Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure

Abstract

We conducted a large-scale meta-analysis of heart failure (HF) genome-wide association studies (GWAS) consisting of over 90,000 HF cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for HF. Using the GWAS results and blood protein quantitative loci (pQTLs), we performed Mendelian randomization (MR) and colocalization analyses on human proteins to provide causal evidence for the role of druggable proteins in the genesis of HF. We identified 39 genome-wide significant HF risk variants, of which 18 are previously unreported. Using a combination of MR proteomics and genetic cis-only colocalization analyses, we identified 10 additional putatively causal genes for HF. Findings from GWAS and MR-proteomics identified seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of HF.

Large-scale Mendelian randomization identifies novel pathways as therapeutic targets for heart failure with reduced ejection fraction and with preserved ejection fraction

“…Our analysis explored the causal roles of the human proteome and transcriptome on the largest HFrEF and HFpEF genetics dataset and identified 58 novel targets 8,9,[18][19][20][21][22][23] , for which we developed a therapeutic target profile encompassing efficacy, safety, and novelty of mechanism to help inform early drug discovery programs for HFrEF and HFpEF.…”

“…To define novelty of hits, we compared our findings against all previously published GWAS and MR studies in HF and HF subtypes 8,9,[18][19][20][21][22][23] and categorized hits as one of three categories: novel, partially novel, and replication. Novel genes are defined as those that have not been previously reported and are not in LD (𝑟 + < 0.4) with a variant that has been published as a GWAS hit or as an instrument used for a MR hit; for further details, see section on "assessment of confounding by LD".…”

Identification of plasma proteomic markers underlying polygenic risk of type 2 diabetes and related comorbidities

“…We performed two-sample Mendelian randomization (MR) analysis to conduct a proteome-wide scan for proteins suspected to play a potential causal role in the development of T2D, a T2D comorbidity, or a T2D complication. To identify weak instruments, we calculated the F-statistic 30 for each instrument (F-statistic = {3 2 ⁄Se 2 ). We performed MR on all proteins with 3 or more cis pQTLs using the MendelianRandomization 31 R package (version 0.7.0) and applying the simple and weighted median, IVW, and MR-Egger methods, finding the consensus effect by taking the median of the estimate, standard error, 95% confidence interval, and p-value across all methods.…”

Immunological Drivers and Potential Novel Drug Targets for Major Psychiatric, Neurodevelopmental, and Neurodegenerative Conditions

“…Open Targets have categorised target tractability based on eight buckets/groups for small molecules and nine buckets/groups for antibodies (see https://github.com/chembl/tractability_pipeline_v2). In order to aid interpretation, we categorised tractability into three mutually exclusive groups, in line with previous work 53 : Group 1. Strong druggability evidence: buckets 1, 2 & 3 for small molecules, antibodies, other modalities; Group 2.…”