Language

English

Publication Date

2-1-2024

Journal

Nature Metabolism

DOI

10.1038/s42255-023-00970-0

PMID

38278947

PMCID

PMC10896722

PubMedCentral® Posted Date

1-26-2024

PubMedCentral® Full Text Version

Post-print

Abstract

The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily1, producing a growing public health concern1 that disproportionately affects minority groups2. The genetic basis of youth-onset T2D and its relationship to other forms of diabetes are unclear3. Here we report a detailed genetic characterization of youth-onset T2D by analysing exome sequences and common variant associations for 3,005 individuals with youth-onset T2D and 9,777 adult control participants matched for ancestry, including both males and females. We identify monogenic diabetes variants in 2.4% of individuals and three exome-wide significant (P < 2.6 × 10−6) gene-level associations (HNF1A, MC4R, ATXN2L). Furthermore, we report rare variant association enrichments within 25 gene sets related to obesity, monogenic diabetes and β-cell function. Many youth-onset T2D associations are shared with adult-onset T2D, but genetic risk factors of all frequencies—and rare variants in particular—are enriched within youth-onset T2D cases (5.0-fold increase in the rare variant and 3.4-fold increase in common variant genetic liability relative to adult-onset cases). The clinical presentation of participants with youth-onset T2D is influenced in part by the frequency of genetic risk factors within each individual. These findings portray youth-onset T2D as a heterogeneous disease situated on a spectrum between monogenic diabetes and adult-onset T2D.

Keywords

Male, Adult, Female, Humans, Adolescent, Child, Diabetes Mellitus, Type 2, Pediatric Obesity, Exome, Genome-Wide Association Study, Biology, Diabetes, Population genetics, Metabolism, Genetics, Endocrine system and metabolic diseases

Published Open-Access

yes

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