Common genetic risk variants identified in the SPARK cohort support DDHD2 as a candidate risk gene for autism

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of a limited number of common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants are...

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Veröffentlicht in:Translational psychiatry Jg. 10; H. 1; S. 265
Hauptverfasser: Matoba, Nana, Liang, Dan, Sun, Huaigu, Aygün, Nil, McAfee, Jessica C., Davis, Jessica E., Raffield, Laura M., Qian, Huijun, Piven, Joseph, Li, Yun, Kosuri, Sriam, Won, Hyejung, Stein, Jason L.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 03.08.2020
Nature Publishing Group
Schlagworte:
631/208
692/699/476/1373
Autism
Autism Spectrum Disorder - genetics
Autistic Disorder
Behavioral Sciences
Biological Psychology
Genome-Wide Association Study
Genomes
Humans
Medicine
Medicine & Public Health
Neurodevelopmental disorders
Neurosciences
Pharmacotherapy
Phospholipases
Polymorphism, Single Nucleotide
Psychiatry
Quantitative Trait Loci
Risk Factors
ISSN:2158-3188, 2158-3188
Online-Zugang:Volltext
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Zusammenfassung:Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of a limited number of 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) on 6222 case-pseudocontrol pairs from the Simons Foundation Powering Autism Research for Knowledge (SPARK) dataset to identify additional common genetic risk factors and molecular mechanisms underlying risk for ASD. We identified one novel GWS locus from the SPARK GWAS and four significant loci, including an additional novel locus from meta-analysis with a previous GWAS. We replicated the previous observation of 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. We further employed a massively parallel reporter assay (MPRA) and identified a putative causal variant at the novel locus from SPARK GWAS with strong impacts on gene regulation (rs7001340). 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 prenatal brains. In conclusion, 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.
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ISSN:2158-3188
2158-3188
DOI:10.1038/s41398-020-00953-9