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

Nuno R G Carvalho; Yixuan He; Patrick Smadbeck; Jason Flannick; Josep M Mercader; Miriam Udler; Arjun K Manrai; Jordi Moreno; Chirag J Patel

doi:10.1101/2024.01.30.24302019

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

medRxiv [Preprint]. 2024 Jan 31:2024.01.30.24302019. doi: 10.1101/2024.01.30.24302019.

Authors

Nuno R G Carvalho¹, Yixuan He^{2

3

4}, Patrick Smadbeck², Jason Flannick^{2

5

6}, Josep M Mercader², Miriam Udler², Arjun K Manrai⁷, Jordi Moreno^{2

8

9}, Chirag J Patel⁷

Affiliations

¹ School of Biological Sciences; Georgia Institute of Technology; Atlanta, GA, 30332, USA.
² Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Boston, MA, 02142, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁵ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, 02115, USA.
⁶ Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
⁷ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA.
⁸ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
⁹ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.

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 [r_g] = 0.57) and Homeostatic Model Assessment for Insulin Resistance (r_g = 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.

Keywords: behavior; cardiometabolic health; gene-environment correlation; individual-level exposures; polyexposure; shared environment; type 2 diabetes.

Publication types

Preprint

Abstract

Publication types

Grants and funding