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

Author:

Baird Denis A.ORCID,Liu Jimmy Z.ORCID,Zheng JieORCID,Sieberts Solveig K.,Perumal ThanneerORCID,Elsworth BenjaminORCID,Richardson Tom G.ORCID,Chen Chia-YenORCID,Carrasquillo Minerva M.ORCID,Allen Mariet,Reddy Joseph S.ORCID,De Jager Philip L.ORCID,Ertekin-Taner NiluferORCID,Mangravite Lara M.,Logsdon BenORCID,Estrada Karol,Haycock Philip C.ORCID,Hemani GibranORCID,Runz Heiko,Smith George DaveyORCID,Gaunt Tom R.ORCID,

Abstract

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

Funder

Biogen

CRUK/Integrative Cancer Epidemiology Programme

Wellcome Trust / Royal Society

UK Medical Research Council

National Institute on Aging

NIHR Biomedical Research Centre and the University of Bristol

Publisher

Public Library of Science (PLoS)

Subject

Cancer Research,Genetics (clinical),Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics

Reference68 articles.

1. Validating therapeutic targets through human genetics;RM Plenge;Nat Rev Drug Discov,2013

2. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures;JL Cummings;Alzheimers Res Ther,2014

3. Analysis of shared heritability in common disorders of the brain;Brainstorm Consortium;Science,2018

4. A decade in psychiatric GWAS research;T Horwitz;Mol Psychiatry,2019

5. Genome-wide association studies in neurology;M-S Tan;Ann Transl Med,2014

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