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Assessing the genetic contribution of cumulative behavioral factors associated with longitudinal type 2 diabetes risk highlights adiposity and the brain-metabolic axis

Carvalho, N.; He, Y.; Smadbeck, P.; Flannick, J.; Mercader, J.; Udler, M.; Manrai, A. K.; Merino, J.; Patel, C. J.

2024-01-31 endocrinology
10.1101/2024.01.30.24302019 medRxiv
Show abstract

While genetic factors, behavior, and environmental exposures form a complex web of interrelated associations in type 2 diabetes (T2D), their interaction is poorly understood. Here, using data from [~]500K participants of the UK Biobank, we identify the genetic determinants of a "polyexposure risk score" (PXS) a new risk factor that consists of an accumulation of 25 associated individual-level behaviors and environmental risk factors that predict longitudinal T2D incidence. PXS-T2D had a non-zero heritability (h2 = 0.18) extensive shared genetic architecture with established clinical and biological determinants of T2D, most prominently with body mass index (genetic correlation [rg] = 0.57) and Homeostatic Model Assessment for Insulin Resistance (rg = 0.51). Genetic loci associated with PXS-T2D were enriched for expression in the brain. Biobank scale data with genetic information illuminates how complex and cumulative exposures and behaviors as a whole impact T2D risk but whose biology have been elusive in genome-wide studies of T2D.

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