Genome-wide Mendelian randomization identifies actionable novel drug targets for psychiatric disorders

Abstract

Psychiatric disorders impose tremendous economic burden on society and are leading causes of disability worldwide. However, only limited drugs are available for psychiatric disorders and the efficacy of most currently used drugs is poor for many patients. To identify novel therapeutic targets for psychiatric disorders, we performed genome-wide Mendelian randomization analyses by integrating brain-derived molecular quantitative trait loci (mRNA expression and protein abundance quantitative trait loci) of 1263 actionable proteins (targeted by approved drugs or drugs in clinical phase of development) and genetic findings from large-scale genome-wide association studies (GWASs). Using transcriptome data, we identified 25 potential drug targets for psychiatric disorders, including 12 genes for schizophrenia, 7 for bipolar disorder, 7 for depression, and 1 (TIE1) for attention deficit and hyperactivity. We also identified 10 actionable drug targets by using brain proteome data, including 4 (HLA-DRB1, CAMKK2, P2RX7, and MAPK3) for schizophrenia, 1 (PRKCB) for bipolar disorder, 6 (PSMB4, IMPDH2, SERPINC1, GRIA1, P2RX7 and TAOK3) for depression. Of note, MAPK3 and HLA-DRB1 were supported by both transcriptome and proteome-wide MR analyses, suggesting that these two proteins are promising therapeutic targets for schizophrenia. Our study shows the power of integrating large-scale GWAS findings and transcriptomic and proteomic data in identifying actionable drug targets. Besides, our findings prioritize actionable novel drug targets for development of new therapeutics and provide critical drug-repurposing opportunities for psychiatric disorders.

Fig. 1. The Manhattan plots of MR analysis results using QTLs and SCZ GWAS summary statistics (33,640 SCZ cases and 43,456 controls).

The red dashed line is the Bonferroni corrected significant level. a The MR result using GTEx brain eQTL as instruments. b The MR result using PsychENCODE eQTL as instruments. c The MR result using ROSMAP pQTL as instruments.

Fig. 2. The Manhattan plot of MR analysis using QTLs and BP GWAS summary statistics (41,917 BP cases and 371,549 controls).

The red dashed line is the Bonferroni corrected significant level. a The MR result using GTEx brain eQTL as genetic instruments. b The MR result using PsychENCODE eQTL as genetic instruments. c The MR result using ROSMAP pQTL as genetic instruments.

Fig. 3. The Manhattan plot of MR analysis result using QTLs and depression GWAS summary statistics (170,756 cases, 329,443 controls).

The red dashed line is the Bonferroni corrected significant level. a The MR result using GTEx brain eQTL as instruments. b The MR result using PsychENCODE eQTL as instruments. c The MR result using ROSMAP pQTL as instruments.

Fig. 4. The Manhattan plot of MR analysis result using QTLs and ADHD GWAS summary statistics (20,183 cases, 35,191 controls).

The red dashed line is the Bonferroni corrected significant level. a The MR result using GTEx brain eQTL as genetic instruments. b The MR result using PsychENCODE eQTL as genetic instruments. c The MR result using ROSMAP pQTL as genetic instruments.