economic analysis revealed differences between the variants of the three tested SNPs. The T/C variant of the rs136813430(T/C) SNP was characterized by the highest gross margin, the highest direct profitability index and the lowest costs incurred to produce 1 liter of milk. The T/A variant of rs110785912(T/A) was related to low lnSCC and was characterized by the highest direct profitability index. In turn, the C/C variant of the rs41587003(T/C) was related to the lowest level of lactose and the highest costs of milk production. It appears that rs136813430(T/C) may be the most promising of the tested SNPs for increasing the profitability of milk production. To our knowledge, it is the first effort to assess directly a correlation between the DNA polymorphism and economic output of a dairy enterprise.
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3
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Neyhart JL, Kantar MB, Zalapa J, Vorsa N. Genomic-environmental associations in wild cranberry (Vaccinium macrocarpon Ait.). G3 (BETHESDA, MD.) 2022; 12:jkac203. [PMID: 35944211 PMCID: PMC9526045 DOI: 10.1093/g3journal/jkac203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/01/2022] [Indexed: 06/01/2023]
Abstract
Understanding the genetic basis of local adaptation in natural plant populations, particularly crop wild relatives, may be highly useful for plant breeding. By characterizing genetic variation for adaptation to potentially stressful environmental conditions, breeders can make targeted use of crop wild relatives to develop cultivars for novel or changing environments. This is especially appealing for improving long-lived woody perennial crops such as the American cranberry (Vaccinium macrocarpon Ait.), the cultivation of which is challenged by biotic and abiotic stresses. In this study, we used environmental association analyses in a collection of 111 wild cranberry accessions to identify potentially adaptive genomic regions for a range of bioclimatic and soil conditions. We detected 126 significant associations between SNP marker loci and environmental variables describing temperature, precipitation, and soil attributes. Many of these markers tagged genes with functional annotations strongly suggesting a role in adaptation to biotic or abiotic conditions. Despite relatively low genetic variation in cranberry, our results suggest that local adaptation to divergent environments is indeed present, and the identification of potentially adaptive genetic variation may enable a selective use of this germplasm for breeding more stress-tolerant cultivars.
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Affiliation(s)
- Jeffrey L Neyhart
- USDA, Agricultural Research Service, Genetic Improvement for Fruits & Vegetables Laboratory, Chatsworth, NJ 08019, USA
| | - Michael B Kantar
- Department of Tropical Plant and Soil Sciences, University of Hawaii at Manoa, Honolulu, HI 96822, USA
| | - Juan Zalapa
- USDA, Agricultural Research Service, Vegetable Crops Research Unit, Madison, WI 53706, USA
- Department of Horticulture, University of Wisconsin—Madison, Madison, WI 53706, USA
| | - Nicholi Vorsa
- Department of Plant Biology, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ 08901, USA
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4
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Rahimmadar S, Ghaffari M, Mokhber M, Williams JL. Linkage Disequilibrium and Effective Population Size of Buffalo Populations of Iran, Turkey, Pakistan, and Egypt Using a Medium Density SNP Array. Front Genet 2021; 12:608186. [PMID: 34950186 PMCID: PMC8689148 DOI: 10.3389/fgene.2021.608186] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 11/03/2021] [Indexed: 11/21/2022] Open
Abstract
Linkage disequilibrium (LD) across the genome provides information to identify the genes and variations related to quantitative traits in genome-wide association studies (GWAS) and for the implementation of genomic selection (GS). LD can also be used to evaluate genetic diversity and population structure and reveal genomic regions affected by selection. LD structure and Ne were assessed in a set of 83 water buffaloes, comprising Azeri (AZI), Khuzestani (KHU), and Mazandarani (MAZ) breeds from Iran, Kundi (KUN) and Nili-Ravi (NIL) from Pakistan, Anatolian (ANA) buffalo from Turkey, and buffalo from Egypt (EGY). The values of corrected r2 (defined as the correlation between two loci) of adjacent SNPs for three pooled Iranian breeds (IRI), ANA, EGY, and two pooled Pakistani breeds (PAK) populations were 0.24, 0.28, 0.27, and 0.22, respectively. The corrected r2 between SNPs decreased with increasing physical distance from 100 Kb to 1 Mb. The LD values for IRI, ANA, EGY, and PAK populations were 0.16, 0.23, 0.24, and 0.21 for less than 100Kb, respectively, which reduced rapidly to 0.018, 0.042, 0.059, and 0.024, for a distance of 1 Mb. In all the populations, the decay rate was low for distances greater than 2Mb, up to the longest studied distance (15 Mb). The r2 values for adjacent SNPs in unrelated samples indicated that the Affymetrix Axiom 90 K SNP genomic array was suitable for GWAS and GS in these populations. The persistency of LD phase (PLDP) between populations was assessed, and results showed that PLPD values between the populations were more than 0.9 for distances of less than 100 Kb. The Ne in the recent generations has declined to the extent that breeding plans are urgently required to ensure that these buffalo populations are not at risk of being lost. We found that results are affected by sample size, which could be partially corrected for; however, additional data should be obtained to be confident of the results.
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Affiliation(s)
- Shirin Rahimmadar
- Department of Animal Science, Faculty of Agricultural Science, Urmia University, Urmia, Iran
| | - Mokhtar Ghaffari
- Department of Animal Science, Faculty of Agricultural Science, Urmia University, Urmia, Iran
| | - Mahdi Mokhber
- Department of Animal Science, Faculty of Agricultural Science, Urmia University, Urmia, Iran
| | - John L Williams
- Davies Research Centre, School of Animal and Veterinary Sciences, University of Adelaide, Roseworthy, SA, Australia.,Department of Animal Science, Food and Nutrition, Università Cattolica Del Sacro Cuore, Piacenza, Italy
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Further insight into the global variability of the OCA2-HERC2 locus for human pigmentation from multiallelic markers. Sci Rep 2021; 11:22530. [PMID: 34795370 PMCID: PMC8602267 DOI: 10.1038/s41598-021-01940-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 11/02/2021] [Indexed: 11/20/2022] Open
Abstract
The OCA2-HERC2 locus is responsible for the greatest proportion of eye color variation in humans. Numerous studies extensively described both functional SNPs and associated patterns of variation over this region. The goal of our study is to examine how these haplotype structures and allelic associations vary when highly variable markers such as microsatellites are used. Eleven microsatellites spanning 357 Kb of OCA2-HERC2 genes are analyzed in 3029 individuals from worldwide populations. We found that several markers display large differences in allele frequency (10% to 35% difference) among Europeans, East Asians and Africans. In Europe, the alleles showing increased frequency can also discriminate individuals with (IrisPlex) predicted blue and brown eyes. Distinct haplotypes are identified around the variants C and T of the functional SNP rs12913832 (associated to blue eyes), with linkage disequilibrium r2 values significant up to 237 Kb. The haplotype carrying the allele rs12913832 C has high frequency (76%) in blue eye predicted individuals (30% in brown eye predicted individuals), while the haplotype associated to the allele rs12913832 T is restricted to brown eye predicted individuals. Finally, homozygosity values reach levels of 91% near rs12913832. Odds ratios show values of 4.2, 7.4 and 10.4 for four markers around rs12913832 and 7.1 for their core haplotype. Hence, this study provides an example on the informativeness of multiallelic markers that, despite their current limited potential contribution to forensic eye color prediction, supports the use of microsatellites for identifying causing variants showing similar genetic features and history.
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Kling D, Phillips C, Kennett D, Tillmar A. Investigative genetic genealogy: Current methods, knowledge and practice. Forensic Sci Int Genet 2021; 52:102474. [PMID: 33592389 DOI: 10.1016/j.fsigen.2021.102474] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 01/12/2021] [Accepted: 01/27/2021] [Indexed: 12/15/2022]
Abstract
Investigative genetic genealogy (IGG) has emerged as a new, rapidly growing field of forensic science. We describe the process whereby dense SNP data, commonly comprising more than half a million markers, are employed to infer distant relationships. By distant we refer to degrees of relatedness exceeding that of first cousins. We review how methods of relationship matching and SNP analysis on an enlarged scale are used in a forensic setting to identify a suspect in a criminal investigation or a missing person. There is currently a strong need in forensic genetics not only to understand the underlying models to infer relatedness but also to fully explore the DNA technologies and data used in IGG. This review brings together many of the topics and examines their effectiveness and operational limits, while suggesting future directions for their forensic validation. We further investigated the methods used by the major direct-to-consumer (DTC) genetic ancestry testing companies as well as submitting a questionnaire where providers of forensic genetic genealogy summarized their operation/services. Although most of the DTC market, and genetic genealogy in general, has undisclosed, proprietary algorithms we review the current knowledge where information has been discussed and published more openly.
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Affiliation(s)
- Daniel Kling
- Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden; Department of Forensic Sciences, Oslo University Hospital, Oslo, Norway.
| | - Christopher Phillips
- Forensic Genetics Unit, Institute of Forensic Sciences, University of Santiago de Compostela, Santiago de Compostela, Spain.
| | - Debbie Kennett
- Research Department of Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, United Kingdom
| | - Andreas Tillmar
- Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
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7
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Yong SY, Raben TG, Lello L, Hsu SDH. Genetic architecture of complex traits and disease risk predictors. Sci Rep 2020; 10:12055. [PMID: 32694572 PMCID: PMC7374622 DOI: 10.1038/s41598-020-68881-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 06/30/2020] [Indexed: 01/30/2023] Open
Abstract
Genomic prediction of complex human traits (e.g., height, cognitive ability, bone density) and disease risks (e.g., breast cancer, diabetes, heart disease, atrial fibrillation) has advanced considerably in recent years. Using data from the UK Biobank, predictors have been constructed using penalized algorithms that favor sparsity: i.e., which use as few genetic variants as possible. We analyze the specific genetic variants (SNPs) utilized in these predictors, which can vary from dozens to as many as thirty thousand. We find that the fraction of SNPs in or near genic regions varies widely by phenotype. For the majority of disease conditions studied, a large amount of the variance is accounted for by SNPs outside of coding regions. The state of these SNPs cannot be determined from exome-sequencing data. This suggests that exome data alone will miss much of the heritability for these traits-i.e., existing PRS cannot be computed from exome data alone. We also study the fraction of SNPs and of variance that is in common between pairs of predictors. The DNA regions used in disease risk predictors so far constructed seem to be largely disjoint (with a few interesting exceptions), suggesting that individual genetic disease risks are largely uncorrelated. It seems possible in theory for an individual to be a low-risk outlier in all conditions simultaneously.
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Affiliation(s)
- Soke Yuen Yong
- Department of Physics and Astronomy, Michigan State University, East Lansing, USA.
| | - Timothy G Raben
- Department of Physics and Astronomy, Michigan State University, East Lansing, USA
| | - Louis Lello
- Department of Physics and Astronomy, Michigan State University, East Lansing, USA.,Genomic Prediction, North Brunswick, NJ, USA
| | - Stephen D H Hsu
- Department of Physics and Astronomy, Michigan State University, East Lansing, USA.,Genomic Prediction, North Brunswick, NJ, USA
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8
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Zhang C, Dong SS, Xu JY, He WM, Yang TL. PopLDdecay: a fast and effective tool for linkage disequilibrium decay analysis based on variant call format files. Bioinformatics 2020; 35:1786-1788. [PMID: 30321304 DOI: 10.1093/bioinformatics/bty875] [Citation(s) in RCA: 831] [Impact Index Per Article: 166.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 09/20/2018] [Accepted: 10/12/2018] [Indexed: 01/02/2023] Open
Abstract
MOTIVATION Linkage disequilibrium (LD) decay is of great interest in population genetic studies. However, no tool is available now to do LD decay analysis from variant call format (VCF) files directly. In addition, generation of pair-wise LD measurements for whole genome SNPs usually resulting in large storage wasting files. RESULTS We developed PopLDdecay, an open source software, for LD decay analysis from VCF files. It is fast and is able to handle large number of variants from sequencing data. It is also storage saving by avoiding exporting pair-wise results of LD measurements. Subgroup analyses are also supported. AVAILABILITY AND IMPLEMENTATION PopLDdecay is freely available at https://github.com/BGI-shenzhen/PopLDdecay.
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Affiliation(s)
- Chi Zhang
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.,BGI Genomics, BGI-Shenzhen, Shenzhen, China
| | - Shan-Shan Dong
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | | | - Wei-Ming He
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.,BGI Genomics, BGI-Shenzhen, Shenzhen, China
| | - Tie-Lin Yang
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China
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9
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dos Santos BA, Pereira GL, Bussiman FDO, Paschoal VR, de Souza Júnior SM, Balieiro JCDC, Chardulo LAL, Curi RA. Genomic analysis of the population structure in horses of the Brazilian Mangalarga Marchador breed. Livest Sci 2019. [DOI: 10.1016/j.livsci.2019.09.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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10
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Kling D, Tillmar A. Forensic genealogy—A comparison of methods to infer distant relationships based on dense SNP data. Forensic Sci Int Genet 2019; 42:113-124. [DOI: 10.1016/j.fsigen.2019.06.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 05/15/2019] [Accepted: 06/24/2019] [Indexed: 12/16/2022]
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11
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Zhang W, Liu J, Goodman J, Weir BS, Fewster RM. Stationary distribution of the linkage disequilibrium coefficient r 2. Theor Popul Biol 2019; 128:19-26. [PMID: 31145877 DOI: 10.1016/j.tpb.2019.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 05/15/2019] [Accepted: 05/21/2019] [Indexed: 11/25/2022]
Abstract
The linkage disequilibrium coefficient r2 is a measure of statistical dependence of the alleles possessed by an individual at different genetic loci. It is widely used in association studies to search for the locations of disease-causing genes on chromosomes. Most studies to date treat r2 as a fixed property of two loci in a finite population, and investigate the sampling distribution of estimators due to the statistical sampling of individuals from the population. Here, we instead consider the distribution of r2 itself under a process of genetic sampling through the generations. Using a classical two-locus model for genetic drift, mutation, and recombination, we investigate the probability density function of r2 at stationarity. This density function provides a tool for inference on evolutionary parameters such as mutation and recombination rates. We reconstruct the approximate stationary density of r2 by calculating a finite sequence of the distribution's moments and applying the maximum entropy principle. Our approach is based on the diffusion approximation, under which we demonstrate that for certain models in population genetics, moments of the stationary distribution can be obtained without knowing the probability distribution itself. To illustrate our approach, we show how the stationary probability density of r2 can be used in a maximum likelihood framework to estimate mutation and recombination rates from sample data of r2.
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Affiliation(s)
- Wei Zhang
- Department of Statistics, University of Auckland, Private Bag 92019, Auckland, New Zealand.
| | - Jing Liu
- Department of Statistics, University of Auckland, Private Bag 92019, Auckland, New Zealand; University of Michigan - Shanghai Jiao Tong University Joint Institute, Shanghai 200240, China
| | - Jesse Goodman
- Department of Statistics, University of Auckland, Private Bag 92019, Auckland, New Zealand
| | - Bruce S Weir
- Department of Biostatistics, University of Washington, Box 357232, Seattle, WA 98195-7232, USA
| | - Rachel M Fewster
- Department of Statistics, University of Auckland, Private Bag 92019, Auckland, New Zealand
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12
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Dey S, Krishna S, Anthony NB, Rhoads DD. Further investigation of a quantitative trait locus for ascites on chromosome 9 in broiler chicken lines. Poult Sci 2017; 96:788-797. [PMID: 28339549 DOI: 10.3382/ps/pew380] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 09/20/2016] [Indexed: 01/05/2023] Open
Abstract
Previously, we reported a genome wide association study (GWAS) that had shown association of a region between 11.8 and 13.6 Mbp on chromosome 9 with ascites phenotype in broilers. We had used microsatellite loci to demonstrate an association of particular genotypes for this region with ascites in experimental ascites lines and commercial broiler breeder lines. We identified two potential candidate genes, AGTR1 and UTS2D, within that chromosomal region for mediating the quantitative effect. We have now extended our analysis using SNPs for these genes to assess association with resistance or susceptibility to ascites in these same broiler lines. Surprisingly, in contrast to our previous GWAS and microsatellite data for this region, we find no association of the SNP genotypes or haplotypes in the region suggesting that the two genes might have limited association with the disease phenotype.
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Affiliation(s)
- Shatovisha Dey
- Program in Cell and Molecular Biology, University of Arkansas, Fayetteville, AR 72701.,Department of Biological Sciences, University of Arkansas, Fayetteville, AR 72701
| | - Sriram Krishna
- Program in Cell and Molecular Biology, University of Arkansas, Fayetteville, AR 72701
| | - Nicholas B Anthony
- Program in Cell and Molecular Biology, University of Arkansas, Fayetteville, AR 72701.,Department of Poultry Sciences, University of Arkansas, Fayetteville, AR 72701
| | - Douglas D Rhoads
- Program in Cell and Molecular Biology, University of Arkansas, Fayetteville, AR 72701.,Department of Biological Sciences, University of Arkansas, Fayetteville, AR 72701
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13
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Chu HY, Sprouffske K, Wagner A. The role of recombination in evolutionary adaptation of Escherichia coli to a novel nutrient. J Evol Biol 2017; 30:1692-1711. [PMID: 28612351 DOI: 10.1111/jeb.13132] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 05/11/2017] [Accepted: 06/05/2017] [Indexed: 12/11/2022]
Abstract
The benefits and detriments of recombination for adaptive evolution have been studied both theoretically and experimentally, with conflicting predictions and observations. Most pertinent experiments examine recombination's effects in an unchanging environment and do not study its genomewide effects. Here, we evolved six replicate populations of either highly recombining R+ or lowly recombining R- E. coli strains in a changing environment, by introducing the novel nutrients L-arabinose or indole into the environment. The experiment's ancestral strains are not viable on these nutrients, but 130 generations of adaptive evolution were sufficient to render them viable. Recombination conferred a more pronounced advantage to populations adapting to indole. To study the genomic changes associated with this advantage, we sequenced the genomes of 384 clones isolated from selected replicates at the end of the experiment. These genomes harbour complex changes that range from point mutations to large-scale DNA amplifications. Among several candidate adaptive mutations, those in the tryptophanase regulator tnaC stand out, because the tna operon in which it resides has a known role in indole metabolism. One of the highly recombining populations also shows a significant excess of large-scale segmental DNA amplifications that include the tna operon. This lineage also shows a unique and potentially adaptive combination of point mutations and DNA amplifications that may have originated independently from one another, to be joined later by recombination. Our data illustrate that the advantages of recombination for adaptive evolution strongly depend on the environment and that they can be associated with complex genomic changes.
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Affiliation(s)
- H-Y Chu
- Department of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland
| | - K Sprouffske
- Department of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland
| | - A Wagner
- Department of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland.,The Swiss Institute of Bioinformatics, Quartier Sorge, Batiment Genopode, Lausanne, Switzerland.,The Santa Fe Institute, Santa Fe, NM, USA
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14
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Association of early onset myasthenia gravis in Newfoundland dogs with the canine major histocompatibility complex class I. Neuromuscul Disord 2017; 27:409-416. [DOI: 10.1016/j.nmd.2017.01.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 01/08/2017] [Accepted: 01/27/2017] [Indexed: 12/19/2022]
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15
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Hormozdiari F, van de Bunt M, Segrè AV, Li X, Joo JWJ, Bilow M, Sul JH, Sankararaman S, Pasaniuc B, Eskin E. Colocalization of GWAS and eQTL Signals Detects Target Genes. Am J Hum Genet 2016; 99:1245-1260. [PMID: 27866706 DOI: 10.1016/j.ajhg.2016.10.003] [Citation(s) in RCA: 467] [Impact Index Per Article: 51.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 10/03/2016] [Indexed: 01/01/2023] Open
Abstract
The vast majority of genome-wide association study (GWAS) risk loci fall in non-coding regions of the genome. One possible hypothesis is that these GWAS risk loci alter the individual's disease risk through their effect on gene expression in different tissues. In order to understand the mechanisms driving a GWAS risk locus, it is helpful to determine which gene is affected in specific tissue types. For example, the relevant gene and tissue could play a role in the disease mechanism if the same variant responsible for a GWAS locus also affects gene expression. Identifying whether or not the same variant is causal in both GWASs and expression quantitative trail locus (eQTL) studies is challenging because of the uncertainty induced by linkage disequilibrium and the fact that some loci harbor multiple causal variants. However, current methods that address this problem assume that each locus contains a single causal variant. In this paper, we present eCAVIAR, a probabilistic method that has several key advantages over existing methods. First, our method can account for more than one causal variant in any given locus. Second, it can leverage summary statistics without accessing the individual genotype data. We use both simulated and real datasets to demonstrate the utility of our method. Using publicly available eQTL data on 45 different tissues, we demonstrate that eCAVIAR can prioritize likely relevant tissues and target genes for a set of glucose- and insulin-related trait loci.
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Affiliation(s)
- Farhad Hormozdiari
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Martijn van de Bunt
- Oxford Centre for Diabetes, Endocrinology, & Metabolism, University of Oxford, Oxford OX3 7LJ, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Ayellet V Segrè
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Xiao Li
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Jong Wha J Joo
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Michael Bilow
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jae Hoon Sul
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Semel Center for Informatics and Personalized Genomics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Sriram Sankararaman
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Bogdan Pasaniuc
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Eleazar Eskin
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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16
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Tamura T, Osawa M, Kakimoto Y, Ochiai E, Suzuki T, Nakamura T. Combined effects of multiple linked loci on pairwise sibling tests. Int J Legal Med 2016; 131:95-102. [PMID: 27878372 DOI: 10.1007/s00414-016-1491-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 11/02/2016] [Indexed: 11/24/2022]
Abstract
The advanced multiplex STR system, PowerPlex Fusion, includes four linked locus pairs. The conventional Identifiler system has one pair of linked loci. Therefore, sibling tests conducted using the advanced system might be more affected by linkage than those conducted using the conventional system. This study simulated single and combined effects of the four linked locus pairs on pairwise sibling tests. Simulated genotypes of 100,000 pairs of full siblings and nonrelatives were constructed according to allele frequencies of the Japanese population. The single linkage effect was evaluated for simulated genotype data by calculating both the likelihood ratio accounting for the linkage between two loci and the likelihood ratio ignoring the linkage. The combined effect was obtained by multiplication of the respective single effects. Furthermore, we investigated the possibility that ignoring the linkage affects subject classification by introducing a scale of the likelihood ratio into sibling tests. The single effect in the Identifiler analysis was 0.645-1.746 times if the linkage was ignored. Overestimations and underestimations were predictable from the identical-by-state status at two linked loci. The combined effect in the PowerPlex Fusion analysis was 0.217-7.390 times. Ignoring the linkage rarely caused a false conclusive or inconclusive result, even from PowerPlex Fusion analysis. Application of the advanced system improved sibling tests considerably. The additional examined loci were more beneficial than the adverse effect of the linkage derived from the four linked locus pairs.
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Affiliation(s)
- Tomonori Tamura
- Department of Forensic Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa, 259-1193, Japan.,Scientific Crime Laboratory, Kanagawa Prefectural Police, Yamashita-cho 155, Naka-ku, Yokohama, 231-0023, Japan
| | - Motoki Osawa
- Department of Forensic Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa, 259-1193, Japan.
| | - Yu Kakimoto
- Department of Forensic Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa, 259-1193, Japan
| | - Eriko Ochiai
- Department of Forensic Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa, 259-1193, Japan
| | - Takanori Suzuki
- Scientific Crime Laboratory, Kanagawa Prefectural Police, Yamashita-cho 155, Naka-ku, Yokohama, 231-0023, Japan
| | - Takashi Nakamura
- Scientific Crime Laboratory, Kanagawa Prefectural Police, Yamashita-cho 155, Naka-ku, Yokohama, 231-0023, Japan
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17
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Hormozdiari F, Kang EY, Bilow M, Ben-David E, Vulpe C, McLachlan S, Lusis AJ, Han B, Eskin E. Imputing Phenotypes for Genome-wide Association Studies. Am J Hum Genet 2016; 99:89-103. [PMID: 27292110 PMCID: PMC5005435 DOI: 10.1016/j.ajhg.2016.04.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 04/28/2016] [Indexed: 01/23/2023] Open
Abstract
Genome-wide association studies (GWASs) have been successful in detecting variants correlated with phenotypes of clinical interest. However, the power to detect these variants depends on the number of individuals whose phenotypes are collected, and for phenotypes that are difficult to collect, the sample size might be insufficient to achieve the desired statistical power. The phenotype of interest is often difficult to collect, whereas surrogate phenotypes or related phenotypes are easier to collect and have already been collected in very large samples. This paper demonstrates how we take advantage of these additional related phenotypes to impute the phenotype of interest or target phenotype and then perform association analysis. Our approach leverages the correlation structure between phenotypes to perform the imputation. The correlation structure can be estimated from a smaller complete dataset for which both the target and related phenotypes have been collected. Under some assumptions, the statistical power can be computed analytically given the correlation structure of the phenotypes used in imputation. In addition, our method can impute the summary statistic of the target phenotype as a weighted linear combination of the summary statistics of related phenotypes. Thus, our method is applicable to datasets for which we have access only to summary statistics and not to the raw genotypes. We illustrate our approach by analyzing associated loci to triglycerides (TGs), body mass index (BMI), and systolic blood pressure (SBP) in the Northern Finland Birth Cohort dataset.
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Affiliation(s)
- Farhad Hormozdiari
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Eun Yong Kang
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Michael Bilow
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Eyal Ben-David
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Chris Vulpe
- Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Stela McLachlan
- Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, UK
| | - Aldons J Lusis
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Buhm Han
- Department of Convergence Medicine, University of Ulsan College of Medicine & Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.
| | - Eleazar Eskin
- Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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18
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Anderson JE, Kono TJY, Stupar RM, Kantar MB, Morrell PL. Environmental Association Analyses Identify Candidates for Abiotic Stress Tolerance in Glycine soja, the Wild Progenitor of Cultivated Soybeans. G3 (BETHESDA, MD.) 2016; 6:835-43. [PMID: 26818076 PMCID: PMC4825654 DOI: 10.1534/g3.116.026914] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 01/22/2016] [Indexed: 01/04/2023]
Abstract
Natural populations across a species range demonstrate population structure owing to neutral processes such as localized origins of mutations and migration limitations. Selection also acts on a subset of loci, contributing to local adaptation. An understanding of the genetic basis of adaptation to local environmental conditions is a fundamental goal in basic biological research. When applied to crop wild relatives, this same research provides the opportunity to identify adaptive genetic variation that may be used to breed for crops better adapted to novel or changing environments. The present study explores an ex situ conservation collection, the USDA germplasm collection, genotyped at 32,416 SNPs to identify population structure and test for associations with bioclimatic and biophysical variables in Glycine soja, the wild progenitor of Glycine max (soybean). Candidate loci were detected that putatively contribute to adaptation to abiotic stresses. The identification of potentially adaptive variants in this ex situ collection may permit a more targeted use of germplasm collections.
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Affiliation(s)
- Justin E Anderson
- Department of Agronomy and Plant Genetics, University of Minnesota, St. Paul, Minnesota 55108
| | - Thomas J Y Kono
- Department of Agronomy and Plant Genetics, University of Minnesota, St. Paul, Minnesota 55108
| | - Robert M Stupar
- Department of Agronomy and Plant Genetics, University of Minnesota, St. Paul, Minnesota 55108
| | - Michael B Kantar
- Department of Agronomy and Plant Genetics, University of Minnesota, St. Paul, Minnesota 55108 Biodiversity Research Centre and Department of Botany, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
| | - Peter L Morrell
- Department of Agronomy and Plant Genetics, University of Minnesota, St. Paul, Minnesota 55108
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19
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Zou W, Ouyang H. Using local multiplicity to improve effect estimation from a hypothesis-generating pharmacogenetics study. THE PHARMACOGENOMICS JOURNAL 2016; 16:107-112. [PMID: 25802090 DOI: 10.1038/tpj.2015.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 12/29/2014] [Accepted: 01/28/2015] [Indexed: 06/04/2023]
Abstract
We propose a multiple estimation adjustment (MEA) method to correct effect overestimation due to selection bias from a hypothesis-generating study (HGS) in pharmacogenetics. MEA uses a hierarchical Bayesian approach to model individual effect estimates from maximal likelihood estimation (MLE) in a region jointly and shrinks them toward the regional effect. Unlike many methods that model a fixed selection scheme, MEA capitalizes on local multiplicity independent of selection. We compared mean square errors (MSEs) in simulated HGSs from naive MLE, MEA and a conditional likelihood adjustment (CLA) method that model threshold selection bias. We observed that MEA effectively reduced MSE from MLE on null effects with or without selection, and had a clear advantage over CLA on extreme MLE estimates from null effects under lenient threshold selection in small samples, which are common among 'top' associations from a pharmacogenetics HGS.
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Affiliation(s)
- W Zou
- Biostatistics, Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA
| | - H Ouyang
- Global Statistical Sciences (GSS) - Oncology, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN, USA
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20
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Xing C, Huang J, Hsu YH, DeStefano AL, Heard-Costa NL, Wolf PA, Seshadri S, Kiel DP, Cupples LA, Dupuis J. Evaluation of power of the Illumina HumanOmni5M-4v1 BeadChip to detect risk variants for human complex diseases. Eur J Hum Genet 2015; 24:1029-34. [PMID: 26577045 DOI: 10.1038/ejhg.2015.244] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 10/09/2015] [Accepted: 10/14/2015] [Indexed: 01/20/2023] Open
Abstract
Although emerging sequencing technologies can characterize all genetic variants, the cost is still high. Illumina released the HumanOmni5M-4v1 (Omni5) genotype array with ~4.3M assayed SNPs, a much denser array compared with other available arrays. The Omni5 balances both cost and array density. In this article, we illustrate the power of Omni5 to detect genetic associations. The Omni5 includes variants with a wide range of minor allele frequencies down to <1%. The theoretical power calculation examples indicate the increased power of the Omni5 array compared with other arrays with lower density when evaluating associations with some known loci, although there are exceptions. We further evaluate the genetic associations between known loci and several quantitative traits in the Framingham Heart Study: femoral neck bone mineral density, lumbar spine bone mineral density and hippocampal volume. Finally, we search genome wide for novel associations using the Omni5 genotypes. We compare our association results from Affymetrix 500K+MIPS 50K arrays and two imputed data sets: (1) HapMap Phase II and (2) 1000 Genomes reference panel. We observed increased evidence for genotype-phenotype associations with smaller P-values for selected known loci using the Omni5 genotypes. With limited sample sizes, we identify novel variants with genome-wide significant P-values. Our observations support the notion that dense genotyping using the Omni5 can be powerful in detecting novel associated variants. Comparison with imputed data with higher density also suggests that imputation helps but cannot replace genotyping, especially when imputation quality is low.
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Affiliation(s)
- Chuanhua Xing
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Jie Huang
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
| | - Yi-Hsiang Hsu
- Hebrew SeniorLife, Institute for Aging Research, Boston, MA, USA.,Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.,Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA
| | - Anita L DeStefano
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.,Department of Neurology, Boston University School of Medicine, Boston, MA, USA.,Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA, USA
| | - Nancy L Heard-Costa
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA.,Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA, USA
| | - Philip A Wolf
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA.,Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA, USA
| | - Sudha Seshadri
- Department of Neurology, Boston University School of Medicine, Boston, MA, USA.,Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA, USA
| | - Douglas P Kiel
- Hebrew SeniorLife, Institute for Aging Research, Boston, MA, USA.,Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - L Adrienne Cupples
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.,Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA, USA
| | - Josée Dupuis
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.,Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, MA, USA
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21
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Christofidou P, Nelson CP, Nikpay M, Qu L, Li M, Loley C, Debiec R, Braund PS, Denniff M, Charchar FJ, Arjo AR, Trégouët DA, Goodall AH, Cambien F, Ouwehand WH, Roberts R, Schunkert H, Hengstenberg C, Reilly MP, Erdmann J, McPherson R, König IR, Thompson JR, Samani NJ, Tomaszewski M. Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in Monocytes and Macrophages. Am J Hum Genet 2015; 97:228-37. [PMID: 26166477 PMCID: PMC4573243 DOI: 10.1016/j.ajhg.2015.06.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 06/04/2015] [Indexed: 02/07/2023] Open
Abstract
Runs of homozygosity (ROHs) are recognized signature of recessive inheritance. Contributions of ROHs to the genetic architecture of coronary artery disease and regulation of gene expression in cells relevant to atherosclerosis are not known. Our combined analysis of 24,320 individuals from 11 populations of white European ethnicity showed an association between coronary artery disease and both the count and the size of ROHs. Individuals with coronary artery disease had approximately 0.63 (95% CI: 0.4-0.8) excess of ROHs when compared to coronary-artery-disease-free control subjects (p = 1.49 × 10(-9)). The average total length of ROHs was approximately 1,046.92 (95% CI: 634.4-1,459.5) kb greater in individuals with coronary artery disease than control subjects (p = 6.61 × 10(-7)). None of the identified individual ROHs was associated with coronary artery disease after correction for multiple testing. However, in aggregate burden analysis, ROHs favoring increased risk of coronary artery disease were much more common than those showing the opposite direction of association with coronary artery disease (p = 2.69 × 10(-33)). Individual ROHs showed significant associations with monocyte and macrophage expression of genes in their close proximity-subjects with several individual ROHs showed significant differences in the expression of 44 mRNAs in monocytes and 17 mRNAs in macrophages when compared to subjects without those ROHs. This study provides evidence for an excess of homozygosity in coronary artery disease in outbred populations and suggest the potential biological relevance of ROHs in cells of importance to the pathogenesis of atherosclerosis.
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Affiliation(s)
| | - Christopher P Nelson
- Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester LE3 9QP, UK
| | - Majid Nikpay
- Ruddy Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada; Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, ON K1Y 3V5, Canada
| | - Liming Qu
- Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mingyao Li
- Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Christina Loley
- Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck 23562, Germany
| | - Radoslaw Debiec
- Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK
| | - Peter S Braund
- Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK
| | - Matthew Denniff
- Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK
| | - Fadi J Charchar
- Faculty of Science and Technology, School of Applied and Biomedical Sciences, Federation University Australia, Ballarat, VIC 3350, Australia
| | - Ares Rocanin Arjo
- ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France; INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 1166, Paris 75013, France
| | - David-Alexandre Trégouët
- ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France; INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 1166, Paris 75013, France
| | - Alison H Goodall
- Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester LE3 9QP, UK
| | - Francois Cambien
- ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France; INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France; Sorbonne Universités, UPMC University, Paris 06, UMR_S 1166, Paris 75013, France
| | - Willem H Ouwehand
- Department of Haematology, Cambridge Biomedical Campus, University of Cambridge and NHS Blood and Transplant, Cambridge CB2 0PT, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK
| | - Robert Roberts
- Ruddy Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada; Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, ON K1Y 3V5, Canada
| | - Heribert Schunkert
- Deutsches Herzzentrum München, Technische Universität München, Munich 80636, Germany; Deutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK), Munich 80636, Germany
| | - Christian Hengstenberg
- Deutsches Herzzentrum München, Technische Universität München, Munich 80636, Germany; Deutsches Zentrum für Herz- und Kreislauf-Forschung (DZHK), Munich 80636, Germany
| | - Muredach P Reilly
- Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19148, USA
| | - Jeanette Erdmann
- Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck 23562, Germany
| | - Ruth McPherson
- Ruddy Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada; Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, ON K1Y 3V5, Canada
| | - Inke R König
- Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck 23562, Germany
| | - John R Thompson
- Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK
| | - Nilesh J Samani
- Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester LE3 9QP, UK
| | - Maciej Tomaszewski
- Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester LE3 9QP, UK.
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22
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Liao B, Li X, Cai L, Cao Z, Chen H. A Hierarchical Clustering Method of Selecting Kernel SNP to Unify Informative SNP and Tag SNP. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2015; 12:113-122. [PMID: 26357082 DOI: 10.1109/tcbb.2014.2351797] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Various strategies can be used to select representative single nucleotide polymorphisms (SNPs) from a large number of SNPs, such as tag SNP for haplotype coverage and informative SNP for haplotype reconstruction, respectively. Representative SNPs are not only instrumental in reducing the cost of genotyping, but also serve an important function in narrowing the combinatorial space in epistasis analysis. The capacity of kernel SNPs to unify informative SNP and tag SNP is explored, and inconsistencies are minimized in further studies. The correlation between multiple SNPs is formalized using multi-information measures. In extending the correlation, a distance formula for measuring the similarity between clusters is first designed to conduct hierarchical clustering. Hierarchical clustering consists of both information gain and haplotype diversity, so that the proposed approach can achieve unification. The kernel SNPs are then selected from every cluster through the top rank or backward elimination scheme. Using these kernel SNPs, extensive experimental comparisons are conducted between informative SNPs on haplotype reconstruction accuracy and tag SNPs on haplotype coverage. Results indicate that the kernel SNP can practically unify informative SNP and tag SNP and is therefore adaptable to various applications.
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23
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Edea Z, Kim SW, Lee KT, Kim TH, Kim KS. Genetic Structure of and Evidence for Admixture between Western and Korean Native Pig Breeds Revealed by Single Nucleotide Polymorphisms. ASIAN-AUSTRALASIAN JOURNAL OF ANIMAL SCIENCES 2014; 27:1263-9. [PMID: 25178369 PMCID: PMC4150192 DOI: 10.5713/ajas.2014.14096] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 03/31/2014] [Accepted: 05/06/2014] [Indexed: 12/04/2022]
Abstract
Comprehensive information on genetic diversity and introgression is desirable for the design of rational breed improvement and conservation programs. Despite the concerns regarding the genetic introgression of Western pig breeds into the gene pool of the Korean native pig (KNP), the level of this admixture has not yet been quantified. In the present study, we genotyped 93 animals, representing four Western pig breeds and KNP, using the porcine SNP 60K BeadChip to assess their genetic diversity and to estimate the level of admixture among the breeds. Expected heterozygosity was the lowest in Berkshire (0.31) and highest in Landrace (0.42). Population differentiation (FST) estimates were significantly different (p<0.000), accounting for 27% of the variability among the breeds. The evidence of inbreeding observed in KNP (0.029) and Yorkshire (0.031) may result in deficient heterozygosity. Principal components one (PC1) and two (PC2) explained approximately 35.06% and 25.20% of the variation, respectively, and placed KNP somewhat proximal to the Western pig breeds (Berkshire and Landrace). When K = 2, KNP shared a substantial proportion of ancestry with Western breeds. Similarly, when K = 3, over 86% of the KNP individuals were in the same cluster with Berkshire and Landrace. The linkage disquilbrium (LD) values at r20.3, the physical distance at which LD decays below a threshold of 0.3, ranged from 72.40 kb in Landrace to 85.86 kb in Yorkshire. Based on our structure analysis, a substantial level of admixture between Western and Korean native pig breeds was observed.
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Affiliation(s)
- Zewdu Edea
- Division of Animal Genomics and Bioinformatics, National Institute of Animal Science, Suwon 441-706, Korea
| | - Sang-Wook Kim
- Division of Animal Genomics and Bioinformatics, National Institute of Animal Science, Suwon 441-706, Korea
| | - Kyung-Tai Lee
- Division of Animal Genomics and Bioinformatics, National Institute of Animal Science, Suwon 441-706, Korea
| | - Tae Hun Kim
- Division of Animal Genomics and Bioinformatics, National Institute of Animal Science, Suwon 441-706, Korea
| | - Kwan-Suk Kim
- Division of Animal Genomics and Bioinformatics, National Institute of Animal Science, Suwon 441-706, Korea
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24
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Küchler EC, Deeley K, Ho B, Linkowski S, Meyer C, Noel J, Kouzbari MZ, Bezamat M, Granjeiro JM, Antunes LS, Antunes LA, de Abreu FV, Costa MC, Tannure PN, Seymen F, Koruyucu M, Patir A, Mereb JC, Poletta FA, Castilla EE, Orioli IM, Marazita ML, Vieira AR. Genetic mapping of high caries experience on human chromosome 13. BMC MEDICAL GENETICS 2013; 14:116. [PMID: 24192446 PMCID: PMC3907033 DOI: 10.1186/1471-2350-14-116] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 10/31/2013] [Indexed: 02/04/2023]
Abstract
Background Our previous genome-wide linkage scan mapped five loci for caries experience. The purpose of this study was to fine map one of these loci, the locus 13q31.1, in order to identify genetic contributors to caries. Methods Seventy-two pedigrees from the Philippines were studied. Caries experience was recorded and DNA was extracted from blood samples obtained from all subjects. Sixty-one single nucleotide polymorphisms (SNPs) in 13q31.1 were genotyped. Association between caries experience and alleles was tested. We also studied 1,481 DNA samples obtained from saliva of subjects from the USA, 918 children from Brazil, and 275 children from Turkey, in order to follow up the results found in the Filipino families. We used the AliBaba2.1 software to determine if the nucleotide changes of the associated SNPs changed the prediction of the presence of transcription-binding site sequences and we also analyzed the gene expression of the genes selected based on binding predictions. Mutation analysis was also performed in 33 Filipino individuals of a segment of 13q31.1 that is highly conserved in mammals. Results Statistically significant association with high caries experience was found for 11 markers in 13q31.1 in the Filipino families. Haplotype analysis also confirmed these results. In the populations used for follow-up purposes, associations were found between high caries experience and a subset of these markers. Regarding the prediction of the transcription-binding site, the base change of the SNP rs17074565 was found to change the predicted-binding of genes that could be involved in the pathogenesis of caries. When the sequence has the allele C of rs17074565, the potential transcription factors binding the sequence are GR and GATA1. When the subject carries the G allele of rs17074565, the potential transcription factor predicted to bind to the sequence is GATA3. The expression of GR in whole saliva was higher in individuals with low caries experience when compared to individuals with high caries experience (p = 0.046). No mutations were found in the highly conserved sequence. Conclusions Genetic factors contributing to caries experience may exist in 13q31.1. The rs17074565 is located in an intergenic region and is predicted to disrupt the binding sites of two different transcription factors that might be involved with caries experience. GR expression in saliva may be a biomarker for caries risk and should be further explored.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Alexandre R Vieira
- Department of Oral Biology, University of Pittsburgh, 614 Salk Hall, Pittsburgh, PA, USA.
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Genome-wide association study of schizophrenia using microsatellite markers in the Japanese population. Psychiatr Genet 2013; 23:117-23. [PMID: 23474461 DOI: 10.1097/ypg.0b013e32835fe4f1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVES To search for schizophrenia susceptibility loci, we carried out a case-control study using 28601 microsatellite markers distributed across the entire genome. MATERIALS AND METHODS To control the highly multiple testing, we designed three sequential steps of screening using three independent sets of pooled samples, followed by the confirmatory step using an independent sample set (>2200 case-control pairs). RESULTS The first screening using pooled samples of 157 case-control pairs showed 2966 markers to be significantly associated with the disorder (P<0.05). After the second and the third screening steps using pooled samples of 150 pairs each, 374 markers remained significantly associated with the disorder. We individually genotyped all screening samples using a total of 1536 tag single nucleotide polymorphisms (SNPs) located in the vicinity of ~200 kb from the 59 positive microsatellite markers. Of the 167 SNPs that replicated the significance, we selected 31 SNPs on the basis of the levels of P values for the confirmatory association test using an independent-sample set. The best association signal was observed in rs13404754, located in the upstream region of SLC23A3. We genotyped six additional SNPs in the vicinity of rs13404754. Significant associations were observed in rs13404754, rs6436122, and rs1043160 in the cumulative samples (2617 cases and 2698 controls) (P=0.005, 0.035, and 0.011, respectively). These SNPs are located in the linkage disequilibrium block of 20 kb in size containing SLC23A3, CNPPD1, and FAM134A genes. CONCLUSION Genome-wide association study using microsatellite markers suggested SLC23A3, CNPPD1, and FAM134A genes as candidates for schizophrenia susceptibility in the Japanese population.
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A systematic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes. Eur J Hum Genet 2013; 22:402-8. [PMID: 23881057 DOI: 10.1038/ejhg.2013.161] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 04/05/2013] [Accepted: 06/19/2013] [Indexed: 01/03/2023] Open
Abstract
Candidate gene and genome-wide association studies (GWAS) represent two complementary approaches to uncovering genetic contributions to common diseases. We systematically reviewed the contributions of these approaches to our knowledge of genetic associations with cancer risk by analyzing the data in the Cancer Genome-wide Association and Meta Analyses database (Cancer GAMAdb). The database catalogs studies published since January 1, 2000, by study and cancer type. In all, we found that meta-analyses and pooled analyses of candidate genes reported 349 statistically significant associations and GWAS reported 269, for a total of 577 unique associations. Only 41 (7.1%) associations were reported in both candidate gene meta-analyses and GWAS, usually with similar effect sizes. When considering only noteworthy associations (defined as those with false-positive report probabilities≤0.2) and accounting for indirect overlap, we found 202 associations, with 27 of those appearing in both meta-analyses and GWAS. Our findings suggest that meta-analyses of well-conducted candidate gene studies may continue to add to our understanding of the genetic associations in the post-GWAS era.
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Li Y, Yao Y, Yang M, Shi L, Li X, Yang Y, Zhang Y, Xiao C. Association between HLA-B*46 allele and Graves disease in Asian populations: a meta-analysis. Int J Med Sci 2013; 10:164-70. [PMID: 23329888 PMCID: PMC3547214 DOI: 10.7150/ijms.5158] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Accepted: 12/28/2012] [Indexed: 01/20/2023] Open
Abstract
Graves' disease (GD) is a leading cause of hyperthyroidism, which affects 1.0-1.6% of the general population. Previous studies reported a higher GD prevalence in Asian populations compared to Caucasian populations. The etiology of GD involves complex interactions between predisposing genes and environmental triggers. Genetic studies have shown that the human leukocyte antigen (HLA) is an important candidate genetic region associated with GD in Asian populations. However, the results were inconsistent and inconclusive. Here, we performed a meta-analysis to evaluate the role of the HLA-B*46 allele in GD in Asian populations. A total of 14 case-controlled studies on the association of the HLA-B*46 allele in 1743 GD patients and 5689 controls were included. Our results showed a trend toward an increased risk of GD in HLA-B*46-positive subjects compared to those HLA-B*46-negative (OR = 2.48; 95% CI = 1.96-3.13, P < 0.01). However, there were some limitations to the current meta-analysis, such as heterogeneity (P(heterogeneity )< 0.01 and I(2 )= 68.0%) or the different typing methods (serological and genotyping methods). The meta-analysis indicated that the HLA-B*46 allele is a risk factor for GD in Asian populations. Future studies on the role of the HLA-B*46 allele in GD should consider complications such as periodic paralysis, ophthalmopathy and recurrence.
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Affiliation(s)
- Yiping Li
- School of Medicine, Yunnan University, Kunming 650091, Yunnan, China
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Lu D, Sargolzaei M, Kelly M, Li C, Vander Voort G, Wang Z, Plastow G, Moore S, Miller SP. Linkage disequilibrium in Angus, Charolais, and Crossbred beef cattle. Front Genet 2012; 3:152. [PMID: 22912646 PMCID: PMC3418579 DOI: 10.3389/fgene.2012.00152] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Accepted: 07/27/2012] [Indexed: 12/22/2022] Open
Abstract
Linkage disequilibrium (LD) and the persistence of its phase across populations are important for genomic selection as well as fine scale mapping of quantitative trait loci (QTL). However, knowledge of LD in beef cattle, as well as the persistence of LD phase between crossbreds (C) and purebreds, is limited. The objective of this study was to understand the patterns of LD in Angus (AN), Charolais (CH), and C beef cattle based on 31,073, 32,088, and 33,286 SNP in each population, respectively. Amount of LD decreased rapidly from 0.29 to 0.23 to 0.19 in AN, 0.22 to 0.16 to 0.12 in CH, 0.21 to 0.15 to 0.11 in C, when the distance range between markers changed from 0-30 kb to 30-70 kb and then to 70-100 kb, respectively. Breeds and chromosomes had significant effects (P < 0.001) on LD decay. There was significant interaction between breeds and chromosomes (P < 0.001). Correlations of LD phase were high between C and AN (0.84), C and CH (0.81), as well as between AN and CH (0.77) for distances less than or equal to 70 kb. These dropped when the distance increased. Estimated effective population sizes for AN and CH were 207 and 285, respectively, for 10 generations ago. Given a useful LD of at least 0.3 between pairs of SNPs, the LD phase between any pair of the three breed groups was highly persistent. The current SNP density would allow the capture of approximately 49% of useful LD between SNP and marker QTL in AN, and 38% in CH. A higher density SNP panel or redesign of the current panel is needed to achieve more of useful LD for the purpose of genomic selection beef cattle.
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Affiliation(s)
- Duc Lu
- Centre for Genetic Improvement of Livestock, Department of Animal and Poultry Science, University of GuelphGuelph, ON, Canada
| | - Mehdi Sargolzaei
- Centre for Genetic Improvement of Livestock, Department of Animal and Poultry Science, University of GuelphGuelph, ON, Canada
| | - Matthew Kelly
- Centre for Genetic Improvement of Livestock, Department of Animal and Poultry Science, University of GuelphGuelph, ON, Canada
| | - Changxi Li
- Lacombe Research Centre, Agriculture and Agri-Food CanadaLacombe, AB, Canada
- Department of Agricultural, Food and Nutritional Science, University of AlbertaEdmonton, AB, Canada
| | - Gordon Vander Voort
- Centre for Genetic Improvement of Livestock, Department of Animal and Poultry Science, University of GuelphGuelph, ON, Canada
| | - Zhiquan Wang
- Department of Agricultural, Food and Nutritional Science, University of AlbertaEdmonton, AB, Canada
| | - Graham Plastow
- Department of Agricultural, Food and Nutritional Science, University of AlbertaEdmonton, AB, Canada
| | - Stephen Moore
- Centre for Animal Science, Queensland Alliance for Agriculture and Food Innovation, University of QueenslandSt. Lucia, QLD, Australia
| | - Stephen P. Miller
- Centre for Genetic Improvement of Livestock, Department of Animal and Poultry Science, University of GuelphGuelph, ON, Canada
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Windelinckx A, De Mars G, Huygens W, Peeters MW, Vincent B, Wijmenga C, Lambrechts D, Aerssens J, Vlietinck R, Beunen G, Thomis MAI. Identification and prioritization of NUAK1 and PPP1CC as positional candidate loci for skeletal muscle strength phenotypes. Physiol Genomics 2011; 43:981-92. [PMID: 21750233 DOI: 10.1152/physiolgenomics.00200.2010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Muscle strength is an important determinant in elite sports performance as well as in the activities of daily living. Muscle metabolism also plays a role in the genesis, and therefore prevention, of common pathological conditions and chronic diseases. Even though heritability estimates between 31 and 78% suggest a significant genetic component in muscle strength, only a limited number of genes influencing muscle strength have been identified. This study aimed to identify and prioritize positional candidate genes within a skeletal muscle strength quantitative trait locus on chromosome 12q22-23 for follow-up. A two-staged gene-centered fine-mapping approach using 122 single nucleotide polymorphisms (SNPs) in stage 1 identified a family-based association (n=500) between several tagSNPs located in the ATPase, Ca2+ transporting, cardiac muscle, slow twitch 2 (ATP2A2; rs3026468), the NUAK family, SNF1-like kinase, 1 (NUAK1; rs10861553 and rs3741886), and the protein phosphatase 1, catalytic subunit, gamma isoform (PPP1CC; rs1050587 and rs7901769) genes and knee torque production (P values up to 0.00092). In stage 2, family-based association tests on additional putatively functional SNPs (e.g., exonic SNPs, SNPs in transcription factor binding sites or in conserved regions) in an enlarged sample (n=536; 464 individuals overlap with stage 1) did not identify additional associations with muscle strength characteristics. Further in-depth analyses will be necessary to elucidate the exact role of ATP2A2, PPP1CC, and NUAK1 in muscle strength and to find out which functional polymorphisms are at the base of the interindividual strength differences.
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Affiliation(s)
- An Windelinckx
- Research Center for Exercise and Health, Department of Biomedical Kinesiology, Faculty of Kinesiology and Rehabilitation Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
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Zhang C, Plastow G. Genomic Diversity in Pig (Sus scrofa) and its Comparison with Human and other Livestock. Curr Genomics 2011; 12:138-46. [PMID: 21966252 PMCID: PMC3129048 DOI: 10.2174/138920211795564386] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Revised: 01/21/2011] [Accepted: 01/22/2011] [Indexed: 11/22/2022] Open
Abstract
We have reviewed the current pig (Sus scrofa) genomic diversity within and between sites and compared them with human and other livestock. The current Porcine 60K single nucleotide polymorphism (SNP) panel has an average SNP distance in a range of 30 - 40 kb. Most of genetic variation was distributed within populations, and only a small proportion of them existed between populations. The average heterozygosity was lower in pig than in human and other livestock. Genetic inbreeding coefficient (F(IS)), population differentiation (F(ST)), and Nei's genetic distance between populations were much larger in pig than in human and other livestock. Higher average genetic distance existed between European and Asian populations than between European or between Asian populations. Asian breeds harboured much larger variability and higher average heterozygosity than European breeds. The samples of wild boar that have been analyzed displayed more extensive genetic variation than domestic breeds. The average linkage disequilibrium (LD) in improved pig breeds extended to 1 - 3 cM, much larger than that in human (~ 30 kb) and cattle (~ 100 kb), but smaller than that in sheep (~ 10 cM). European breeds showed greater LD that decayed more slowly than Asian breeds. We briefly discuss some processes for maintaining genomic diversity in pig, including migration, introgression, selection, and drift. We conclude that, due to the long time of domestication, the pig possesses lower heterozygosity, higher F(IS), and larger LD compared with human and cattle. This implies that a smaller effective population size and less informative markers are needed in pig for genome wide association studies.
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Affiliation(s)
| | - Graham Plastow
- 1400 College Plaza, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2C8, Canada
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Pacheco PR, Branco CC, Gomes CT, Cabral R, Mota-Vieira L. HLA Class I and II profiles in São Miguel Island (Azores): genetic diversity and linkage disequilibrium. BMC Res Notes 2010; 3:134. [PMID: 20462405 PMCID: PMC2883542 DOI: 10.1186/1756-0500-3-134] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Accepted: 05/12/2010] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Human leukocyte antigen (HLA) genes are characterized by high levels of polymorphism and linkage disequilibrium (LD), important characteristics to study the genetic background of human populations and their genetic structure. Here, we analyse the allele distribution and LD extent of HLA class I and II in São Miguel Island population (Azores archipelago, Portugal). FINDINGS The sample set was composed of 106 healthy blood donors living in São Miguel Island obtained from the anonymized Azorean DNA bank. HLA class I (-A, -B and -Cw) and class II (-DRB1, -DQB1, -DPA1 and -DPB1) genotyping was performed by PCR-SSP Olerup SSP (GenoVision Inc.), according to the manufacturer's instructions.Genetic diversity values, based on the 7 loci, ranged from 0.821 both for HLA-DPA1 and -DQB1 to 0.934 for HLA-B, with a mean value of 0.846. Analysis of 5 HLA-A-Cw-B-DRB1-DQB1 haplotypes revealed that A*01-Cw*07-B*08-DRB1*03-DQB1*02 is the most frequent in São Miguel (7.9%) followed by A*24-B*08-Cw*07-DRB1*03-DQB1*02 (3.8%). In addition, even though the reports of high LD for HLA markers in worldwide populations, São Miguel islanders do not have extensive LD (average D' = 0.285). CONCLUSIONS In summary, the results demonstrate high variability of HLA in São Miguel Island population as well as absence of genetic structure and extensive LD. The data here presented suggest that in São Miguel islanders autoimmune diseases studies will necessarily encompass a more focused analysis of HLA extended haplotypes as well as the evaluation of other non-HLA candidate genes.
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Affiliation(s)
- Paula R Pacheco
- Molecular Genetics and Pathology Unit, Hospital of Divino Espírito Santo of Ponta Delgada, EPE, São Miguel Island, Azores, Portugal.
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Capurso C, Solfrizzi V, Colacicco AM, D'Introno A, Frisardi V, Imbimbo BP, Lorusso M, Vendemiale G, Denitto M, Santamato A, Seripa D, Pilotto A, Fiore P, Capurso A, Panza F. Interleukin 6-174 G/C promoter and variable number of tandem repeats (VNTR) gene polymorphisms in sporadic Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:177-82. [PMID: 19897004 DOI: 10.1016/j.pnpbp.2009.10.022] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Revised: 09/22/2009] [Accepted: 10/30/2009] [Indexed: 10/20/2022]
Abstract
BACKGROUND Previous studies examining the association between the interleukin 6 (IL-6)-174 C/G polymorphism and Alzheimer's disease (AD) have yielded conflicting results. Furthermore, the C allele of the IL-6 variable number of tandem repeats (VNTR) polymorphism was associated with a delayed onset and a decreased risk of AD. METHODS A total sample of 149 AD patients, and 298 age- and sex-matched unrelated caregivers from Apulia, southern Italy, were genotyped for the apolipoprotein E (APOE) polymorphism, the VNTR polymorphism in the 3' flanking region, and the -174G/C single-nucleotide polymorphism (SNP) in the promoter region of IL-6 gene on chromosome 7. Furthermore, we performed a haplotype analysis on these two polymorphisms on IL-6 locus. RESULTS IL-6 VNTR and -174G/C allele and genotype frequencies were similar between AD patients and controls, also after stratification for late-onset (> or =65 years) and early-onset (<65 years) or APOE epsilon4 status. Furthermore, there was no evidence of linkage disequilibrium between the VNTR and -174G/C polymorphisms, not supporting a previous reported additive effect of both IL-6 polymorphisms on AD risk. CONCLUSIONS Our findings did not support a role of IL-6-174 G/C and IL-6 VNTR polymorphisms in the risk of sporadic AD in southern Italy, suggesting that these polymorphisms of IL-6 gene were at most weak genetic determinants of AD.
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Affiliation(s)
- Cristiano Capurso
- Department of Geriatrics, University of Foggia, Ospedali Riuniti, Viale L. Pinto, 71100 Foggia, Italy.
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Invernizzi P, Gershwin ME. The genetics of human autoimmune disease. J Autoimmun 2009; 33:290-9. [DOI: 10.1016/j.jaut.2009.07.008] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Accepted: 07/15/2009] [Indexed: 10/20/2022]
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Colacicco AM, Solfrizzi V, D’Introno A, Capurso C, Kehoe PG, Seripa D, Pilotto A, Santamato A, Capurso A, Panza F. Alpha-2-macroglobulin gene, oxidized low-density lipoprotein receptor-1 locus, and sporadic Alzheimer's disease. Neurobiol Aging 2009; 30:1518-20. [DOI: 10.1016/j.neurobiolaging.2007.11.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2007] [Revised: 11/07/2007] [Accepted: 11/14/2007] [Indexed: 12/26/2022]
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Rebaï M, Kharrat N, Ayadi I, Rebaï A. Haplotype structure of five SNPs within the ACE gene in the Tunisian population. Ann Hum Biol 2009; 33:319-29. [PMID: 17092869 DOI: 10.1080/03014460600621977] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
BACKGROUND The Angiotensin-Converting Enzyme (ACE) is a candidate gene in the aetiology of several common diseases. The study of the haplotype structure of this gene is of interest in diagnosis and in pharmacogenomics. AIM The study investigated the haplotype profile of single nucleotide polymorphisms (SNPs) within the ACE gene in the Tunisian population and compared it with other populations. SUBJECTS AND METHODS Five SNPs (rs1800764, rs4291, rs4309, rs4331, rs4340) covering a region of 15.6 kb of the ACE gene were typed by PCR-digestion in a sample of 100 healthy subjects. RESULTS All SNPs were polymorphic and in Hardy-Weinberg equilibrium. A total of 21 haplotypes were identified but only eight had a frequency of more than 1%. The four most common haplotypes had a cumulative frequency of 87.4%. The 'Yin-Yang' phenomenon (the two major haplotypes are complementary at all sites) was found. Linkage disequilibrium between all pairs of loci was highly significant (p<10-5). A simple and efficient statistical procedure was used to identify three important SNPs. CONCLUSION The Tunisian population showed a different haplotype structure from the European one for the ACE gene and three important SNPs were identified. These will be very helpful in future association studies in the Tunisian and North African populations.
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Affiliation(s)
- Maha Rebaï
- Bioinformatics Unit, Centre of Biotechnology of Sfax, Sfax, Tunisia
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Branco CC, Pacheco PR, Cabrol E, Cabral R, Vicente AM, Mota-Vieira L. Linkage disequilibrium and diversity for three genomic regions in Azoreans and mainland Portuguese. Genet Mol Biol 2009; 32:220-6. [PMID: 21637671 PMCID: PMC3036928 DOI: 10.1590/s1415-47572009000200003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2008] [Accepted: 01/02/2009] [Indexed: 11/22/2022] Open
Abstract
Studies on linkage disequilibrium (LD) across the genome and populations have been used in recent years with the main objective of improving gene mapping of complex traits. Here, we characterize the patterns of genetic diversity of HLA loci and evaluate LD (D') extent in three genomic regions: Xq13.3, NRY and HLA. In addition, we examine the distribution of DXS1225-DXS8082 haplotype diversity in Azoreans and mainland Portuguese. Allele distribution has demonstrated that the São Miguel population is genetically very diverse; haplotype analysis revealed 100% discriminatory power for X- and Y-markers and 94.3% for HLA markers. Standardized multiallelic D' in these three genomic regions shows values lower than 0.33, thereby suggesting there is no extensive LD in the São Miguel population. Data regarding the distribution of DXS1225-DXS8082 haplotypes indicate that there are no significant differences among all the populations studied, (Azorean geographical groups, the Azores archipelago and mainland Portugal). Moreover, in these as well as in other European populations, the most frequent DXS1225-DXS8082 haplotype is 210-219. Even though São Miguel islanders and Azoreans do not constitute isolated populations and show LD for only very short physical distances, certain characteristics, such as the absence of genetic structure, the same environment and the possibility of constructing extensive pedigrees through church and civil records, offer an opportunity for dissecting the genetic background of complex diseases in these populations.
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Affiliation(s)
- Claudia C Branco
- Molecular Genetics and Pathology Unit, Hospital of Divino Espírito Santo of Ponta Delgada, São Miguel Island, Azores Portugal
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Ordóñez D, Sánchez AJ, Martínez-Rodríguez JE, Cisneros E, Ramil E, Romo N, Moraru M, Munteis E, López-Botet M, Roquer J, García-Merino A, Vilches C. Multiple sclerosis associates with LILRA3 deletion in Spanish patients. Genes Immun 2009; 10:579-85. [DOI: 10.1038/gene.2009.34] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Abstract
Genetic factors contribute substantially to the development of reading disability (RD). Family linkage studies have implicated many chromosomal regions containing RD susceptibility genes, of which putative loci at 1p34-p36 (DYX8), 2p (DYX3), 6p21.3 (DYX2), and 15q21 (DYX1) have been frequently replicated, whereas those at 3p12-q12 (DYX5), 6q13-q16 (DYX4), 11p15 (DYX7), 18p11 (DYX6), and Xq27 (DYX9) have less evidence. Association studies of positional candidate genes have implicated DCDC2 and KIAA0319 in DYX2, as well as C2ORF3 and MRPL19 (DYX3), whereas DYX1C1/EKN1 (DYX1) and ROBO1 (DYX5) were found to be disrupted by rare translocation breakpoints in reading-disabled individuals. Four of the candidate genes (DYX1C1, KIAA0319, DCDC2, and ROBO1) appear to function in neuronal migration and guidance, suggesting the importance of early neurodevelopmental processes in RD. Future studies to help us understand the function of these and other RD candidate genes promise to yield enormous insight into the neurobiologic mechanisms underlying the pathophysiology of this disorder.
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Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex. Genes Immun 2009; 10:323-33. [PMID: 19295542 DOI: 10.1038/gene.2009.13] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1(*)03-DQA1(*)0501-DQB1(*)0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1(*)0401-DQA1(*)03-DQB1(*)0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1(*)0401-DQA1(*)03-DQB1(*)0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.
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Ménard V, Girard H, Harvey M, Pérusse L, Guillemette C. Analysis of inherited genetic variations at theUGT1locus in the French-Canadian population. Hum Mutat 2009; 30:677-87. [DOI: 10.1002/humu.20946] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Rao YS, Liang Y, Xia MN, Shen X, Du YJ, Luo CG, Nie QH, Zeng H, Zhang XQ. Extent of linkage disequilibrium in wild and domestic chicken populations. Hereditas 2009; 145:251-7. [PMID: 19076693 DOI: 10.1111/j.1601-5223.2008.02043.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Linkage disequilibrium (LD) analyses play a fundamental role in gene mapping, both as a tool for fine mapping of complex trait gene and in genome-wide association studies. The use of LD analyses in practice depends crucially on the understanding of the patterns of LD in the genome. In the present study, a total of 36 SNP were selected initially in a region (200 kb) of Contig.060226.1 on GGA1 based on the average physical distance. After verifying their level of polymorphism, 21 SNP were selected finally to genotype one wild and two domestic chicken populations, Red Jungle Fowl (RJF), Taihe Silkie chicken (TS) and White Recessive Rock chicken (WRR). Two distinct measures of linkage disequilibrium, D' and r(2), between marker pairs were used. The D'map of RJF is spurious. Many marker pairs showed complete LD. TS and WRR showed distinct characteristic of decreasing D' value over increasing physical distance. The r(2) showed much less inflation than did D' in RJF population, and also showed a characteristic decreasing value over increasing physical distance. In TS and WRR populations, although the two measures differed in scale, their decay profiles were similar. The data in the present study suggested that the extent of LD in this region is about 150 kb, corresponding to 0.4 cM. Our results imply that a very dense map of SNP markers will be required for LD mapping methods. Thus, association studies based on polymorphisms within all known genes, and candidate QTL mapping, may ultimately prove to be a more effective strategy.
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Affiliation(s)
- You Sheng Rao
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
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Liu YJ, Papasian CJ, Liu JF, Hamilton J, Deng HW. Is replication the gold standard for validating genome-wide association findings? PLoS One 2008; 3:e4037. [PMID: 19112512 PMCID: PMC2605260 DOI: 10.1371/journal.pone.0004037] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2008] [Accepted: 11/21/2008] [Indexed: 01/27/2023] Open
Abstract
With the advent of genome-wide association (GWA) studies, researchers are hoping that reliable genetic association of common human complex diseases/traits can be detected. Currently, there is an increasing enthusiasm about GWA and a number of GWA studies have been published. In the field a common practice is that replication should be used as the gold standard to validate an association finding. In this article, based on empirical and theoretical data, we emphasize that replication of GWA findings can be quite difficult, and should not always be expected, even when true variants are identified. The probability of replication becomes smaller with the increasing number of independent GWA studies if the power of individual replication studies is less than 100% (which is usually the case), and even a finding that is replicated may not necessarily be true. We argue that the field may have unreasonably high expectations on success of replication. We also wish to raise the question whether it is sufficient or necessary to treat replication as the ultimate and gold standard for defining true variants. We finally discuss the usefulness of integrating evidence from multiple levels/sources such as genetic epidemiological studies (at the DNA level), gene expression studies (at the RNA level), proteomics (at the protein level), and follow-up molecular and cellular studies for eventual validation and illumination of the functional relevance of the genes uncovered.
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Affiliation(s)
- Yong-Jun Liu
- School of Medicine, University of Missouri - Kansas City, Kansas City, Missouri, United States of America
| | - Christopher J. Papasian
- School of Medicine, University of Missouri - Kansas City, Kansas City, Missouri, United States of America
| | - Jian-Feng Liu
- School of Medicine, University of Missouri - Kansas City, Kansas City, Missouri, United States of America
| | - James Hamilton
- School of Medicine, University of Missouri - Kansas City, Kansas City, Missouri, United States of America
| | - Hong-Wen Deng
- School of Medicine, University of Missouri - Kansas City, Kansas City, Missouri, United States of America
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences Hunan Normal University, Changsha, Hunan, People's Republic of China
- * E-mail:
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Zhang F, Wang Y, Deng HW. Comparison of population-based association study methods correcting for population stratification. PLoS One 2008; 3:e3392. [PMID: 18852890 PMCID: PMC2562035 DOI: 10.1371/journal.pone.0003392] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2008] [Accepted: 09/06/2008] [Indexed: 11/19/2022] Open
Abstract
Population stratification can cause spurious associations in population-based association studies. Several statistical methods have been proposed to reduce the impact of population stratification on population-based association studies. We simulated a set of stratified populations based on the real haplotype data from the HapMap ENCODE project, and compared the relative power, type I error rates, accuracy and positive prediction value of four prevailing population-based association study methods: traditional case-control tests, structured association (SA), genomic control (GC) and principal components analysis (PCA) under various population stratification levels. Additionally, we evaluated the effects of sample sizes and frequencies of disease susceptible allele on the performance of the four analytical methods in the presence of population stratification. We found that the performance of PCA was very stable under various scenarios. Our comparison results suggest that SA and PCA have comparable performance, if sufficient ancestral informative markers are used in SA analysis. GC appeared to be strongly conservative in significantly stratified populations. It may be better to apply GC in the stratified populations with low stratification level. Our study intends to provide a practical guideline for researchers to select proper study methods and make appropriate inference of the results in population-based association studies.
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Affiliation(s)
- Feng Zhang
- Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Departments of Orthopedic Surgery and Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, United States of America
| | - Yuping Wang
- School of Computing and Engineering, University of Missouri-Kansas City, Kansas City, Missouri, United States of America
| | - Hong-Wen Deng
- Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Departments of Orthopedic Surgery and Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, United States of America
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China
- * E-mail:
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McQuillan R, Leutenegger AL, Abdel-Rahman R, Franklin CS, Pericic M, Barac-Lauc L, Smolej-Narancic N, Janicijevic B, Polasek O, Tenesa A, Macleod AK, Farrington SM, Rudan P, Hayward C, Vitart V, Rudan I, Wild SH, Dunlop MG, Wright AF, Campbell H, Wilson JF. Runs of homozygosity in European populations. Am J Hum Genet 2008; 83:359-72. [PMID: 18760389 DOI: 10.1016/j.ajhg.2008.08.007] [Citation(s) in RCA: 811] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2008] [Revised: 08/12/2008] [Accepted: 08/13/2008] [Indexed: 12/28/2022] Open
Abstract
Estimating individual genome-wide autozygosity is important both in the identification of recessive disease variants via homozygosity mapping and in the investigation of the effects of genome-wide homozygosity on traits of biomedical importance. Approaches have tended to involve either single-point estimates or rather complex multipoint methods of inferring individual autozygosity, all on the basis of limited marker data. Now, with the availability of high-density genome scans, a multipoint, observational method of estimating individual autozygosity is possible. Using data from a 300,000 SNP panel in 2618 individuals from two isolated and two more-cosmopolitan populations of European origin, we explore the potential of estimating individual autozygosity from data on runs of homozygosity (ROHs). Termed F(roh), this is defined as the proportion of the autosomal genome in runs of homozygosity above a specified length. Mean F(roh) distinguishes clearly between subpopulations classified in terms of grandparental endogamy and population size. With the use of good pedigree data for one of the populations (Orkney), F(roh) was found to correlate strongly with the inbreeding coefficient estimated from pedigrees (r = 0.86). Using pedigrees to identify individuals with no shared maternal and paternal ancestors in five, and probably at least ten, generations, we show that ROHs measuring up to 4 Mb are common in demonstrably outbred individuals. Given the stochastic variation in ROH number, length, and location and the fact that ROHs are important whether ancient or recent in origin, approaches such as this will provide a more useful description of genomic autozygosity than has hitherto been possible.
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Affiliation(s)
- Ruth McQuillan
- Public Health Sciences, University of Edinburgh Medical School, Edinburgh EH8 9AG, UK
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Pattaro C, Ruczinski I, Fallin DM, Parmigiani G. Haplotype block partitioning as a tool for dimensionality reduction in SNP association studies. BMC Genomics 2008; 9:405. [PMID: 18759977 PMCID: PMC2547855 DOI: 10.1186/1471-2164-9-405] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Accepted: 08/29/2008] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Identification of disease-related genes in association studies is challenged by the large number of SNPs typed. To address the dilution of power caused by high dimensionality, and to generate results that are biologically interpretable, it is critical to take into consideration spatial correlation of SNPs along the genome. With the goal of identifying true genetic associations, partitioning the genome according to spatial correlation can be a powerful and meaningful way to address this dimensionality problem. RESULTS We developed and validated an MCMC Algorithm To Identify blocks of Linkage DisEquilibrium (MATILDE) for clustering contiguous SNPs, and a statistical testing framework to detect association using partitions as units of analysis. We compared its ability to detect true SNP associations to that of the most commonly used algorithm for block partitioning, as implemented in the Haploview and HapBlock software. Simulations were based on artificially assigning phenotypes to individuals with SNPs corresponding to region 14q11 of the HapMap database. When block partitioning is performed using MATILDE, the ability to correctly identify a disease SNP is higher, especially for small effects, than it is with the alternatives considered. Advantages can be both in terms of true positive findings and limiting the number of false discoveries. Finer partitions provided by LD-based methods or by marker-by-marker analysis are efficient only for detecting big effects, or in presence of large sample sizes. The probabilistic approach we propose offers several additional advantages, including: a) adapting the estimation of blocks to the population, technology, and sample size of the study; b) probabilistic assessment of uncertainty about block boundaries and about whether any two SNPs are in the same block; c) user selection of the probability threshold for assigning SNPs to the same block. CONCLUSION We demonstrate that, in realistic scenarios, our adaptive, study-specific block partitioning approach is as or more efficient than currently available LD-based approaches in guiding the search for disease loci.
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Affiliation(s)
- Cristian Pattaro
- Unit of Genetic Epidemiology and Biostatistics, Institute of Genetic Medicine, European Academy, Viale Druso 1, I-39100, Bolzano, Italy.
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Jin H, Kim SH, Kim YU, Park YK, Ji MH, Kim YJ. Development of KHapmap Browser using DAS for Korean HapMap Research. Genomics Inform 2008. [DOI: 10.5808/gi.2008.6.2.057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Nuchnoi P, Ohashi J, Naka I, Nacapunchai D, Tokunaga K, Nishida N, Patarapotikul J. Linkage disequilibrium structure of the 5q31-33 region in a Thai population. J Hum Genet 2008; 53:850-856. [PMID: 18574552 DOI: 10.1007/s10038-008-0309-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2008] [Accepted: 05/24/2008] [Indexed: 01/14/2023]
Abstract
A number of loci related to the immune response are located on human chromosomal region 5q31-33, and polymorphisms in this region have been reported to be associated with autoimmune and infectious diseases. In Southeast Asian populations, no systematic survey with dense SNP markers has been performed for the 5q31-33 region. In this study, the LD and haplotype structures for a 472-kb region on 5q31 were investigated in a Thai population to provide useful information for association studies. In addition, the LD structure in Thais was compared with that of the CHB and JPT HapMap populations (CHB + JPT) to evaluate the transferability of tagging SNPs from CHB + JPT for Thais. We show that the minor allele frequency, pattern of LD block, and genetic structure in the 5q31-33 region were highly concordant between Thais and CHB + JPT. A high transferability of tagging SNPs from CHB + JPT for Thais was observed. Our results suggest that tagging SNPs from CHB + JPT (Northeast Asians) can efficiently capture common variants in Southeast Asians, and that the HapMap data are useful for association studies in Southeast Asian populations.
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Affiliation(s)
- Pornlada Nuchnoi
- Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.,Department of Medical Technology, Faculty of Allied Health Science, Naresuan University, Phitsanulok, Thailand
| | - Jun Ohashi
- Department of Human Genetics, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan.
| | - Izumi Naka
- Department of Human Genetics, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Duangporn Nacapunchai
- Department of Parasitology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
| | - Nao Nishida
- Department of Human Genetics, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-0033, Japan
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Moen T, Hayes B, Baranski M, Berg PR, Kjøglum S, Koop BF, Davidson WS, Omholt SW, Lien S. A linkage map of the Atlantic salmon (Salmo salar) based on EST-derived SNP markers. BMC Genomics 2008; 9:223. [PMID: 18482444 PMCID: PMC2405805 DOI: 10.1186/1471-2164-9-223] [Citation(s) in RCA: 131] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2007] [Accepted: 05/15/2008] [Indexed: 11/18/2022] Open
Abstract
Background The Atlantic salmon is a species of commercial and ecological significance. Like other salmonids, the species displays residual tetrasomy and a large difference in recombination rate between sexes. Linkage maps with full genome coverage, containing both type I and type II markers, are needed for progress in genomics. Furthermore, it is important to estimate levels of linkage disequilibrium (LD) in the species. In this study, we developed several hundred single nucleotide polymorphism (SNP) markers for the Atlantic salmon, and constructed male and female linkage maps containing SNP and microsatellite markers. We also investigated further the distribution of male and female recombination events across the genome, and estimated levels of LD between pairs of markers. Results The male map had 29 linkage groups and was 390 cM long. The female map had 30 linkage groups as was 1983 cM long. In total, the maps contained 138 microsatellite markers and 304 SNPs located within genes, most of which were successfully annotated. The ratio of male to female recombination events was either close to zero or very large, indicating that there is little overlap between regions in which male and female crossovers occur. The female map is likely to have close to full genome coverage, while the majority of male linkage groups probably lack markers in telomeric regions where male recombination events occur. Levels of r2 increased with decreasing inter-marker distance in a bimodal fashion; increasing slowly from ~60 cM, and more rapidly more from ~12 cM. Long-ranging LD may be consequence of recent admixture in the population, the population being a 'synthetic' breeding population with contributions from several distinct rivers. Levels of r2 dropped to half its maximum value (above baseline) within 15 cM, and were higher than 0.2 above baseline for unlinked markers ('useful LD') at inter-marker distances less than 5 cM. Conclusion The linkage map presented here is an important resource for genetic, comparative, and physical mapping of the Atlantic salmon. The female map is likely to have a map coverage that is not far from complete, whereas the male map length is likely to be significantly shorter than the true map, due to suboptimal marker coverage in the apparently small physical regions where male crossovers occur. 'Useful LD' was found at inter-marker distances less than 5 cM.
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Affiliation(s)
- Thomas Moen
- CIGENE - Centre of Integrative Genetics, As, Norway.
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Payseur BA, Place M, Weber JL. Linkage disequilibrium between STRPs and SNPs across the human genome. Am J Hum Genet 2008; 82:1039-50. [PMID: 18423524 PMCID: PMC2427224 DOI: 10.1016/j.ajhg.2008.02.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2007] [Revised: 01/06/2008] [Accepted: 02/29/2008] [Indexed: 01/10/2023] Open
Abstract
Patterns of linkage disequilibrium (LD) reveal the action of evolutionary processes and provide crucial information for association mapping of disease genes. Although recent studies have described the landscape of LD among single nucleotide polymorphisms (SNPs) from across the human genome, associations involving other classes of molecular variation remain poorly understood. In addition to recombination and population history, mutation rate and process are expected to shape LD. To test this idea, we measured associations between short-tandem-repeat polymorphisms (STRPs), which can mutate rapidly and recurrently, and SNPs in 721 regions across the human genome. We directly compared STRP-SNP LD with SNP-SNP LD from the same genomic regions in the human HapMap populations. The intensity of STRP-SNP LD, measured by the average of D', was reduced, consistent with the action of recurrent mutation. Nevertheless, a higher fraction of STRP-SNP pairs than SNP-SNP pairs showed significant LD, on both short (up to 50 kb) and long (cM) scales. These results reveal the substantial effects of mutational processes on LD at STRPs and provide important measures of the potential of STRPs for association mapping of disease genes.
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Affiliation(s)
- Bret A Payseur
- Laboratory of Genetics, University of Wisconsin, Madison, WI 53706, USA.
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Lee JE, Jang HY, Kim S, Yoo YK, Hwang JJ, Jun HJ, Lee KS, Son OK, Yang JM, Ahn KS, Kim EE, Lee HW, Song KY, Kim HL, Lee SG, Yoon YS, Kimm KC, Han BG, Oh BS, Kim CB, Jin H, Choi KO, Kang HJ, Kim YJ. Chromosome 22 LD Map Comparison between Korean and Other Populations. Genomics Inform 2008. [DOI: 10.5808/gi.2008.6.1.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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