The contribution of tissue-grouped BMI-associated gene sets to cardiometabolic-disease risk: a Mendelian randomization study. (4th June 2020)

• Record Type: Journal Article
• Authors: Verkouter, Inge; de Mutsert, Renée; Smit, Roelof A J; Trompet, Stella; Rosendaal, Frits R; van Heemst, Diana; Willems van Dijk, Ko; Noordam, Raymond
• Is Part Of: International journal of epidemiology. Volume 49:Number 4(2020)
• Page Start: 1246
• Page End: 1256
• Publication Date: 2020-06-04
• Subjects: Mendelian randomization analysis -- body mass index -- type 2 diabetes mellitus -- coronary artery disease -- waist circumference -- anthropometry; Epidemiology -- Periodicals; 614.4
• DOI: 10.1093/ije/dyaa070
• Languages: English
• ISSNs: 0300-5771

Abstract

Abstract: Background: Body mass index (BMI)-associated loci are used to explore the effects of obesity using Mendelian randomization (MR), but the contribution of individual tissues to risks remains unknown. We aimed to identify tissue-grouped pathways of BMI-associated loci and relate these to cardiometabolic disease using MR analyses. Methods: Using Genotype-Tissue Expression (GTEx) data, we performed overrepresentation tests to identify tissue-grouped gene sets based on mRNA-expression profiles from 634 previously published BMI-associated loci. We conducted two-sample MR with inverse-variance-weighted methods, to examine associations between tissue-grouped BMI-associated genetic instruments and type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), with use of summary-level data from published genome-wide association studies (T2DM: 74 124 cases, 824 006 controls; CAD: 60 801 cases, 123 504 controls). Additionally, we performed MR analyses on T2DM and CAD using randomly sampled sets of 100 or 200 BMI-associated genetic variants. Results: We identified 17 partly overlapping tissue-grouped gene sets, of which 12 were brain areas, where BMI-associated genes were differentially expressed. In tissue-grouped MR analyses, all gene sets were similarly associated with increased risks of T2DM and CAD. MR analyses with randomly sampled genetic variants on T2DM and CAD resulted in a distribution of effect estimates similar to tissue-grouped gene sets. Conclusions: Overrepresentation tests revealed differential expression of BMI-associated genes in 17 different tissues. However, with our biology-based approach using tissue-grouped MR analyses, we did not identify different risks of T2DM or CAD for the BMI-associated gene sets, which was reflected by similar effect estimates obtained by randomly sampled gene sets.