The contribution of tissue-grouped BMI-associated gene sets to cardiometabolic-disease risk: a Mendelian randomization study

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.

Keywords: Mendelian randomization analysis; anthropometry; body mass index; coronary artery disease; type 2 diabetes mellitus; waist circumference.

Figure 1

The analysis procedure. (i) We selected 656 single nucleotide polymorphisms (SNPs) independently associated with BMI. (ii) Using the SNP2GENE function in the FUMA web application, gene annotation was performed for the selected SNPs based on positional mapping obtained from Annotate Variation (ANNOVAR). In this step, 22 SNPs were omitted based on a r² threshold of ≥0.6. (iii) The 634 BMI-associated genes were grouped into 17 tissue-grouped gene sets using the GENE2FUNC function in Functional Mapping and Annotation (FUMA). These gene sets were based on differential gene expression in different tissues with the use of GTEx version 8. (iv) The 17 tissue-grouped gene sets were used as exposures in Mendelian randomization (MR) analyses, with the outcomes type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), waist circumference and total body fat. The genetic instrument rs7903146 was removed from the gene sets (and thereby all MR analyses) given its pleiotropic effect.

Figure 2

Based on the analyses using GTEx v8 54 tissue-types data, we identified 17 tissues in which body mass index (BMI)-associated genes were differentially expressed, indicated by black/red bars. (A) Was directly taken from the online tool Functional Mapping and Annotation (FUMA). (B) Clustering of the BMI-associated genes in the tissue-grouped gene sets. Differentially expressed genes in a given tissue are shown in black/red; grey/blue indicates no differential expression in a given tissue.

Figure 2

Based on the analyses using GTEx v8 54 tissue-types data, we identified 17 tissues in which body mass index (BMI)-associated genes were differentially expressed, indicated by black/red bars. (A) Was directly taken from the online tool Functional Mapping and Annotation (FUMA). (B) Clustering of the BMI-associated genes in the tissue-grouped gene sets. Differentially expressed genes in a given tissue are shown in black/red; grey/blue indicates no differential expression in a given tissue.

Figure 3

Histograms displaying the distribution of odds ratios [from inverse-variance weighted (IVW) analyses] for the association between randomly sampled sets of 100 or 200 genetic variants and type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). (A) Random sample of 100 genetic variants—T2DM. (B) Random sample of 200 genetic variants—T2DM. (C) Random sample of 100 genetic variants—CAD. (D) Random sample of 200 genetic variants—CAD.