Investigating regions of shared genetic variation in attention deficit/hyperactivity disorder and major depressive disorder: A GWAS meta-analysis

Abstract

Attention deficit/hyperactivity disorder (ADHD) demonstrates a high level of comorbidity with major depressive disorder (MDD). One possible contributor to this is that the two disorders show high genetic correlation. However, the specific regions of the genome that may be responsible for this overlap are unclear. To identify variants associated with both ADHD and MDD, we performed a meta-analysis of GWAS of ADHD and MDD. All genome wide significant (p=5x10 -8 ) SNPs in the meta-analysis that were also strongly associated (p=5x10 -4 ) independently with each disorder were followed up. These putatively pleiotropic SNPs were tested for additional associations across a broad range of phenotypes. Fourteen linkage disequilibrium-independent SNPs were identified that were associated with each disorder separately (p=5x10 -4 ) and in the cross-disorder meta-analysis (p=5x10 -8 ). Nine of these SNPs had not been reported previously in either individual GWAS and can be considered as novel signals. Evidence supported nine of the fourteen SNPs acting as eQTL and two of the SNPs as brain eQTL. Index SNPs and their genomic regions demonstrated associations with other mental health phenotypes. Through conducting meta-analysis on ADHD and MDD only, our results build upon the previously observed genetic correlation between ADHD and MDD and reveal novel regions of the genome that may be implicated in this overlap.

GWAS Meta-Analysis Reveals Shared Genes and Biological Pathways Between Major Depressive Disorder and Insomnia

“…The second strongest signal we identified was rs12658032 (P = 3.77 x 10-19), located in the intron of lincRNA RP11-6N13.1. This locus was not reported by Wray et al [16] or Lane et al [21] but was shown to be associated with MDD and attention deficit/hyperactivity disorder (ADHD) [41]. The third significant SNP was rs12552 (P = 5.69 x 10-16) in the 3'UTR of OLFM4, which was also reported in Wray et al [16] (Supplementary Fig.…”

The Habenula in the Link Between ADHD and Mood Disorder

“…Two GWAS meta-analyses by the Cross-Disorder Group of the Psychiatric Genomics Consortium that examined associations in five and eight psychiatric disorders have demonstrated genetic correlations of similar strengths between ADHD and MDD to those reported in other meta-analysis studies, along with identification of associations of single nucleotide polymorphisms (SNPs) on chromosomes 3p21 and 10q24 and CACNB2, the gene encoding a voltage-gated L-type calcium channel, suggesting that L-type calcium channels could be a candidate molecule linking MDD and ADHD ( Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013 , 2019 ). A GWAS meta-analysis by Powell et al also compared ADHD and MDD, identifying 14 SNPs with concordant directions of effect for both disorders, with the estimated genetic correlation being r g = 0.52 ( Powell et al, 2021 ).…”