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.
Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Overview publication
| Title | 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. |
| Date | September 15th, 2020 |
| Issue name | Biological psychiatry |
| Issue number | v88.6:470-479 |
| DOI | 10.1016/j.biopsych.2020.05.002 |
| Authors | |
| Info | Agbessi M, Ahsan H, Alves I, Andiappan A, Arindrarto W, Awadalla P, Battle A, Beutner F, Bonder MJ, Boomsma DI, Christiansen M, Claringbould A, Deelen P, Esko T, Favé MJ, Franke L, Frayling T, Gharib SA, Gibson G, Heijmans BT, Hemani G, Jansen R, Kähönen M, Kalnapenkis A, Kasela S, Kettunen J, Kim Y, Kirsten H, Kovacs P, Krohn K, Kronberg-Guzman J, Kukushkina V, Kutalik Z, Lee B, Lehtimäki T, Loeffler M, Marigorta UM, Mei H, Milani L, Montgomery GW, Müller-Nurasyid M, Nauck M, Nivard M, Penninx B, Perola M, Pervjakova N, Pierce BL, Powell J, Prokisch H, Psaty BM, Raitakari OT, Ripatti S, Rotzschke O, Rüeger S, Saha A, Scholz M, Schramm K, Seppälä I, Slagboom EP, Stehouwer CDA, Stumvoll M, Sullivan P, 't Hoen PAC, Teumer A, Thiery J, Tong L, Tönjes A, van Dongen J, van Iterson M, van Meurs J, Veldink JH, Verlouw J, Visscher PM, Völker U, Võsa U, Westra HJ, Wijmenga C, Yaghootkar H, Yang J, Zeng B, Zhang F, Heijmans BT, 't Hoen PAC, van Meurs J, Isaacs A, Jansen R, Franke L, Boomsma DI, Pool R, van Dongen J, Hottenga JJ, van Greevenbroek MM, Stehouwer CDA, van der Kallen CJH, Schalkwijk CG, Wijmenga C, Franke L, Zhernakova S, Tigchelaar EF, Slagboom PE, Beekman M, Deelen J, van Heemst D, Veldink JH, van den Berg LH, van Duijn CM, Hofman BA, Isaacs A, Uitterlinden AG, van Meurs J, Jhamai PM, Verbiest M, Suchiman HED, Verkerk M, van der Breggen R, van Rooij J, Lakenberg N, van Iterson M, van Galen M, Bot J, Zhernakova DV, Jansen R, Hof PV', Deelen P, Nooren I, Heijmans BT, Moed M, Franke L, Vermaat M, Zhernakova DV, Luijk R, Bonder MJ, van Iterson M, Deelen P, van Dijk F, van Galen M, Arindrarto W, Kielbasa SM, Swertz MA, van Zwet EW, Jansen R, Hoen P', Heijmans BT |
| Keywords | Fetal brain, Pleiotropy, Psychiatric disorders, SMR, eQTL, mQTL |
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