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Autism Spectrum Disorder GWAS Highlights Common Risk Variants, Overlap With Other Conditions

NEW YORK (GenomeWeb) – An international team led by investigators in Denmark and the US has found five common genetic loci with genome-wide significant ties to autism spectrum disorder (ASD) using a genome-wide association study (GWAS) meta-analysis involving tens of thousands of individuals from Denmark.

The researchers considered 18,381 individuals with ASD and almost 28,000 unaffected control individuals from the same Danish population cohort for the meta-analysis, before incorporating prior findings from association studies on schizophrenia, major depression, and educational attainment to uncover still more loci with shared roles in ASD and one or more of the other phenotypes.

"We describe strong genetic correlations between ASD and other complex disorders and traits, confirming shared etiology, and we show results indicating differences in the polygenic architecture across clinical subtypes of ASD," co-corresponding authors Anders Børglum and Mark Daly, and their colleagues wrote.

Borglum is a human genetics, integrative sequencing, and psychiatrics researcher affiliated with Aarhus University and iPSYCH, while Daly is the chief of Massachusetts General Hospital's analytic and translational genetics unit, co-director of the Broad Institute's medical and population genetic program, and director of the University of Helsinki's Institute for Molecular Medicine Finland.

The team published its findings online today in Nature Genetics, where it went on to incorporate brain gene expression and chromatin interaction data to delve into the potential causal variants, functional roles for common risk variants, and overlap with genes containing rare ASD risk contributors.

"[W]e established an initial, robust set of common variant associations with ASD," the authors explained, "and have begun laying the groundwork through which the biology of ASD and related phenotypes will inevitably be better articulated."

For the analysis, the researchers randomly selected ASD cases and population-matched controls from the iPSYCH Danish population cohort comprised of individuals born between May, 1981 and December, 2005, using registry data to gauge ASD diagnoses.

Based on information at directly genotyped or imputed SNPs for 13,076 individuals with ASD and 22,664 controls that passed quality control steps, they searched for common variants that were over-represented in the cases in this discovery set and in a meta-analysis that encompassed another 5,305 ASD cases and 5,305 controls of European ancestry from Psychiatric Genomics Consortium trio cohorts.

The team took variants at 88 suspicious loci forward for further testing in 2,119 individuals of European ancestry with ASD and 142,379 controls, validating ASD associations for 53 loci, including five with genome-wide significant ties to the neurodevelopmental conditions.

The researchers' combined analysis, using GWAS summary data from the Broad Institute's LD Hub, led to seven loci with significant associations involving ASD and other conditions such as schizophrenia, major depression, and/or cognitive abilities based on educational attainment.

"Of these, five loci were defined in ASD alone, and seven additional [were] suggested at a stricter threshold by using GWAS results from three correlated phenotypes (schizophrenia, depression, and educational attainment) and a recently introduced analytic approach, MTAG," the authors reported.

The team's gene-centered analysis pointed to at least 15 genes that were significantly impacted by ASD-related SNPs, including genes from co-expression modules marked by intolerance for loss-of-function alterations, genes expressed in the human neocortex, and genes known for their roles in neurodevelopment.

Using data for almost 1,900 ASD cases with intellectual delay and more than 3,300 without, as well as genotypes for more than 1,600 individuals with atypical autism and 4,622 Asperger's syndrome cases, the researchers explored polygenic risk scores for distinct ASD phenotypes or subtypes.

Their functional and fine-mapping analyses, done using Hi-C mapping data and transcriptomic maps from pre- and post-natal brain samples spanning six weeks post-conception to 42 years after birth, highlighted enhancers that appear to be active in the fetal brain and other regulators contributing to cerebral cortex neurodevelopment, called corticogenesis.

"Interestingly, both common and rare variation in ASD preferentially affects genes expressed during corticogenesis, thus highlighting a potential spatiotemporal convergence of genetic risk on this specific developmental epoch, despite the disorder's profound genetic heterogeneity," the authors wrote.