Distinct pathway-based effects of blood pressure and body mass index on cardiovascular traits: comparison of novel Mendelian Randomization approaches

Background Mendelian randomization (MR) leverages genetic variants as instrumental variables to determine causal relationships in epidemiology. However, challenges persist due to heterogeneity arising from horizontal pleiotropy. On the other hand, exploration of the biological underpinnings of such heterogeneity across variants can enhance our understanding of disease mechanisms and inform therapeutic strategies. Here, we introduce a new approach to instrument partitioning based on enrichment of Mendelian disease categories and compare it to a method based on genetic colocalisation in contrasting tissues. Methods We employed one-sample and two-sample MR methodologies using blood pressure (BP) exposure SNPs grouped by proximity to Mendelian disease genes affecting the renal system or vasculature, or body mass index (BMI) variants related to mental health and metabolic Mendelian disorders. We then compared the causal effects of Mendelian-partitioned SNPs on cardiometabolic outcomes with subsets inferred from gene expression colocalisation in kidney, artery (for BP), adipose, and brain tissues (for BMI). Additionally, we assessed whether effects from these groupings could emerge by chance using random SNP subset sampling. Results Our findings suggest that the causal relationship between systolic BP and coronary heart disease is predominantly driven by SNPs associated with vessel- related Mendelian diseases over renal. However, kidney-oriented SNPs showed more pronounced effect size in the colocalization-based analysis, hinting at a multifaceted interplay between pathways in the disease aetiology. We consistently identified a dominant role of Mendelian vessel and coloc artery exposures in driving the negative effect of diastolic BP on left ventricular stroke volume and positive effect of systolic BP on type 2 diabetes. We also found higher causal estimates for metabolic versus mental health SNPs when dissecting BMI pathway contribution to atrial fibrillation risk using Mendelian disease. In contrast, brain variants yielded higher causal estimates than adipose in the colocalization method. Conclusions This study presents a novel approach to dissecting heterogeneity in MR by integrating clinical phenotypes associated with Mendelian disease. Our findings emphasize the importance of understanding tissue-/pathway- specific contributions in interpreting causal relationships in MR. Importantly, we advocate caution in interpreting pathway-partitioned effect size differences without robust statistical validation. ### Competing Interest Statement TRG receives funding from Biogen for unrelated research. TGR is a full-time employee of GlaxoSmithKline outside of this research. ### Funding Statement This work was funded by the UK Medical Research Council (MRC) as part of the MRC Integrative Epidemiology Unit (MC\_UU\_00032/03). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: GWAS summary statistics availability is provided by relevant publications. We accessed the following summary statistics via OpenGWAS: ebi-a-GCST006414, ebi-a-GCST006906, ebi-a-GCST009541, ieu-a-7, ieu-a-26, ieu-a-798, ieu-b-38, ieu-b-39, ieu-b-40. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes GWAS summary statistics availability is provided by relevant publications. We accessed the following summary statistics via OpenGWAS: ebi-a-GCST006414, ebi-a-GCST006906, ebi-a-GCST009541, ieu-a-7, ieu-a-26, ieu-a-798, ieu-b-38, ieu-b-39, ieu-b-40.