Mendelian randomization integrating GWAS and eQTL data revealed genes pleiotropically associated with major depressive disorder

Abstract

Objectives: To prioritize genes that are pleiotropically or potentially causally associated with the risk of MDD. Methods: We applied the summary data-based Mendelian randomization (SMR) method integrating GWAS and expression quantitative trait loci (eQTL) data in 13 brain regions to identify genes that were pleiotropically associated with the risk of MDD. In addition, we repeated the analysis by using the meta-analyzed version of the eQTL summary data in the brain (brain-eMeta). Results: We identified multiple significant genes across different brain regions that may be involved in the pathogenesis of MDD. The prime-specific gene BTN3A2 (corresponding probe: ENSG00000186470.9) was the top hit showing pleotropic association with MDD in 9 of the 13 brain regions and in brain-eMeta, after correction for multiple testing. Many of the identified genes are located in the human major histocompatibility complex (MHC) region on chromosome 6 and are mainly involved in immune response. Conclusions: Our SMR analysis revealed that multiple genes showed pleiotropic association with MDD across the brain regions. These findings provide important leads to a better understanding of the mechanism of MDD, and reveals potential therapeutic targets for the prevention and effective treatment of MDD.

Exploring the possible causal role of the immune response to varicella-zoster virus on multiple traits: a phenome-wide Mendelian randomization study

“…The MHC region is a complex genomic region due to its linkage disequilibrium and its roles in multiple diseases [40]. Some researchers ignored this region in their MR studies [41], but concerns have been raised about possible pleiotropy when using MHC instruments.…”

CADM2is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice

“…We detected one significant hit (rs2958162, p=2.50E-10), located on chromosome 18 in the TCF4 gene, which encodes a helix-loop-helix transcription factor and is widely expressed throughout the body and during development. Polymorphisms in TCF4 have been associated with risk-taking and adventurousness (15), alcohol consumption (59), schizophrenia (60), depression (61,62), and neuroticism (63,64) (Table S9); TCF4 is also a non-GWAS candidate gene for other psychiatric and neurological conditions (65).…”