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

被引:53
作者
Matoba, Nana [1 ,2 ]
Liang, Dan [1 ,2 ]
Sun, Huaigu [1 ,2 ]
Aygun, Nil [1 ,2 ]
McAfee, Jessica C. [1 ,2 ]
Davis, Jessica E. [3 ,4 ,5 ,6 ,7 ,8 ]
Raffield, Laura M. [1 ]
Qian, Huijun [9 ]
Piven, Joseph [10 ,11 ]
Li, Yun [1 ,12 ,13 ]
Kosuri, Sriam [3 ,4 ,5 ,6 ,7 ,8 ]
Won, Hyejung [1 ,2 ]
Stein, Jason L. [1 ,2 ]
机构
[1] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA
[3] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA
[4] Univ Calif Los Angeles, UCLA DOE Inst Genom & Prote, Los Angeles, CA 90095 USA
[5] Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA
[6] Univ Calif Los Angeles, Quantitat & Computat Biol Inst, Los Angeles, CA 90095 USA
[7] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA
[8] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA
[9] Univ N Carolina, Dept Stat & Operat Res, Chapel Hill, NC 27599 USA
[10] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA
[11] Univ N Carolina, Carolina Inst Dev Disabil, Chapel Hill, NC 27599 USA
[12] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA
[13] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA
关键词
GENOME-WIDE ASSOCIATION; DE-NOVO MUTATIONS; SPECTRUM DISORDER; PHOSPHOLIPASE A(1); EXPRESSION; DISEASE; GENOTYPE; RARE; TRANSCRIPTOME; CHILDREN;
D O I
10.1038/s41398-020-00953-9
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
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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页数:14
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