Exploring genetic variation that influences brain methylation in attention-deficit/hyperactivity disorder
Laura Pineda-Cirera1,2,3, Anu Shivalikanjli1,3,4, Judit Cabana-Domínguez1,2,3,4
1Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.
Translational Psychiatry
|October 5, 2019
Summary
Genetic risk variants for attention-deficit/hyperactivity disorder (ADHD) are linked to allele-specific methylation (ASM), a key epigenetic mechanism. This study identified three novel genes, ARTN, PIDD1, and C2orf82, contributing to ADHD through altered gene expression.
Area of Science:
- Neuroscience
- Genetics
- Epigenetics
Background:
- Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder influenced by genetic and environmental factors.
- Epigenetics, particularly DNA methylation, plays a role in gene expression changes relevant to ADHD.
- Allele-specific methylation (ASM), where single nucleotide polymorphisms (SNPs) correlate with differential DNA methylation, is a potential mechanism in ADHD.
Purpose of the Study:
- To investigate the contribution of ASM to ADHD risk.
- To identify specific genetic risk variants associated with differential DNA methylation in ADHD.
- To explore the impact of these variants on gene expression and potential links to ADHD pathophysiology.
Main Methods:
- Utilized summary statistics from a large ADHD Genome-Wide Association Study (GWAS) meta-analysis (20,183 cases, 35,191 controls).
- Selected 3896 tagSNPs known to influence methylation in brain regions for association analysis.
- Performed case-control association study, followed by expression quantitative trait loci (eQTL) analysis in brain tissues.
Main Results:
- Genetic risk variants for ADHD were enriched in ASM SNPs.
- Identified eight significant tagSNPs associated with ADHD at a 5% false discovery rate (FDR).
- Discovered that ADHD risk alleles correlate with altered expression of three genes: ARTN (increased expression, decreased methylation), PIDD1 (increased expression, decreased methylation), and C2orf82 (decreased expression, increased methylation).
- Genetic variants in C2orf82 were also associated with brain volumes.
Conclusions:
- ADHD risk variants are associated with differential cis-methylation, highlighting ASM's role in the disorder.
- Identified three novel genes (ARTN, PIDD1, C2orf82) implicated in ADHD pathophysiology through epigenetic mechanisms.
- These findings provide new insights into the genetic and epigenetic underpinnings of ADHD.
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