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

eQTLGen Consortium, BIOS consortium, Meike Bartels, Naomi R. Wray, Christel M. Middeldorp, Holger Prokisch, Bruce M. Psaty, Olli T. Raitakari, Samuli Ripatti, Olaf Rotzschke, Sina Rüeger, Ashis Saha, Markus Scholz, Katharina Schramm, Ilkka Seppälä, P. Eline Slagboom, Coen D.a. Stehouwer, Michael Stumvoll, Patrick Sullivan, Peter A.c. ‘t HoenAlexander Teumer, Joachim Thiery, Lin Tong, Anke Tönjes, Maarten Van Iterson, Joyce Van Meurs, Jan H. Veldink, Joost Verlouw, Peter M. Visscher, Uwe Völker, Urmo Võsa, Harm-jan Westra, Cisca Wijmenga, Hanieh Yaghootkar, Jian Yang, Biao Zeng, Futao Zhang, Peter A.c. ‘t Hoen, Joyce Van Meurs, Aaron Isaacs, René Pool, Jouke J. Hottenga, Marleen Mj. Van Greevenbroek, Coen D.a. Stehouwer, Carla J.h. Van Der Kallen, Cisca Wijmenga, Sasha Zhernakova, Ettje F. Tigchelaar, P. Eline Slagboom, Marian Beekman, Joris Deelen, Diana Van Heemst, Jan H. Veldink, Leonard H. Van Den Berg, Cornelia M. Van Duijn, Bert A. Hofman, Aaron Isaacs, André G. Uitterlinden, Joyce Van Meurs, P. Mila Jhamai, Michael Verbiest, H.eka D. Suchiman, Marijn Verkerk, Ruud Van Der Breggen, Jeroen Van Rooij, Nico Lakenberg, Maarten Van Iterson, Michiel Van Galen, Jan Bot, Daria V. Zhernakova, Peter Van ‘t Hof, Irene Nooren, Matthijs Moed, Martijn Vermaat, Daria V. Zhernakova, René Luijk, Maarten Van Iterson, Michiel Van Galen, Szymon M. Kielbasa, Morris A. Swertz, Erik. W. Van Zwet, Peter-bram ‘t Hoen

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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.

Original languageEnglish
Pages (from-to)470-479
Number of pages10
JournalBiological Psychiatry
Volume88
Issue number6
Early online date16 May 2020
DOIs
Publication statusPublished - 15 Sept 2020

Keywords

  • Fetal brain
  • Pleiotropy
  • Psychiatric disorders
  • SMR
  • eQTL
  • mQTL

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