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- Title
The contribution of tissue-grouped BMI-associated gene sets to cardiometabolic-disease risk: a Mendelian randomization study.
- Authors
Verkouter, Inge; Mutsert, Renée de; Smit, Roelof A J; Trompet, Stella; Rosendaal, Frits R; Heemst, Diana van; Dijk, Ko Willems van; Noordam, Raymond; de Mutsert, Renée; van Heemst, Diana; Willems van Dijk, Ko
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
TYPE 2 diabetes; HEART metabolism disorders; GENES; RESEARCH; SEQUENCE analysis; RESEARCH methodology; GENETIC polymorphisms; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; BODY mass index
- Publication
International Journal of Epidemiology, 2020, Vol 49, Issue 4, p1246
- ISSN
0300-5771
- Publication type
journal article
- DOI
10.1093/ije/dyaa070