Genome-Wide Association Studies of Copy Number Variation in Autism Spectrum Disorder

Abstract

Autism is a syndrome with a broad spectrum of phenotypes characterized by deficits in social interaction and communication, repetitive or stereotyped behaviors, and restricted interests (Rutter, 2005). Autism spectrum disorder (ASD) manifests mostly before 3 years of age (Klauck, 2006). ASDs include two related diagnoses; pervasive developmental disorder (PDD) including atypical autism, impairment in the same areas, but not meeting criteria for autism; Asperger's syndrome, which is milder than PDD, showing similar impairments in social interaction, behaviors and interests, but no significant delay in linguistic and cognitive development (Weiss, 2009). The prevalence rate of ASDs is ~0.6% and ASDs are approximately four times more common in males than in females (Veenstra-VanderWeele, 2004). Many studies have been performed to elucidate the pathogenesis of ASDs, but identified risk factors do not explain a significant proportion of the disease prevalence. Genetic epidemiological data have been suggesting that ASDs are heritable both in autism families and in the general population (Freitag, 2007). The concordance rates of autism in monozygotic twins were reported to be significantly higher (~ 60–90%) than those in dizygotic twins (~ 10%) and the recurrence rates are known to be approximately 10-20 times higher in siblings than in normal population (Folstein & Rosen-Sheidley, 2001; Cohen et al., 2005; Bailey et al., 1995; Lauritsen et al., 2005). ASD is not a single-gene disorder with Mendelian inheritance but rather a component of various genetic disorders with apparent cytogenetic abnormalities (Eapen, 2011). Cytogenetic alterations were detected in 7.4% of ASD (Vorstman et al., 2006), and some of them have been suggested as causative factors of neurodevelopmental disorders (Merikangas et al., 2009). However, discrepancies in study results and diverse modes of inheritance have hindered the discovery of common genetic susceptibility factors to ASDs. For these reasons, despite the growing evidence supporting the genetic susceptibility to ASD development (Folstein & Rosen-Sheidley, 2001; VeenstraVanderWeele & Cook, 2004), the genetic mechanisms of ASD is still largely unknown. Recent technical advance in microarray-based whole-genome analysis has enabled identification of common and rare genetic alterations associated with ASDs. Several recent studies have suggested that ASDs are associated with genetic variations including single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), and that these genetic variations may work together (Veenstra-VanderWeele & Cook, 2004). For example, de novo CNVs were found in ~7% of idiopathic ASD families via oligoarray-comparative