Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder

摘要: Autism spectrum disorders (ASDs) are male-biased and genetically heterogeneous. While sequencing of sporadic cases has identified de novo risk variants, the heritable genetic contribution mechanisms driving male bias less understood. Here, we aimed to identify familial sex-differential loci in largest available, uniformly ascertained, densely genotyped sample multiplex ASD families from Genetics Resource Exchange (AGRE), compare results with earlier findings AGRE. From a total 1,008 families, performed genome-wide, non-parametric linkage analysis discovery 847 separately on subsets only male, affected children (male-only, MO) or at least one female, child (female-containing, FC). Loci showing evidence for suggestive (logarithm odds ≥2.2) this sample, previous AGRE samples, were re-evaluated an extension study utilizing all available families. For regions genome-wide significant signal stage, those not included corresponding then evaluated independent replication linkage. Association testing common single nucleotide polymorphisms (SNPs) was also within regions. We observed previously chromosome 20p13 (P < 0.01), while 6q27 8q13.2 showed our extended sample. Suggestive 1p31.3 (MO), 8p21.2 (FC), 8p12 (FC) MO supported expanded No signals met criteria, no SNPs significantly associated any With few exceptions, analyses cohort different loci, consistent extreme locus heterogeneity ASD. Large samples appear yield more results, sex-stratified facilitate identification suggesting that large cohorts useful identifying loci. Additional work, such as targeted re-sequencing, is needed specific variants these responsible increasing risk.