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Refining Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Genetic Loci by Integrating Summary Data From Genome-wide Association, Gene Expression, and DNA Methylation Studies

      Abstract

      Background

      Recent genome-wide association studies (GWASs) identified the first genetic loci associated with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The next step is to use these results to increase our understanding of the biological mechanisms involved. Most of the identified variants likely influence gene regulation. The aim of the current study is to shed light on the mechanisms underlying the genetic signals and prioritize genes by integrating GWAS results with gene expression and DNA methylation (DNAm) levels.

      Methods

      We applied summary-data–based Mendelian randomization to integrate ADHD and ASD GWAS data with fetal brain expression and methylation quantitative trait loci, given the early onset of these disorders. We also analyzed expression and methylation quantitative trait loci datasets of adult brain and blood, as these provide increased statistical power. We subsequently used summary-data–based Mendelian randomization to investigate if the same variant influences both DNAm and gene expression levels.

      Results

      We identified multiple gene expression and DNAm levels in fetal brain at chromosomes 1 and 17 that were associated with ADHD and ASD, respectively, through pleiotropy at shared genetic variants. The analyses in brain and blood showed additional associated gene expression and DNAm levels at the same and additional loci, likely because of increased statistical power. Several of the associated genes have not been identified in ADHD and ASD GWASs before.

      Conclusions

      Our findings identified the genetic variants associated with ADHD and ASD that likely act through gene regulation. This facilitates prioritization of candidate genes for functional follow-up studies.

      Keywords

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      Linked Article

      • Integrative Genomics for the Interpretation of Genetic Loci Implicated in Neurodevelopmental Disorders
        Biological PsychiatryVol. 88Issue 6
        • Preview
          Our understanding of neuropsychiatric disorders has gained tremendous progress with the advancement of genetics studies, both in establishing the high heritability for these classes of disorders and through the identification of specific genetic associations (1). Large-scale genetic studies—both rare-variant, family-based studies and common variant, genome-wide association studies (GWASs)—have uncovered the genetic architecture of neuropsychiatric disease and implicate common variants as the largest contributor to disease liability for the majority of these disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder (2).
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