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Transl Psychiatry. 2019 Oct 3;9(1):242. doi: 10.1038/s41398-019-0574-7.

Exploring genetic variation that influences brain methylation in attention-deficit/hyperactivity disorder.

Author information

1
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.
2
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
3
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain.
4
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain.
5
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
6
Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
7
Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.
8
Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA.
9
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain. bcormand@ub.edu.
10
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. bcormand@ub.edu.
11
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain. bcormand@ub.edu.
12
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain. bcormand@ub.edu.
13
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain. noefernandez@ub.edu.
14
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. noefernandez@ub.edu.
15
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain. noefernandez@ub.edu.
16
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain. noefernandez@ub.edu.

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder caused by an interplay of genetic and environmental factors. Epigenetics is crucial to lasting changes in gene expression in the brain. Recent studies suggest a role for DNA methylation in ADHD. We explored the contribution to ADHD of allele-specific methylation (ASM), an epigenetic mechanism that involves SNPs correlating with differential levels of DNA methylation at CpG sites. We selected 3896 tagSNPs reported to influence methylation in human brain regions and performed a case-control association study using the summary statistics from the largest GWAS meta-analysis of ADHD, comprising 20,183 cases and 35,191 controls. We observed that genetic risk variants for ADHD are enriched in ASM SNPs and identified associations with eight tagSNPs that were significant at a 5% false discovery rate (FDR). These SNPs correlated with methylation of CpG sites lying in the promoter regions of six genes. Since methylation may affect gene expression, we inspected these ASM SNPs together with 52 ASM SNPs in high LD with them for eQTLs in brain tissues and observed that the expression of three of those genes was affected by them. ADHD risk alleles correlated with increased expression (and decreased methylation) of ARTN and PIDD1 and with a decreased expression (and increased methylation) of C2orf82. Furthermore, these three genes were predicted to have altered expression in ADHD, and genetic variants in C2orf82 correlated with brain volumes. In summary, we followed a systematic approach to identify risk variants for ADHD that correlated with differential cis-methylation, identifying three novel genes contributing to the disorder.

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