Assessing the Genetic Contribution of Cumulative Behavioral Factors Associated with Longitudinal Type 2 Diabetes Risk Highlights Adiposity and the Brain-metabolic Axis

Overview

Journal medRxiv

Date 2024 Feb 14

PMID 38352440

Authors

Nuno R G Carvalho

Yixuan He

Patrick Smadbeck

Jason Flannick

Josep M Mercader

Miriam Udler

Arjun K Manrai

Jordi Moreno

Chirag J Patel

Affiliations

Soon will be listed here.

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 (h = 0.18) extensive shared genetic architecture with established clinical and biological determinants of T2D, most prominently with body mass index (genetic correlation [r] = 0.57) and Homeostatic Model Assessment for Insulin Resistance (r = 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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