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Localizing regions in the genome contributing to ADHD, aggressive and antisocial behavior

By Mariana Lizbeth Rodriguez Lopez, Barbara Franke, Marieke Klein

Posted 29 Aug 2019
bioRxiv DOI: 10.1101/750091

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder. ADHD co-morbidities cover a broad range of traits, including aggressive behavior (AGG) and antisocial behavior (ASB). Genetics has a high percentage on the heritability of the three traits, mainly attributed to large numbers of common variants (SNPs) with very small effect sizes. We believe that some of this common variants could give insights to other elements overlapping between ADHD, AGG and ASB. Therefore, we worked at regions where these variants group are, tested how some of these regions contribute and looked for candidate genes within these. Methods: We tested for genome-wide genetic correlations using LD score regression analysis (LDSC), followed by analyses for local SNP-based heritability and cross-trait analyses for local genetic correlations. Propective genes were followed up by further investigations of gene expression patterns and genetic associations with structural subcortical brain volumes. Results: ADHD, AGG and ASB showed global positive genetic correlations among them, but also with neuroticism. Negative global genetic correlations were observed between ADHD, AGG, ASB and Primary Sclerosing Cholangitis. At the locus level, large heterogeneity between regions was observed. Cross-trait comparisons revealed 53 shared loci of interest and prioritized 20 genes which are expressed in the human brain and showed association with subcortical brain volumes. Conclusions: This study emphasizes the importance of investigating shared genetic effects between correlated traits at the locus level. Converging evidence from different cross-trait analyses approaches highlights novel candidate genes underlying the shared biological mechanisms of ADHD, AGG and ASB.

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