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 language | English |
|---|---|
| Pages (from-to) | 470-479 |
| Number of pages | 10 |
| Journal | Biological Psychiatry |
| Volume | 88 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 15 Sept 2020 |
Bibliographical note
Funding Information:This work was supported by strategic funding from the University of Queensland and the Children’s Hospital Foundation (to ARH); the European Union Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie Grant No. 721567 (CAPICE [Childhood and Adolescence Psychopathology: unraveling the complex etiology by a large Interdisciplinary Collaboration in Europe] [to CMM]); National Health and Medical Research Council Grant Nos. 1113400 (to NRW) and 1078901 (to NRW); European Research Council Consolidator Grant No. ERC-COG WELL-BEING 771057 (to MB); and the National Health and Medical Research Council of Australia Grant Nos. 1087889, 1145645, 1113400, 1078901, and 1078037 (to EMB).
Funding Information:
This work was supported by strategic funding from the University of Queensland and the Children's Hospital Foundation (to ARH); the European Union Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie Grant No. 721567 (CAPICE [Childhood and Adolescence Psychopathology: unraveling the complex etiology by a large Interdisciplinary Collaboration in Europe] [to CMM]); National Health and Medical Research Council Grant Nos. 1113400 (to NRW) and 1078901 (to NRW); European Research Council Consolidator Grant No. ERC-COG WELL-BEING 771057 (to MB); and the National Health and Medical Research Council of Australia Grant Nos. 1087889, 1145645, 1113400, 1078901, and 1078037 (to EMB). We thank the research participants and employees of 23andMe, Inc. for contributing to this study. We thank T. Qi for providing analysis scripts for MeCS (meta-analyze cis-eQTL data in correlated samples) analyses. The authors report no biomedical financial interests or potential conflicts of interest. Mawuss? Agbessi1, Habibul Ahsan2, Isabel Alves1, Anand Andiappan3, Wibowo Arindrarto4, Philip Awadalla1, Alexis Battle5,6, Frank Beutner7, Marc Jan Bonder8,9,10, Dorret I Boomsma11, Mark Christiansen12, Annique Claringbould8, Patrick Deelen8,13, T?nu Esko14, Marie-Julie Fav?1, Lude Franke8, Timothy Frayling15, Sina A. Gharib16,12, Gregory Gibson17, Bastiaan T. Heijmans4, Gibran Hemani18, Rick Jansen19, Mika K?h?nen20, Anette Kalnapenkis14, Silva Kasela14, Johannes Kettunen21, Yungil Kim6,22, Holger Kirsten23, Peter Kovacs24, Knut Krohn25, Jaanika Kronberg-Guzman14, Viktorija Kukushkina14, Zoltan Kutalik26, Bernett Lee3, Terho Lehtim?ki27, Markus Loeffler23, Urko M. Marigorta17, Hailang Mei4, Lili Milani14, Grant W. Montgomery28, Martina M?ller-Nurasyid29,30,31, Matthias Nauck32,33, Michel Nivard11, Brenda Penninx19, Markus Perola34, Natalia Pervjakova14, Brandon L. Pierce2, Joseph Powell35, Holger Prokisch36,37, Bruce M. Psaty12,38,39, Olli T. Raitakari40, Samuli Ripatti41, Olaf Rotzschke3, Sina R?eger26, Ashis Saha6, Markus Scholz23, Katharina Schramm29,30,31, Ilkka Sepp?l?27, Eline P. Slagboom4, Coen D.A. Stehouwer42, Michael Stumvoll43, Patrick Sullivan44, Peter A.C. ?t Hoen45, Alexander Teumer46, Joachim Thiery47, Lin Tong2, Anke T?njes43, Jenny van Dongen11, Maarten van Iterson4, Joyce van Meurs48, Jan H. Veldink49, Joost Verlouw48, Peter M. Visscher28, Uwe V?lker50, Urmo V?sa8,14, Harm-Jan Westra8, Cisca Wijmenga8, Hanieh Yaghootkar15, Jian Yang28,51, Biao Zeng17, Futao Zhang28
Publisher Copyright:
© 2020 Society of Biological Psychiatry