Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome

• DOI: 10.1371/journal.pgen.1009224
• Publication Date: 2021-01-08T20:51:02Z
• Authors: Denis A. Baird; Jimmy Z. Liu; Jie Zheng; Solveig K. Sieberts; Thanneer Perumal; Benjamin Elsworth; Tom G. Richardson; Chia-Yen Chen; Minerva M. Carras...; Mariet Allen; Joseph S. Reddy; Philip L. De Jager; Nilufer Ertekin-T...; Lara M. Mangravite; Ben Logsdon; Karol Estrada; Philip C. Haycock; Gibran Hemani; Heiko Runz; George Davey Smith; Tom R. Gaunt
• Keywords: Mendelian Randomization; Genome-wide Association Study

Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants modulate the expression of potential drug targets can be utilized to assess efficacy therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene measured in tissue identify involved neurological and psychiatric diseases. conducted a two-sample MR using cis-acting brain-derived quantitative trait loci (eQTLs) from Accelerating Medicines Partnership for Alzheimer’s Disease consortium (AMP-AD) CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments predict effects 7,137 genes 12 disorders. Bayesian colocalization analysis top findings (using P<6x10 -7 evidence threshold, Bonferroni-corrected 80,557 tests) confirm sharing same causal between each genomic region. then intersected colocalized with known monogenic disease recorded Online Inheritance Man (OMIM) annotated Open Targets platform promising targets. 80 eQTLs showed effect, which we prioritised 47 based trait. causally linked 23 schizophrenia single anorexia, bipolar disorder major depressive within 9 disease, 6 Parkinson’s 4 multiple sclerosis two amyotrophic lateral tested. From these identified five ( ACE , GPNMB KCNQ5 RERE SUOX ) attractive may warrant follow-up functional studies clinical trials, demonstrating value this design discovering neuropsychiatric