Disentangling adiposity-related and non-adiposity-related genetic pathways for type 2 diabetes

OBJECTIVETo identify circulating proteins associated with type 2 diabetes (T2D) risk through pathways not fully explained by body mass index (BMI), and to assess therapeutic actionability. RESEARCH DESIGN AND METHODSWe applied GWAS-by-subtraction within a genomic structural equation model to European ancestry summary statistics for T2D (74,124 cases, 824,006 controls) and BMI (n = 681,275), partitioning T2D liability into BMI-related and BMI-subtracted components. We then performed proteome-wide Mendelian randomization (MR) using cis-protein quantitative trait loci from four plasma proteomics cohorts: ARIC, deCODE, Fenland, and the UK Biobank Pharma Proteomics Project. Prioritized proteins passed sensitivity analyses with alternative MR methods and were supported by colocalization evidence. Tissue-resolution regulatory support was assessed using cis-eQTL colocalization across GTEx and pancreatic islet, subcutaneous adipose, and whole-blood resources. Actionability was evaluated using the druggable genome and Open Targets. RESULTSGWAS-by-subtraction attenuated the genetic correlation between BMI and BMI-subtracted T2D from 0.54 (SE 0.02) to 0.35 (SE 0.02). Proteome-wide MR prioritized 29 proteins for BMI-subtracted T2D. Thirteen showed eQTL colocalization in at least one tissue, implicating liver and intermediary metabolism (GCDH, NOTCH2), pancreatic islet biology (CTRB2, MANBA), adipose and Wnt signaling (RSPO3, GALNT3), and whole blood regulatory signals (PAM, SNUPN). Sixteen proteins were classified within druggable-genome Tiers 1-3, and five had existing Open Targets compounds. CONCLUSIONSIntegrating GWAS-by-subtraction, proteome-wide MR, and colocalization nominated 29 proteins associated with T2D liability not fully explained by BMI. These findings highlight genetically supported targets for follow-up studies of T2D therapies that complement weight-centered approaches. Article HighlightsO_LIWhy did we undertake this study? T2D is clinically and biologically heterogeneous. Although human genetics can prioritize disease-relevant pathways, T2D genetic associations are strongly influenced by body mass index (BMI), which obscures identification of targets contributing to T2D beyond adiposity. C_LIO_LIWhat is the specific question we wanted to answer? Which circulating proteins are associated with non-BMI-mediated T2D, and how actionable are they as therapeutic targets? C_LIO_LIWhat did we find? GWAS-by-subtraction, proteome-wide Mendelian randomization, and tissue-resolution colocalization prioritized 29 proteins for BMI-subtracted T2D, implicating metabolic, pancreatic-islet, signaling, and glycosylation-related pathways, with many representing pharmacologically tractable targets. C_LIO_LIWhat are the implications of our findings? These results nominate genetically informed protein targets for non-BMI-mediated T2D pathways, supporting follow-up studies of therapies that complement weight-centered approaches. C_LI