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
Published Open-Access
yes
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
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.
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Community Health and Preventive Medicine Commons, Dietetics and Clinical Nutrition Commons, Endocrinology, Diabetes, and Metabolism Commons, Genetic Phenomena Commons, Genetic Processes Commons, Medical Genetics Commons, Nutrition Commons, Pediatrics Commons