Table 1.

ASD-associated genes affecting brain morphology and function.

Gene (s)	Risk allele/polymorphism	Subjects	Method used	Brain region affected/potentially could be affected	Findings
ANK2		ankB mutant mice	DTI	Cortex	Increased interhemispheric asymmetry in the cortex and increased overall connectivity46
HOXA1	HOXA1 A218G polymorphism	Autistic individuals and ethnically matched controls	Family-based association analyses	Could potentially affect hindbrain neural networks that could, in turn, affect brainstem	Enlarged cranial circumference68,143
HOXA1 HOXB1		Mice mutants of HOXA1/HOXB1	Immunohistochemistry, RNA in situ hybridization, SEM, cell apoptotic and proliferation assay	Hindbrain	Loss of rhombomere 4 and 5 and loss of second branchial arch in HOXA1/HOXB1 mutant mice53
PTEN		ASD and macrocephaly	Gene mutation analysis	Cerebral cortex (as one of the subject’s brain MRI showed dilatation of perivascular spaces in the basal ganglia)	Larger head circumference72
CHD8		ASD and Developmental delay	Analysis of CHD8 gene expression using Zebrafish model	Forebrain and midbrain	Increased head size55
CNTNAP2	rs779475	Healthy controls	DTI, sMRI	Frontal lobe, occipital lobe, cerebellum	Reduction in WM and GM volumes in the cerebellum, frontal and occipital lobes in homozygotes for the risk allele77
	rs2710102	ASD and TD individuals	fMRI (reward-guided implicit learning task)	Frontal cortex	Reduced mPFC activation in nonrisk individuals and increased frontal connectivity in the risk allele carriers117
	rs7794745 T rs2710102 C	Healthy individuals	fMRI (language task)	Prefrontal cortex, temporal cortex	Increased activation of the right inferior frontal gyrus and right lateral temporal cortex in the risk allele carriers118
	c.3709DelG mutation	Individuals with syndromic ASD and healthy controls	MRI	Prefrontal cortex	Increased head circumference and GM volume76
			Forebrain organoid culture		Increased total brain volume in individuals carrying the CNTNAP2 c.3709DelG mutation76
		CNTNAP2 knockout mice	Laser-scanning photostimulation, whole-cell recordings, and electron microscopy	Prefrontal cortex	Reduced excitatory and inhibitory synaptic inputs onto L2/3 pyramidal neurons in the mPFC of CNTNAP2 knockout mice with reduced spines and synapses144
MET	rs1858830	Healthy individuals	sMRI	Frontal lobe, temporal lobe, anterior cingulate cortex	Reduction in cortical thickness with increasing C allele dose in temporal gyri, ventral pre- and postcentral gyri, anterior cingulate and in fronto-polar cortex regions78
	rs1858830	ASD and TD individuals	fMRI (observation of emotional faces), resting-state fMRI, DTI	Neocortex	Higher activation of amygdala and striatum and reduced WM integrity and intrinsic connectivity between the posterior cingulate cortex and mPFC regions in MET risk allele carriers79
SLC6A4	5HTTLPR	ASD children	MRI	Cerebrum	5HTTLPR short allele associated with increasing cerebral GM volumes80
NRXN1	rs1045881	ASD and schizophrenia risk allele carriers	sMRI	Frontal lobe	Reduction in frontal WM volumes and altered sensorimotor function115
	bi-allelic NRXN1-α del	ASD individual and healthy controls	Single-cell RNA sequencing		Reduced proliferation capability and calcium signaling and high expression of radial glia-like morphology in NRXN1-α del NES cells116
OXTR	rs2254298A	Healthy Japanese adults	MRI	Amygdala	Larger bilateral amygdala volume81
	rs2254298(G>A)	Healthy females	MRI	Amygdala, anterior cingulate cortex, brainstem	Increased amygdala and GM volume in the brainstem and decreased total GM volume and GM volume in the anterior cingulate cortex in G/A heterozygotes82
	rs53576	Healthy adults	sMRI and fMRI	Hypothalamus and amygdala	Decrease in hypothalamus GM and amygdala activation and increased functional correlation of hypothalamus and amygdala in minor allele carriers for rs5357683
	rs2254298A	Healthy individuals	MRI	Cerebral cortex	Reduced GM volume in the right insula in males with the risk allele84
	rs2268498 T/C	Healthy individuals	fMRI (fear processing task)	Occipital lobe	T-allele homozygotes showed increased activation of inferior occipital gyrus during recognition of fear expressions86
	rs2268493	Healthy individuals	fMRI (reward anticipation task)	Nucleus accumbens, amygdala, insula, thalamus, and prefrontal cortical regions	T-allele homozygotes showed reduced activation in the mesolimbic reward circuitry85
	rs401015	Healthy individuals	fMRI (direct gaze processing task)	Amygdala	Heterozygotes CT variants showed increased amygdala activity87
	rs2254298A	Healthy individuals	VBM, fMRI	Hypothalamus, dorsal anterior cingulate cortex	Decreased hypothalamus GM volume and deactivation of dorsal anterior cingulate gyrus and increased structural coupling of dorsal anterior cingulate gyrus and hypothalamus in A carriers88
	rs53576	Healthy individuals	VBM, fMRI (mentalizing paradigm)	Amygdala, parietal lobe	Higher brain GM volume in the left amygdala and lower GM volume in superior parietal lobule89
CDH9 and CDH11		Mice	In situ hybridization	Cerebellum	High expression of Cdh11 in the central part and Cdh9 in the surrounding areas in lobules VI/VII and Crus I and Crus II regions of the cerebellum145
RELN		Autistic and healthy individuals (postmortem samples)	SDS-PAGE, Western blotting	Cerebellum	Significant reduction of Reelin protein in the cerebellar region of ASD individuals132
SLC25A12		Autistic and healthy individuals (postmortem samples)	qRT-PCR, RNA extraction, in situ hybridization	Prefrontal cortex	Strong expression of SLC25A12 in the BA46 prefrontal cortex of autistic subjects146
PRKCB1	rs3785392 rs3785387	Autistic and healthy individuals (postmortem samples)	qRT-PCR, Western blotting, Microarray analysis	Cerebral cortex	Significant reduction of PRKCB1 gene expression in the temporal neocortex of autistic individuals147
TAOK2		Mice	MRI, DTI	Midbrain, thalamus, hypothalamus and hindbrain regions	Enlarged volumes of the midbrain, hindbrain, hypothalamus, thalamus, cerebellum, and hippocampus and reduced density of fiber tracks in the medial corpus callosum of TAOK2 knockout mice57
MECP2		Autistic and healthy individuals (postmortem samples)	Immunofluorescence and laser-scanning cytometry	Frontal cortex, temporal and occipital lobe	Decreased MECP2 expression in the frontal cortex and fusiform gyrus of autistic individuals148
SHANK3		SHANK3 transgenic Mice	MRI	Hippocampus, forebrain, and midbrain	Reduction in total brain volume and hippocampal size and increase of basal ganglia in SHANK3 knockout mice as compared to prenatal zinc-deficient mouse model of ASD45
NL3		NL3 knockin mice	Ex vivo MRI and DTI	Caudate putamen, substantia nigra, somatosensory cortex, corpus callosum, internal capsule, and cerebral peduncles	Decreased volumes of WM and GM regions in the NL3 knockin mice as compared to wildtype mice43
AVPR1A	RS1, RS3	Healthy individuals	fMRI (face-matching task)	Amygdala	RS3 334bp, RS3 longer variants, RS1 312 bp, and RS1 shorter variants risk allele carriers showed stronger activation of left amygdala120
MECP2 ITGB3 NL3		MECP2 308 truncation, ITGB3 knockout, NL3 knockin mouse models	MRI	Cerebellum	Increased GM and WM volume in crus II lobule and GM volume in paraflocculus in NL3 knockin mice, Expansion of vermis lobules III–X, the anterior lobule, the paraflocculus, and simple, crus I, and crus II hemisphere lobules in the homozygous MECP2 model and reduced cerebellum volume in ITGB3 knockin mice44
CD38	rs3796863	Healthy individuals	fMRI (social, emotional stimuli and gaze processing task)	Temporal cortex	Higher activation of the left fusiform gyrus in homozygous risk allele carriers119
	rs3796863	Healthy individuals	fMRI (social cognition tasks)	Amygdala	Epistasis effect between CD38 and COMT in the amygdala121
		C57BL/6 mice and CD38−/− mice	MRI	Prefrontal cortex	Larger whole brain volume, abnormal cortex development, and impaired synaptic plasticity in the prefrontal cortex of CD38−/− mice108

MRI magnetic resonance imaging, DTI diffusion tensor imaging, fMRI functional magnetic resonance imaging, VBM voxel-based morphometry.