Association of folate metabolism gene polymorphisms with autism susceptibility and symptom severity in the Chinese population

Table 1 Demographic characteristics of participants (n = 410), n (%)

Variables	Case-case study (n = 70)				Case-control study (n = 340)
	Total (n = 70)	Boys (n = 51)	Girls (n = 19)	P value	Total (n = 340)	Control (n = 170)	ASD (n = 170)	P value
Age (year), mean ± SD	5.16 ± 1.97	5.12 ± 2.18	5.26 ± 1.28	0.786	4.48 ± 0.98	4.55 ± 0.83	4.42 ± 1.11	0.225
Gender								0.999
Boys	-	-	-	-	266.0 (78.2)	133.0 (78.2)	133.0 (78.2)
Girls	-	-	-	-	74.0 (21.8)	37.0 (21.8)	37.0 (21.8)
Ethnicity				0.681				0.999
Han	68 (97.1)	49 (96.1)	19 (100.0)		335.0 (98.5)	167.0 (98.2)	168.0 (98.8)
Other	2 (2.9)	2 (3.9)	0 (0.0)		5.0 (1.5)	3.0 (1.8)	2.0 (1.2)
Father’s age at birth, mean ± SD	32.41 ± 5.69	32.27 ± 5.55	32.79 ± 6.21	0.739	32.46 (5.47)	32.38 (4.54)	32.55 (6.28)	0.767
Mother’s age at birth, mean ± SD	30.34 ± 5.00	29.84 ± 4.58	31.68 ± 5.90	0.172	30.08 (4.77)	30.40 (3.83)	29.76 (5.55)	0.216
Father education level				0.546				0.926
Less than high school	9 (12.9)	6 (11.8)	3 (15.8)		70.0 (20.6)	34.0 (20.0)	36.0 (21.2)
High school	24 (34.3)	16 (31.4)	8 (42.1)		92.0 (27.1)	45.0 (26.5)	47.0 (27.6)
College degree or higher	37 (52.9)	29 (56.9)	8 (42.1)		178.0 (52.4)	91.0 (53.5)	87.0 (51.2)
Mother education level				0.714				0.829
Less than high school	14 (20.0)	9 (17.6)	5 (26.3)		77.0 (22.6)	37.0 (21.8)	40.0 (23.5)
High school	23 (32.9)	17 (33.3)	6 (31.6)		99.0 (29.1)	48.0 (28.2)	51.0 (30.0)
College degree or higher	33 (47.1)	25 (49.0)	8 (42.1)		164.0 (48.2)	85.0 (50.0)	79.0 (46.5)
Mode of delivery				0.471				0.825
Vaginal delivery	45 (64.3)	31 (60.8)	14 (73.7)		201.0 (59.1)	99.0 (58.2)	102.0 (60.0)
Cesarean delivery	25 (35.7)	20 (39.2)	5 (26.3)		139.0 (40.9)	71.0 (41.8)	68.0 (40.0)
Birthweight (kg)	3.18 ± 0.54	3.14 ± 0.50	3.29 ± 0.65	0.328	3.17 (0.50)	3.18 (0.46)	3.16 (0.53)	0.702
Premature				0.273				0.550
No	59 (84.3)	41 (80.4)	18 (94.7)		287.0 (84.4)	141.0 (82.9)	146.0 (85.9)
Yes	11 (15.7)	10 (19.6)	1 (5.3)		53.0 (15.6)	29.0 (17.1)	24.0 (14.1)
ABC scores, mean ± SD	62.87 ± 13.05	63.82 ± 13.81	60.32 ± 10.68	0.321	-	-	-	-
CARS scores, mean ± SD	35.67 ± 3.71	36.18 ± 3.81	34.32 ± 3.09	0.061	-	-	-	-

ASD: Autism spectrum disorder; ABC: Autism Behavior Checklist; CARS: Childhood Autism Rating Scale.

Table 2 Association between the genetic model of folate metabolism gene polymorphism and autism spectrum disorder susceptibility

Genetic model		Model 1		Model 2
		OR (95%CI)	P value	AOR (95%CI)	P value
MTHFR C677T
Codominant model	TT vs CC	1.65 (0.78-3.52)	0.190	1.83 (0.83-4.10)	0.138
	CT vs CC	2.03 (1.29-3.24)	0.003	2.38 (1.46-3.92)	< 0.001
Dominant model	TT + CT vs CC	1.95 (1.27-3.01)	0.002	2.28 (1.44-3.65)	< 0.001
Recessive model	TT vs CT + CC	1.22 (0.60-2.55)	0.583	1.33 (0.63-2.82)	0.452
MTRR A66G
Codominant model	GG vs AA	1.70 (0.73-4.04)	0.216	1.71 (0.70-4.29)	0.241
	AG vs AA	1.89 (1.20-2.98)	0.006	1.79 (1.12-2.89)	0.016
Dominant model	GG +AG vs AA	1.86 (1.21-2.87)	0.005	1.74 (1.11-2.73)	0.016
Dominant model	GG vs AG + AA	1.30 (0.57-3.01)	0.534	1.26 (0.54-3.00)	0.594
BHMT G716A
Codominant model	AA vs GG	1.00 (0.45-2.24)	0.995	1.01 (0.42-2.42)	0.981
	AG vs GG	0.87 (0.56-1.35)	0.534	0.85 (0.53-1.35)	0.493
Dominant model	AA+AG vs GG	0.89 (0.58-1.36)	0.585	0.86 (0.55-1.34)	0.505
Recessive model	AA vs AG + GG	1.08 (0.50-2.33)	0.846	1.04 (0.47-2.30)	0.922

Model 1: Unadjusted; model 2: Adjusted for age, gender, ethnicity, parental age at birth, parental education level, mode of delivery, birthweight, premature; AOR: Adjusted odds ratio; CI: Confidence interval; OR: Odds ratio.

Table 3 Association between folate metabolism gene polymorphism and Autism Behavior Checklist.

Variables	Model 1		Model 2
	(95%CI)	P value	(95%CI)	P value
MTHFR C667T
Sensory behavior	-0.01 (-1.29 to1.26)	0.984	0.09 (-1.24 to 1.43)	0.891
Social relating	-0.23 (-1.70 to 1.25)	0.762	-0.00 (-1.56 to 1.55)	0.995
Body and object use	-0.27 (-2.01 to 1.47)	0.758	-0.07 (-1.84 to 1.69)	0.935
Language and communication skills	0.75 (-0.64 to 2.14)	0.289	0.67 (-0.81 to 2.15)	0.371
Social and adaptive skills	-0.08 (-1.26 to 1.10)	0.894	-0.11 (-1.32 to 1.11)	0.864
ABC total score	0.05 (-4.62 to 4.73)	0.983	0.44 (-4.49 to 5.37)	0.861
MTRR A66G
Sensory behavior	0.60 (-0.67 to 1.87)	0.350	0.62 (-0.74 to 1.97)	0.368
Social relating	1.93 (0.49-3.37)	0.009	2.27 (0.73-3.81)	0.004
Body and object use	2.01 (0.31-3.72)	0.021	2.48 (0.73-4.23)	0.006
Language and communication skills	-0.29 (-1.69 to 1.10)	0.679	-0.06 (-1.57 to 1.45)	0.936
Social and adaptive skills	1.79 (0.65-2.93)	0.002	1.80 (0.60-3.00)	0.003
ABC total score	6.17 (1.61-10.74)	0.008	7.24 (2.37-12.12)	0.004

Dominant model was used for analysis. Model 1: Unadjusted; model 2: Adjusted for age, gender, ethnicity, parental age at birth, parental education level, mode of delivery, birthweight, premature; CI: Confidence interval; ABC: Autism Behavior Checklist.

Table 4 Association between folate metabolism gene polymorphism and Childhood Autism Rating Scale

Variables	Model 1		Model 2
	(95%CI)	P value	(95%CI)	P value
MTHFR C667T
Relating to people	0.03 (-0.12 to 0.18)	0.703	0.07 (-0.08 to 0.23)	0.352
limitation	0.12 (-0.08 to 0.31)	0.232	0.13 (-0.07 to 0.33)	0.190
Emotional response	0.11 (-0.07 to 0.28)	0.220	0.07 (-0.10 to 0.25)	0.413
Body use	0.14 (-0.06 to 0.33)	0.167	0.18 (-0.03 to 0.38)	0.087
Object use	0.15 (-0.01 to 0.32)	0.072	0.16 (-0.01 to 0.33)	0.065
Adaptation to change	0.16 (-0.00 to 0.32)	0.054	0.14 (-0.02 to 0.31)	0.081
Visual response	0.05 (-0.09 to 0.18)	0.503	0.09 (-0.05 to 0.22)	0.195
Listening response	0.07 (-0.05 to 0.20)	0.242	0.11 (-0.02 to 0.24)	0.105
Taste, smell, and touch response and use	-0.08 (-0.27 to 0.10)	0.383	-0.08 (-0.26 to 0.11)	0.416
Fear or nervousness	0.02 (-0.15 to 0.19)	0.780	0.02 (-0.15 to 0.20)	0.799
Verbal communication	-0.01 (-0.15 to 0.14)	0.941	0.03 (-0.12 to 0.18)	0.675
Nonverbal communication	-0.12 (-0.28 to 0.04)	0.133	-0.10 (-0.26 to 0.07)	0.248
Activity level	0.02 (-0.09 to 0.13)	0.718	0.01 (-0.10 to 0.12)	0.863
Level and consistency of intellectual response	0.12 (-0.06 to 0.29)	0.189	0.10 (-0.08 to 0.28)	0.269
General impressions	0.12 (-0.06 to 0.29)	0.200	0.13 (-0.06 to 0.31)	0.170
CARS total score	0.89 (-0.59 to 2.37)	0.236	1.07 (-0.42 to 2.57)	0.157
MTRR A66G
Relating to people	0.04 (-0.12 to 0.19)	0.638	0.02 (-0.14 to 0.18)	0.777
limitation	0.04 (-0.16 to 0.23)	0.703	0.05 (-0.16 to 0.25)	0.645
Emotional response	0.15 (-0.02 to 0.32)	0.090	0.21 (0.03-0.39)	0.021
Body use	0.17 (-0.02 to 0.36)	0.084	0.19 (-0.02 to 0.40)	0.072
Object use	0.07 (-0.09 to 0.24)	0.382	0.11 (-0.06 to 0.29)	0.193
Adaptation to change	0.07 (-0.09 to 0.23)	0.381	0.09 (-0.07 to 0.26)	0.272
Visual response	0.04 (-0.09 to 0.17)	0.546	0.04 (-0.10 to 0.17)	0.611
Listening response	0.01 (-0.12 to 0.13)	0.938	-0.01 (-0.14 to 0.12)	0.884
Taste, smell, and touch response and use	0.07 (-0.12 to 0.25)	0.486	0.12 (-0.07 to 0.30)	0.216
Fear or nervousness	0.06 (-0.11 to 0.23)	0.472	0.07 (-0.11 to 0.25)	0.416
Verbal communication	0.12 (-0.02 to 0.26)	0.106	0.12 (-0.02 to 0.27)	0.100
Nonverbal communication	0.19 (0.03-0.35)	0.020	0.20 (0.03-0.36)	0.019
Activity level	0.11 (-0.01 to 0.21)	0.057	0.13 (0.01-0.24)	0.031
Level and consistency of intellectual response	0.02 (-0.15 to 0.20)	0.791	0.01 (-0.18 to 0.18)	0.994
General impressions	0.04 (-0.13 to 0.22)	0.622	0.11 (-0.08 to 0.29)	0.261
CARS total score	1.19 (-0.28 to 2.65)	0.111	1.44 (-0.06 to 2.95)	0.060

Dominant model was used for analysis. Model 1: Unadjusted; model 2: Adjusted for age, gender, ethnicity, parental age at birth, parental education level, mode of delivery, birthweight, premature; CI: Confidence interval; CARS: Childhood Autism Rating Scale.