A GENOME-WIDE LINKAGE AND ASSOCIATION SCAN REVEALS NOVEL LOCI FOR AUTISM

By L. Weiss, Dan E. Arking. Nature, 2009

641 citations recorded by the source corpus.

Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

Subfields: Cognitive Neuroscience, Genetics

View Paper: https://www.semanticscholar.org/paper/5b902f432a23618d4008cde239c314581eddc06d

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Citations in the corpus

Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities and core autism-related deficits (2011, neutral): “Research into the genetic basis for ASD has identified many genes, including common and rare variants (Sebat et al., 2007; Glessner et al., 2009; Weiss et al., 2009).”
SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs) (2013, neutral): “Letter to the Editor Previous work has crafted curated lists of genes implicated in autism spectrum disorders (ASDs) [1-5], and in some cases developed loosely defined “evidence scores” for entries [6-8].”
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].”
Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. (2011, methodology): “We also considered recent common variant findings, including SEMA5A (Weiss et al., 2009), MACROD2 (Anney et al., 2010), CDH9 and CDH10 (Wang et al., 2009), the MET oncogene (Campbell et al., 2006), EN2 (Gharani et al., 2004), and selected schizophrenia loci (ISC, 2008; McCarthy et al., 2009; Millar…”
Genetic heterogeneity in human disease. (2010, result): “A subsequent analysis did not replicate the association between rs4307059 and autism (Weiss et al., 2009) and in fact found the opposite trend: the minor allele was more frequent among affected persons.”
Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses (2011, background): “…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 al., 2009).”