Insights from rare variants into the genetic architecture and biology of youth-onset type 2 diabetes.

Abstract

Youth-onset type 2 diabetes (T2D) is a growing public health concern. Its genetic basis and relationship to other forms of diabetes are largely unknown. To gain insight into the genetic architecture and biology of youth-onset T2D, we analyzed exome sequences of 3,005 youth-onset T2D cases and 9,777 ancestry matched adult controls. We identified (a) monogenic diabetes variants in 2.1% of individuals; (b) two exome-wide significant (P < 4.3×10-7) common coding variant associations (in WFS1 and SLC30A8); (c) three exome-wide significant (P < 2.5×10-6) rare variant gene-level associations (HNF1A, MC4R, ATX2NL); and (d) rare variant association enrichments within 25 gene sets broadly related to obesity, monogenic diabetes, and β-cell function. Many association signals were shared between youth-onset and adult-onset T2D but had larger effects for youth-onset T2D risk (1.18-fold increase for common variants and 2.86-fold increase for rare variants). Both common and rare variant associations contributed more to youth-onset T2D liability variance than they did to adult-onset T2D, but the relative increase was larger for rare variant associations (5.0-fold) than for common variant associations (3.4-fold). Youth-onset T2D cases showed phenotypic differences depending on whether their genetic risk was driven by common variants (primarily related to insulin resistance) or rare variants (primarily related to β-cell dysfunction). These data paint a picture of youth-onset T2D as a disease genetically similar to both monogenic diabetes and adult-onset T2D, in which genetic heterogeneity might be used to sub-classify patients for different treatment strategies.

• Authors: Soo Heon Kwak, Shylaja Srinivasan, Ling Chen, Jennifer Todd, Josep Mercader, Elizabeth Jensen, Jasmin Divers, Amy Mottl, Catherine Pihoker, Rachelle Gandica, Lori Laffel, Elvira Isganaitis, Morey Haymond, Lynne Levitsky, Toni Pollin, Jose Florez, Jason Flannick
• Journal: Research square (Res Sq) (May 18 2023) United States
• PMID: 37292813 (Publication Type: Preprint)