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 (GWAS) 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 (SMR) to integrate ADHD and ASD GWAS data with fetal brain expression and methylation quantitative trait loci (eQTL and mQTL, respectively) given the early onset of these disorders. We also analysed eQTL and mQTL datasets of adult brain and blood as these provide increased statistical power. We subsequently used SMR 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 chromosome 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 GWAS 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.