UNC Libraries · 2020 · 28 citations · 0 references
Life SciencesGeneticsMolecular GeneticsAutism Spectrum DisordersGenomicsHuman GeneticsAutism Spectrum Disorder GeneticsDisease Susceptibility LociGenetic DisordersGenetic Risk AssessmentGenome-wide Association StudiesPsychiatric GeneticsDisease Susceptibility AllelesDisease-specific Risk AllelesGenome-wide Association MappingGenome-wide Association Study Design
Autism spectrum disorders have a substantial genetic basis, but most known risk is due to rare variants such as copy number variants. The study aims to identify common genetic variants associated with autism spectrum disorders. The Autism Genome Project genotyped 1,558 ASD families for one million SNPs and performed association analyses. A genome‑wide association study identified the SNP rs4141463 in MACROD2 as reaching significance (P < 5 × 10⁻⁸) in one primary analysis, with replication confirming over‑transmission but a reduced effect size; exploratory subtype analyses revealed no significant associations after correction, though several other genes (KIAA0564, PLD5, POU6F2, ST8SIA2, TAF1C) showed strong signals.
Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.