Common genetic risk variants identified in the SPARK cohort implicate DDHD2 as a novel autism risk gene

Abstract

Background: Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of three common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants are expected to contribute to ASD risk given the high heritability. Here, we performed a genome-wide association study (GWAS) using the Simons Foundation Powering Autism Research for Knowledge (SPARK) dataset to identify additional common genetic risk factors and molecular mechanisms underlying risk for ASD. Methods: We performed an association study on 6,222 case-pseudocontrol pairs from SPARK and meta-analyzed with a previous GWAS. We integrated gene regulatory annotations to map non-coding risk variants to their regulated genes. Further, we performed a massively parallel reporter assay (MPRA) to identify causal variant(s) within a novel risk locus. Results: We identified one novel GWS locus from the SPARK GWAS. The meta-analysis identified four significant loci, including an additional novel locus. We observed significant enrichment of ASD heritability within regulatory regions of the developing cortex, indicating that disruption of gene regulation during neurodevelopment is critical for ASD risk. The MPRA identified one variant at the novel locus with strong impacts on gene regulation (rs7001340), and expression quantitative trait loci data demonstrated an association between the risk allele and decreased expression of DDHD2 (DDHD domain containing 2) in both adult and pre-natal brains. Conclusions: By integrating genetic association data with multi-omic gene regulatory annotations and experimental validation, we fine-mapped a causal risk variant and demonstrated that DDHD2 is a novel gene associated with ASD risk.

Evaluating brain structure traits as endophenotypes using polygenicity and discoverability

“…We first obtained GWAS summary statistics of various traits including cortical and subcortical brain structure [Grasby et al, 2020;Hibar et al, 2017;Satizabal et al, 2019]), neuropsychiatric disorders and cognitive phenotypes [Demontis et al, 2019;Howard et al, 2019;Liu et al, 2019;Matoba et al, 2020;Pardiñas et al, 2018;Ripke et al, 2013;Savage et al, 2018; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014; Stahl et al, 2019;Watanabe et al, 2019;Wray et al, 2018], and anthropometric measurements [Yengo et al, 2018] (Supplementary Table 1). All of the GWASs were performed in European ancestries.…”

“…Second, mechanistic insight, because those variants associated with an endophenotype also influence risk for neuropsychiatric disorders, endophenotype associations are informative about the mechanisms leading to risk for neuropsychiatric disorders. Genome-wide association studies (GWAS) have identified common genetic variants associated with many traits, including brain structure [Adams et al, 2016;Elliott et al, 2018;Grasby et al, 2020;Hibar et al, 2015;Hibar et al, 2017;Satizabal et al, 2019;Stein et al, 2012;Zhao et al, 2020] and risk for neuropsychiatric disorders [Demontis et al, 2019;Howard et al, 2019;Matoba et al, 2020;Pardiñas et al, 2018;Stahl et al, 2019]. GWAS results from large sample sizes allow for the comparison of common variant genetic architectures between traits [Watanabe et al, 2019] and the direct evaluation of these endophenotype properties.…”

Genetic effects on brain traits impact cell-type specific gene regulation during neurogenesis

“…Genome wide association studies (GWAS) have identified many common non-coding variants associated with risk for brain structure, neurodevelopmental disorders, and other brain-related traits [1][2][3][4][5][6][7] . However, it is challenging to determine the mechanism of non-coding variants because, in general, (1) the genes impacted by non-coding risk variants are unknown, (2) the cell type(s) and developmental period(s) where the variants have an effect are not known, (3) and there may be limited availability of tissue representing the causal developmental stage and cell type.…”