A translational exploration of the effects of WNT2 variants on altered cortical structures in autism spectrum disorder

Yi-Ling Chien; Yu-Chieh Chen; Yen-Nan Chiu; Wen-Che Tsai; Susan Shur-Fen Gau

doi:10.1503/jpn.210022

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Figure 1
The 9 cortical regions identified with reduced cortical thickness, presented on (A) a standard brain cortex and (B) an inflated brain cortex.
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Figure 2
The genotypes rs6950765 and rs2896218 were associated with mean cortical thickness in both hemispheres. (A) Genotype rs6950765 and the mean thickness of the left hemisphere. (B) Genotype rs6950765 and the mean thickness of the right hemisphere. (C) Genotype rs2896218 and the mean thickness of the left hemisphere. (D) Genotype rs2896218 and the mean thickness of the right hemisphere. The CG of rs6950765 and the AG of rs2896218 showed greater cortical thinning of both hemispheres with age.

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Table 1

Participant demographic characteristics

Characteristic	Autism spectrum disorder^* n = 118	Typically developing controls^* n = 122	F / χ²	p value
Age, yr	13.11 ± 4.64	20.98 ± 9.70	F = 63.27	< 0.001
Male, n (%)	113 (95.8)	75 (61.5)	χ² = 41.6	< 0.001
Left-handedness, n (%)	9 (7.6)	5 (4.1)	χ2 = 1.36	0.24
Verbal IQ	100.8 ± 19.9	111.6 ± 10.9	F = 28.51	< 0.001
Performance IQ	99.7 ± 21.1	111.5 ± 13.3	F = 26.99	< 0.001
Full-scale IQ	100.1 ± 20.1	112.3 ± 11.7	F = 33.31	< 0.001
Autism Diagnostic Interview–Revised^*
Most severe at 4 to 5 yr
Social reciprocal interaction	19.68 ± 6.98	–	–	–
Communication: verbal	14.68 ± 5.03	–	–	–
Communication: nonverbal	7.84 ± 3.43	–	–	–
Repetitive or stereotyped behaviour or interests	7.26 ± 2.67	–	–	–
Current
Social reciprocal interaction	10.29 ± 4.71	–	–	–
Repetitive or stereotyped behaviour or interests	5.27 ± 2.52	–	–	–
Social Responsiveness Scale^†
Social awareness deficits	20.57 ± 5.29	12.50 ± 5.95	F = 78.05	< 0.001
Social communication deficits	40.04 ± 14.95	8.82 ± 7.09	F = 208.91	< 0.001
Social emotion deficits	12.81 ± 4.66	3.57 ± 3.52	F = 161.74	< 0.001
Stereotyped behaviours	20.28 ± 7.54	3.92 ± 4.31	F = 216.78	< 0.001
Total score	93.70 ± 28.74	28.80 ± 17.11	F = 231.99	< 0.001

↵* Values are mean ± standard deviation unless otherwise specified.
↵† The Autism Diagnostic Interview–Revised is an investigator-based interview of the caregiver, and the Social Responsiveness Scale is a caregiver-report measure of autistic traits in natural social settings. The subscores and total scores for both scales are shown here.

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Table 2

Group comparison of the cortical thickness of both hemispheres and 9 altered cortical regions^*

Characteristic	Autism spectrum disorder^† n = 88	Typically developing controls^† n = 51	F / χ² / t	p value	q_FDR	Cohen d
Age, yr (range)	12.68 ± 3.09 (8–20)	13.73 ± 3.61 (8–20)	F = 3.24	0.07	–	–
Male, n (%)	84 (95.5)	45 (88.2)	χ² = 2.52	0.11	–	–
Left-handedness, n (%)	80 (90.9)	48 (94.1)	χ² = 0.46	0.50	–
Full-scale IQ	104 ± 16	113 ± 12	F = 13.51	< 0.001	–	–
Cortical thickness, mm
Right hemisphere	3.101 ± 0.169	3.157 ± 0.100	t = −2.65	0.009	–	0.403
Left hemisphere	3.108 ± 0.165	3.158 ± 0.107	t = −2.50	0.014	–	0.360
Right middle-posterior part of the cingulate gyrus and sulcus (posterior midcingulate cortex)	3.383 ± 0.223	3.498 ± 0.169	t = −3.61	< 0.001	0.004	0.581
Right posterior transverse collateral sulcus	2.730 ± 0.285	2.855 ± 0.246	t = −3.39	0.001	0.004	0.470
Right orbital gyri	3.399 ± 0.219	3.500 ± 0.159	t = −2.93	0.004	0.008	0.528
Right superior segment of the circular sulcus of the insula	3.424 ± 0.227	3.508 ± 0.169	t = −3.22	0.002	0.005	0.420
Right posterior ramus of the lateral sulcus	3.181 ± 0.239	3.294 ± 0.194	t = −2.76	0.007	0.008	0.519
Right triangular part of the inferior frontal gyrus	3.281 ± 0.265	3.380 ± 0.197	t = −2.82	0.006	0.008	0.424
Right superior temporal sulcus (parallel sulcus)	3.156 ± 0.202	3.222 ± 0.165	t = −2.73	0.007	0.008	0.358
Right orbital part of the inferior frontal gyrus	3.409 ± 0.301	3.521 ± 0.226	t = −2.90	0.004	0.008	0.421
Right lateral occipitotemporal gyrus (fusiform gyrus, O4–T4)	3.408 ± 0.211	3.504 ± 0.179	t = −2.61	0.010	0.010	0.491

FDR = false discovery rate.
↵* The comparison of cortical thickness used age, sex, full-scale IQ and intracranial volume as covariates. Multiple comparisons of the 9 regions were adjusted using false discovery rate.
↵† Values are mean ± standard deviation unless otherwise specified.

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Table 3

Significant main effect of SNPs and age × SNP interactions in the entire sample (n = 240)

Region	Main effect of SNP		Age × SNP interaction

	Cohen d	Statistics	Cohen d	Statistics	R²
rs2896218
Left hemisphere (mean thickness)	AA v. GG: 0.038	F = 5.32	Age × AA: −0.316	F = 5.06	0.27
	AG v. GG: 0.175	p = 0.006	Age × AG: −0.475	p = 0.007
			Age × GG: −0.127
Right hemisphere (mean thickness)	AA v. GG: 0.034	F = 5.38	Age × AA: −0.300	F = 4.78	0.26
	AG v. GG: 0.174	p = 0.005	Age × AG: −0.459	p = 0.009
			Age × GG: −0.122
Right middle-posterior part of the cingulate gyrus and sulcus (posterior midcingulate cortex)	AA v. GG: 0.152	F = 10.33	Age × AA: −0.273	F = 9.71	0.24
	AG v. GG: 0.283	p < 0.001^**	Age × AG: −0.437	p < 0.001^**
			Age × GG: 0.008
Right orbital gyri	AA v. GG: 0.098	F = 4.31	Age × AA: −0.320	F = 5.27	0.22
	AG v. GG: 0.183	p = 0.015	Age × AG: −0.386	p = 0.006^*
			age × GG: −0.036
Right superior segment of the circular sulcus of the insula	AA v. GG: 0.090	F = 3.31	Age × AA: −0.222	F = 2.30	0.14
	AG v. GG: 0.161	p = 0.038	Age × AG: −0.297	p = 0.10
			Age × GG: −0.042
Right triangular part of the inferior frontal gyrus	AA v. GG: 0.025	F = 4.10	Age × AA: −0.223	F = 4.40	0.17
	AG v. GG: 0.143	p = 0.018	Age × AG: −0.380	p = 0.013
			Age × GG: −0.096
Right superior temporal sulcus (parallel sulcus)	AA v. GG: −0.017	F = 6.65	Age × AA: −0.286	F = 4.91	0.27
	AG v. GG: 0.149	p = 0.002^*	Age × AG: −0.465	p = 0.008^*
			Age × GG: −0.199
rs6950765
Left hemisphere (mean thickness)	CC v. GG: −0.110	F = 6.79	Age × CC: −0.057	F = 6.01	0.29
	CG v. GG: 0.190	p = 0.001	Age × CG: −0.484	p = 0.003
			Age × GG: −0.344
Right hemisphere (mean thickness)	CC v. GG: −0.107	F = 6.94	Age × CC: −0.050	F = 5.91	0.27
	CG v. GG: 0.196	p = 0.001	Age × CG: −0.471	p = 0.003
			Age × GG: −0.329
Right middle-posterior part of the cingulate gyrus and sulcus (posterior midcingulate cortex)	CC v. GG: −0.229	F = 14.48	Age × CC: 0.089	F = 13.97	0.27
	CG v. GG: 0.184	p < 0.001^**	Age × CG: −0.454	p < 0.001^**
			Age × GG: −0.301
Right orbital gyri	CC v. GG: −0.157	F = 7.04	Age × CC: 0.016	F = 7.09	0.23
	CG v. GG: 0.132	p = 0.001^*	Age × CG: −0.396	p = 0.001^*
			Age × GG: −0.334
Right superior segment of the circular sulcus of the insula	CC v. GG: −0.151	F = 6.26	Age × CC: 0.032	F = 5.97	0.16
	CG v. GG: 0.121	p = 0.002^*	Age × CG: −0.333	p = 0.003^*
			Age × GG: −0.234
Right triangular part of the inferior frontal gyrus	CC v. GG: −0.061	F = 6.27	Age × CC: −0.048	F = 5.00	0.18
	CG v. GG: 0.193	p = 0.002^*	Age × CG: −0.379	p = 0.008^*
			Age × GG: −0.235
Right superior temporal sulcus (parallel sulcus)	CC v. GG: −0.075	F = 8.01	Age × CC: −0.125	F = 6.07	0.27
	CG v. GG: 0.215	p < 0.001^**	Age × CG: −0.486	p = 0.003^*
			Age × GG: −0.315

FDR = false discovery rate; SNP = single nucleotide polymorphism.
Model: Cortical thickness of specific brain region = β₀ + β₁ “SNP” + β₂ “age × SNP” + β₃ “age” + β₄ “sex” + β₅ “full-scale IQ” + β₆ “handedness” + β₇ “intracranial volume” + ɛ. Findings for the main effects of SNP and age × SNP interaction for rs2896218 and rs6950765 are summarized above. For the 9 cortical regions,
↵* q_FDR < 0.05,
↵** q_FDR < 0.01.