Abstract
The prevalence of autism spectrum disorders (ASDs) has increased 20-fold over the past 50 years to >1% of US children. Although twin studies attest to a high degree of heritability, the genetic risk factors are still poorly understood. We analyzed data from two independent populations using u-statistics for genetically structured wide-locus data and added data from unrelated controls to explore epistasis. To account for systematic, but disease-unrelated differences in (non-randomized) genome-wide association studies (GWAS), a correlation between P-values and minor allele frequency with low granularity data and for conducting multiple tests in overlapping genetic regions, we present a novel study-specific criterion for ‘genome-wide significance'. From recent results in a comorbid disease, childhood absence epilepsy, we had hypothesized that axonal guidance and calcium signaling are involved in autism as well. Enrichment of the results in both studies with related genes confirms this hypothesis. Additional ASD-specific variations identified in this study suggest protracted growth factor signaling as causing more severe forms of ASD. Another cluster of related genes suggests chloride and potassium ion channels as additional ASD-specific drug targets. The involvement of growth factors suggests the time of accelerated neuronal growth and pruning at 9–24 months of age as the period during which treatment with ion channel modulators would be most effective in preventing progression to more severe forms of autism. By extension, the same computational biostatistics approach could yield profound insights into the etiology of many common diseases from the genetic data collected over the last decade.
Highlights
Autism spectrum disorders (ASDs) include a broad range of developmental brain disorders that share a complex and heterogeneous etiology characterized by fundamental deficits in social reciprocity, impaired language and communication skills, as well as repetitive and stereotypic behavior
In part, on mouse studies[88,89] and enrichment of copy-number variations (CNV) in a previous analysis of the Autism Genome Project (AGP) I data,[14] there is an emerging consensus building that dysregulation of the Ras pathway is involved in ASDs
SsGWAS have largely failed to elucidate the precise mechanism by which Ras and Ca2+ signaling
Summary
Autism spectrum disorders (ASDs) include a broad range of developmental brain disorders that share a complex and heterogeneous etiology characterized by fundamental deficits in social reciprocity, impaired language and communication skills, as well as repetitive and stereotypic behavior. Despite the high heritability of ASD, with near-perfect concordance in monozygotic twins,[1] a >50% heritability among siblings[2] and a >25% risk for developing ASD in a male sibling,[3] the genetic risk factors are still poorly understood.[4] In the absence of reliable and feasible biomarkers, ASDs are still diagnosed exclusively according to behavioral criteria. ASD-specific therapeutic approaches are urgently needed to meet the challenge of an increasing prevalence, yet genome-wide association studies (GWAS) have not met the need for a better understanding of the etiology of ASD.[5]. Many GWAS have been marred by both low sensitivity and specificity.
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