Background: Body mass index (BMI)-associated loci are used to explore causal relations of obesity using Mendelian Randomization (MR), but contribution of individual tissues to the risks remain unknown. We aimed to identify tissue-specific 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-specific gene sets based on mRNA expression profiles from 77 previously published BMI-associated loci. We conducted two-sample MR with inverse variance weighted methods, to examine associations between tissue-specific BMI-associated genetic instruments and type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD), with use of summary-level data from published genome-wide association studies (T2DM: 74,124 cases, 824,006 controls; CHD: 60,801 cases, 123,504 controls). 
Results: We identified eight partly overlapping tissue-specific gene sets, of which five were brain areas, where BMI-associated genes were differentially expressed. In tissue-specific MR analyses, six gene sets were associated with increased risks of both T2DM and CHD. In contrast, the BMI-associated substantia nigra gene set was related to risk of T2DM (OR 1.9, 1.2;3.1), but not CHD (OR 0.9, 0.7;1.3). Similarly, the set of BMI-associated genetic variants from the cortex was related to increased risk of T2DM (OR 2.0, 1.5;2.7), and attenuated risk of CHD (OR 1.2, 0.9;1.5).
Conclusion: Tissue-specific MR analyses revealed increased risk of T2DM, but not of CHD for BMI-associated gene sets expressed in the substantia nigra and cortex. Our novel approach provides insight in tissue-specific causes of a high BMI leading to cardiometabolic disease risk.

02 - THE CONTRIBUTION OF TISSUE-SPECIFIC BMI-ASSOCIATED GENE SETS TO CARDIOMETABOLIC DISEASE RISK USING MENDELIAN RANDOMIZATION