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

By Kai Wang, Haitao Zhang, D. Ma, Maja Bucan, Joseph Glessner, B. Abrahams, D. Salyakina, Marcin Imielinski, J. Bradfield, P. Sleiman and 46 more. Nature, 2009

1,008 citations recorded by the source corpus.

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 × 10-8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10-8 to 2.1 × 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.

Subfields: Cognitive Neuroscience, Genetics

View Paper: https://www.semanticscholar.org/paper/da6de7ec04292e25f98bbad5912382f07bdfc6d0

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Citations in the corpus

Genetic heterogeneity in human disease. (2010, background): “A recently published genome-wide association study of autism (Wang et al., 2009) provides a particularly dramatic example of the perils of cryptic population stratification.”
Why Are Autism Spectrum Conditions More Prevalent in Males? (2011, background): “A problem for this theory is that the majority of linkage and association studies of ASC have failed to find regions of interest on the X chromosome [59–72].”
Analysing biological pathways in genome-wide association studies (2010, background): “Several pathway-based studies have been conducted for neuropsychiatric disorders: for example, two studies implicated neuronal cell adhesion molecules in the aetiology of autism, schizophrenia and bipolar disorde”
Rare de novo and transmitted copy-number variation in autistic spectrum disorders. (2011, critical): “The hypothesis that autism results from an unfortunate combination of common low-risk variants (Wang et al., 2009; Weiss et al., 2009) can be safely rejected.”
Developmental regulation of human cortex transcription and its clinical relevance at base resolution (2014, neutral): “…in brain disorders thought to be developmental, including RGS4 , a G-protein signaling regulator associated with schizophrenia 23 that has highest expression during adolescence, and CNTNAP1 , a contactin-associated protein associated with autism 24 with highest expression during adulthood.”
Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics (2011, background): “However, it does appear that for some traits, including neurodevelopmental diseases such as schizophrenia (SCZ) (Stefansson et al. 2008; Walsh et al. 2008) and autism (Sebat et al. 2007; Wang et al. 2009), CNVs play a substantial role, so there is still interest in including CNVs in future GWASs.”
A genome-wide scan for common alleles affecting risk for autism (2010, methodology): “1 CDH9–CDH10 and 5p15.”
Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses (2011, background): “Although autism has a very strong genetic component, with an estimatedheritability ashighas90%basedonstudies ofmonozygotic twins (Hyman, 2008), GWAS-based searches have implicatedonlya fewgenes that are associatedwithcommonpolymorphisms reaching genome-wide significance (Wang et al., 2009; Weiss et ”
Behavioural phenotyping assays for mouse models of autism (2010, background): “Rare variants in candidate genes have been reported, both de novo and familial, as well as copy number variants and epigenetic factor”
Autism and Increased Paternal Age Related Changes in Global Levels of Gene Expression Regulation (2011, background): “minority of cases [2,3,4,5,6], while the majority of cases are”
Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. (2011, methodology): “…has not previously been noted to be a risk variant, but the larger family of proteins has been implicated in ASD pathogenesis through CNV studies (Glessner et al., 2009), homozygosity mapping (Morrow et al., 2008), common variant findings (Wang et al., 2009), and our pathway analysis (Figure 6).”