Common genetic variants on 5p14.1 associate with autism spectrum disorders

Abstract

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

Figure 1. Genome-wide association results for the 5p14.1 region

a, A Manhattan plot showing the −log₁₀(P values) of SNPs from the combined association analysis of the AGRE and ACC cohorts. b, The 5p14.1 genomic region is displayed in UCSC Genome Browser, with conserved genomic elements in the PhastCons track. c, Both genotyped (diamonds) and imputed (grey circles) SNPs are plotted with their combined P values in all four cohorts. Genotyped SNPs were coloured on the basis of their correlation with rs4307059 (red: r² ≥ 0.5; yellow: 0.2 ≤ r² < 0.5; white: r² < 0.2). Estimated recombination rates from HapMap data are plotted to reflect the local linkage disequilibrium structure.

Figure 2. Examination of brain expression for CDH10 and CDH9

a, The in situ hybridization of CDH10 in human fetal brain sectioned in the sagittal plane. Medial and lateral sections from a representative sample are shown above corresponding cresyl-violet-stained marker slides. Orbitofrontal cortex (OFC) and frontal cortex (FC) are highlighted, with marked expression enrichment. b, The SNP genotypes of rs4307059 are not associated with CDH9 or CDH10 transcript levels in 93 cortical brain tissues.