Prioritization Of Drug Targets For Neurodegenerative Diseases By Integrating Genetic And Proteomic Data From Brain And Blood

Objective: Neurodegenerative diseases are a heterogeneous group of disorders characterized by the progressive loss of vulnerable neurons and functional decline in the brain.With the aging of the population,the incidence of neurodegenerative diseases will continue to increase,which places a heavy burden on families and society.However,effective prevention and treatment strategies are rarely available in clinical practice.Moreover,an incredibly high drug development failure rate has been observed for neurodegenerative diseases.Encouragingly,historical experience indicates that drug targets supported by the genetic association are more likely to reach approval,of which proteins are the primary source of drug targets.The aim of this study was to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases.Methods: This study was based on publicly available genome-wide association study(GWAS)summary data.The brain and blood proteomic data were collected from 376 and3,301 individuals,respectively.We first selected cis-acting protein quantitative trait loci(p QTLs)as genetic instruments for Mendelian randomization(MR)under strict quality control procedures and then screened the human proteomes through MR to identify candidate causal mediators of Alzheimer’s disease(AD),Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS),multiple sclerosis(MS),frontotemporal dementia,and Lewy body dementia.Subsequently,the identified causal relationships were validated by multi-cis MR,sensitivity MR considering the aptamer-binding effects,transcriptional level MR,as well as the heterogeneity,pleiotropy,and directional tests.Bayesian colocalization was used to investigate whether the protein and the disease share a common causal variant.Replication and correlation analyses were conducted to estimate the consistency of results within and across brain and blood.Finally,we summarized the evidence of causality for all candidate drug targets and expanded our analysis pipeline to the phenome-wide to evaluate the safety by predicting the side effects resulting from targeting the proteins.The safety and druggability of identified targets were also evaluated.Results: We prioritized 16 brain-based and seven blood-based proteins as drug targets for neurodegenerative disorders,given the evidence of medium to high levels of causality.Targeting BIN1,GRN,and RET levels in blood,as well as ACE,ICA1 L,MAP1S,SLC20A2,and TOM1L2 levels in brain might reduce AD risk,while ICA1 L,SLC20A2,and TOM1L2 were not recommended as prioritized drugs due to the identified potential side-effects,such as myocardial infarction.Brain CD38,DGKQ,GPNMB,and SEC23 IP were candidate targets for PD,among which GPNMB was the most promising target.The causal relationship of GPNMB with PD was evidenced by studies on both brain and blood tissues,and the target showed robust on-target safety and druggability.Interventions targeting FCRL3,LMAN2,MAPK3 in blood and DHRS11,FAM120 B,SHMT1,TSFM in brain might affect MS risk.The risk of ALS might be reduced by medications targeting DHRS11,PSMB3,SARM1,and SCFD1 in brain.Conclusion and significance: Our study prioritized 22 proteins as potential targets for neurodegenerative diseases through comprehensive interactive approaches and evaluated their causal effects,safety,and druggability.Our findings would help elucidate the underlying mechanisms of neurodegenerative diseases and provide preliminary evidence for drug development.