‘Omics’ of suicidal behaviour: A path to personalised psychiatry

Table 1 Genome-wide association studies and completed suicide

Type of -omic	Tissue	Number of samples	Main results	Ref.
Illumina Infinium PsychArray platform v 1.0 (approximately 555000 markers)	Blood	216 suicide cases from extended families	SP110 (rs181058279), AGBL2 (rs76215382), SUCLA2 (rs121908538), APH1B (rs745918508)	Coon et al[25], 2020
llumina Omni1-Quad Beadchip (1014770 markers)	Not stated	577 suicide attempters and suicides, 1233 non-attempter psychiatric and healthy controls	SNPs in STK3, ADAMTS14, PSME2, and TBX20 genes	Galfalvy et al[26], 2015
Affimetrix GeneChip Mapping 50K Xba Array (58900 markers)	Brain tissue	68 suicides, 31 non-suicide deaths	58 SNPs in or near 19 known genes	Galfalvy et al[27], 2013
Illumina HumanOmniExpress (733202 markers) and HumanOmniExpressExome BeadChips (273000 markers)	Not stated	Approximately 746 suicides and 14049 non-suicide controls	No genome-wide significant SNP; GTF2IRD1 locus suggested as associated with age at completed suicide	Otsuka et al[28], 2019
Affymetrix United Kingdom BiLEVE Axiom (807411 markers) or the Affymetrix United Kingdom Biobank Axiom (825927 markers) arrays	Blood	> 500000 subjects of different suicide phenotypes and non-suicidal controls	Significant loci for suicidality on chromosomes 9 (ZCCHC7), 11 (CNTN5) and 13 (rs7989250); genetic correlations between suicidality and depression	Strawbridge et al[31], 2019
Illumina Infinium PsychArray platform (593260 markers), Illumina HumanOmniExpress (733202 markers) and HumanOmniExpressExome BeadChips (273000 markers)	Blood	3413 suicides, 14810 controls	Two genome-wide significant loci involving six SNPs: rs34399104, rs35518298, rs34053895, rs66828456, rs35502061, and rs35256367. Additional 52 variants (mapping to 22 genes) with nominal significance	Docherty et al[29], 2020

Table 2 Overview of epigenomic studies that have examined suicidal behaviour

Type of -omic	Tissue	Number of samples	Main results	Ref.
Agilent 400K promoter tiling microarrays	Dentate gyrus	46 suicide completers and 16 comparison subjects	Significantly differential methylation of 366 promoters in suicide victims (273 hypermethylated and 93 hypomethylated)	Labonté et al[35], 2013
Illumina Infinium Human Methylation 27 BeadChip	Orbitoprefrontal cortex	25 depressed suicide cases and 28 non-psychiatric sudden death controls	Significantly increased DNA methylation in suicide victims	Haghighi et al[36], 2014
Illumina Human Methylation 450 BeadChip	Prefrontal cortex	23 suicide and 35 non-suicide	Significant altered methylation at four CpGs (ATP8A1, SKA2, LOC153328 and KCNAB2 in suicide victims	Guintivano et al[37], 2014
Illumina Human Methylation 450 BeadChip	Prefrontal cortex	Six suicide, six non-suicide	Significantly decreased level of methylation in suicide victims	Schneider et al[38], 2015
Illumina 450 K Infinium microarray	Prefrontal cortex	22 suicide completers and 28 control subjects	Significantly differential methylation of 454 CpGs in suicide completers	Kozlenkov et al[47], 2017
Methylation binding domain-2 (MBD2) sequencing	Prefrontal cortex	22 suicide cases and 17 controls	Significantly decreased methylation in suicide victims, with 115 differentially methylated regions	Nagy et al[39], 2015
Reduced-representation bisulphite sequencing	Prefrontal cortex and hippocampus	Nine suicide victims and nine controls	Significantly decreased methylation of 63 and 2406 CpGs and increased methylation of 43 and 328 CpGs in prefrontal cortex and hippocampus, respectively	Kouter et al[40], 2019
Illumina Infinium Human Methylation 450K BeadChip	Prefrontal cortex	21 suicides and six non-suicides	Significant correlation of 22 CpGs with gene expression in suicide victims	Cabrera-Mendoza et al[41], 2020

Table 3 Overview of transcriptomic studies that have examined suicidal behaviour

Type of -omic	Tissue	Number of samples	Main results	Ref.
U133A Oligonucleotide DNA Microarrays	Prefrontal cortex	19 depressed–suicide victims and 19 controls	No significant results	Sibille et al[105], 2004
Illumina Sentrix HumanRef-8 Expression BeadChips	Orbitofrontal cortex	11 suicide victims and ten controls	Significant downregulation of 59 genes and upregulation of 65 genes in suicide victims	Thalmeier et al[51], 2008
Human Genome U133 Set (HG-U133 A and B) microarray	Prefrontal cortex	16 depressed suicides, eight non suicides and 13 controls	Significantly altered expression of 267 genes, associated with cell cycle control and cell division, myelination, ATP biosynthesis and GABAergic neurotransmission in suicide victims	Klempan et al[53], 2009
HG-U133AB chipset	17 brain areas (amygdala, hippocampus, nucleus accumbens and 14 Brodmann areas)	26 suicide cases and 13 controls	Altogether over 4000 differentially expressed genes, association with cell communication and synaptic transmission in suicide victims	Sequeira et al[55], 2009
RNA-seq	Prefrontal cortex	21 major depressive disorder suicides, 9 MDD non-suicides and 29 controls	Significantly altered expression of 35 genes in suicide victims, association with microglial and immune system functions, and angiogenesis	Pantazatos et al[54], 2017
RNA-seq	Hippocampus	17 MDD suicide victims and 23 control subjects	Significant change in expression of 26 genes in depressed suicide victims, association with inflammation and chromatin regulation	Mahajan et al[56], 2018
RNA-seqc	Insula	52 mood disorder suicide victims and 45 non-mood disorder controls	Significant downregulation of 20 genes associated with inflammation response, protein- protein interaction, neurodegeneration, neurodevelopmental and upregulation of 5 genes, associated with intracellular protein transport, inflammation, apoptosis regulation and embryonic development in mood disorder suicide victims	Jabbi et al[52], 2020
RNA-seq	Prefrontal cortex	17 depressed suicide victims and 17 controls	Significant change in cell-type specific expression in depressed suicide victims	Nagy et al[60], 2020
TLDA based miRNA profiler	Prefrontal cortex	18 antidepressant-free MDD suicide victims and 17 controls	Significant downregulation of 21 miRNAs in suicide victims, miRNAs associated with nuclear proteins, transmembrane and signalling proteins	Smalheiser et al[106], 2012
LNA-based miRNA profiler	Prefrontal cortex	Four suicide victims and 4 controls	Significant upregulation of a single miRNA, targeting TrkB-T1, observed in low TrkB-T1 expression suicide victims	Maussion et al[107], 2012
TLDA-based miRNA profiler	Prefrontal cortex	18 suicide victims and 40 control subjects (all mood disorder)	Significant downregulation of 6 miRNAs and upregulation of 2 miRNAs in suicide victims	Smalheiser et al[57], 2014
Small RNA-seq	Prefrontal cortex	Nine suicide victims with depression, nine suicide victims and nine controls	No significant results	Pantazatos et al[54], 2017
TLDA-based miRNA profiler	Locus coeruleus	Nine suicide victims with depression and 11 controls	Significant upregulation of 10 miRNAs and downregulation of 3 miRNAs in suicide victims. Identified miRNAs are targeting multiple genes that were previously associated with psychiatric disorders	Roy et al[58], 2017

Table 4 Overview of proteomic studies examining suicidal behaviour

Type of -omic	Tissue	Number of samples	Main results	Ref.
2D gel electrophoresis	Cerebrospinal fluid	Seven suicide attempter and seven non-attempters	Significantly altered level of a single protein in suicide attempters. Due to limited amount of material the protein could not be identified	Brunner et al[68], 2005
2D gel electrophoresis and MALDI TOF MS	Prefrontal cortex	17 suicide victims and 9 controls	Significantly altered levels of three protein: An isoform of the common astroglia marker glial fibrillary acidic protein (GFAP), manganese superoxide dismutase (SOD2) and α crystallin chain B (CRYAB)	Schlicht et al[64], 2007
DIGE qTOF tandem MS	Prefrontal cortex and amygdala	Six suicide victims and six controls	59 significantly altered protein levels in the cortex and 11 significantly altered proteins in the amygdala. Level of nine proteins were significantly altered in both brain regions, but with varying direction of change (either increased or decreased in suicide victims), suggesting the global change in the brain, yet highlighting the importance of tissue specificity	Kékesi et al[65], 2012
2D gel electrophoresis and-MALDI-TOF MS	Plasma	12 suicide attempters, 12 MDD patients and 12 controls	Significant change in 45 protein, enabling the differentiation between MDD patients exhibiting suicidal behaviour and non-suicidal MDD patients	Yang et al[70], 2016
HPLC and Ion Trap MS	Cerebrospinal fluid	Two suicide victims and two controls	69 proteins with significant change in suicide victims, association with dysregulation of glucose metabolism and oxidative stress response.	Semancikova et al[69], 2018
2D-gel electrophoresis and MALDI MS	Plasma	10 self-harm subjects and 18 controls	Downregulation of apolipoprotein A-IV (Apo A-IV) in deliberate self-harm subjects.	Mathew et al[71], 2019
Liquid chromatography and tandem MS	Cerebellum	Four suicide victims and four controls	99 significantly altered proteins in schizophrenia suicide victims, association with transport function and cell communication. Vacuolar-type proton pump ATPase (VPP1) further validated and associated with suicidal behaviour.	Vidal-Domènech et al[67], 2020
ESI-MS/MS	Dorsolateral prefrontal cortex	Five suicide victims and five controls	33 proteins with significant change in expression (24 decreased and nine increased in the suicide group). Biggest change observed in reduction in protein coded by KCNQ3 (potassium voltage-gated channel subfamily Q member 3) in mood disorder suicide victims.	Cabello-Arreola et al[66], 2020