ABSTRACT
Autism spectrum disorder (ASD) is a neurodevelopmental condition that results in behavioral, social and communication impairments. ASD has a substantial genetic component, with 88-95% trait concordance among monozygotic twins. Efforts to elucidate the causes of ASD have uncovered hundreds of susceptibility loci and candidate genes. However, owing to its polygenic nature and clinical heterogeneity, only a few of these markers represent clear targets for further analyses. In the present study, we used the linkage structure associated with published genetic markers of ASD to simultaneously improve candidate gene detection while providing a means of prioritizing markers of common genetic variation in ASD. We first mined the literature for linkage and association studies of single-nucleotide polymorphisms, copy-number variations and multi-allelic markers in Autism Genetic Resource Exchange (AGRE) families. From markers that reached genome-wide significance, we calculated male-specific genetic distances, in light of the observed strong male bias in ASD. Four of 67 autism-implicated regions, 3p26.1, 3p26.3, 3q25-27 and 5p15, were enriched with differentially expressed genes in blood and brain from individuals with ASD. Of 30 genes differentially expressed across multiple expression data sets, 21 were within 10 cM of an autism-implicated locus. Among them, CNTN4, CADPS2, SUMF1, SLC9A9, NTRK3 have been previously implicated in autism, whereas others have been implicated in neurological disorders comorbid with ASD. This work leverages the rich multimodal genomic information collected on AGRE families to present an efficient integrative strategy for prioritizing autism candidates and improving our understanding of the relationships among the vast collection of past genetic studies.
Subject(s)
Child Development Disorders, Pervasive/genetics , Genetic Markers/genetics , Haplotypes/genetics , Child , Female , Genes/genetics , Genetic Linkage/genetics , Humans , Male , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide/genetics , Sex Factors , Transcriptome/geneticsABSTRACT
Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.