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

Denis Baird ,Heiko Runz,Karol Estrada,Gibran Hemani,Lara M Mangravite,George Davey Smith,Jie Zheng,Philip L De Jager,Benjamin Elsworth,Minerva M Carrasquillo,Joseph S Reddy,Mariet Allen,Tom R Gaunt,Solveig K Sieberts,Yushi Liu ,Thanneer M Perumal ,Nilüfer Ertekin-Taner ,Tom G Richardson ,Chia Yen Chen ,Benjamin A Logsdon ,Philip Haycock

doi:10.1371/journal.pgen.1009224

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.

Highlights

There is a compelling need to improve the processes to discover new drugs for human disease, which is time consuming and expensive, with high rates of attrition [1]
Genetic association studies have been successful in identifying many genetic variants associated with disease risk, but it has been far more challenging to determine the genes through which these act
We used Mendelian randomization (MR) and colocalization, two methods which in combination exploit these genetic variants to estimate the causal effects of individual genes

Summary

Introduction

There is a compelling need to improve the processes to discover new drugs for human disease, which is time consuming and expensive, with high rates of attrition [1]. Attrition rates have been high for therapies against brain-related diseases. A survey of 413 Alzheimer’s disease trials reported a failure rate of 99.6% [2]. Neurological and psychiatric diseases are highly heritable [3]. Genome-wide association studies (GWAS) have identified numerous genetic loci associated with disease risk [4,5], and can provide evidence to identify molecular pathways involved in disease that can be intervened on by drugs. Drug targets with human genetic evidence are more than twice as likely to be approved than those without [6,7]

Methods

Results

Discussion

Conclusion