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

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...

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Detalles Bibliográficos
Autores principales: Kwak, Soo Heon, Srinivasan, Shylaja, Chen, Ling, Todd, Jennifer, Mercader, Josep, Jensen, Elizabeth, Divers, Jasmin, Mottl, Amy, Pihoker, Catherine, Gandica, Rachelle, Laffel, Lori, Isganaitis, Elvira, Haymond, Morey, Levitsky, Lynne, Pollin, Toni, Florez, Jose, Flannick, Jason
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10246295/
https://www.ncbi.nlm.nih.gov/pubmed/37292813
http://dx.doi.org/10.21203/rs.3.rs-2886343/v1
Descripción
Sumario: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.