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서울대학교 의과대학, 서울대학교 병원

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Nat Metab., Jan 26 2024, | https://doi.org/10.1038/s42255-023-00970-0 Genetic architecture and biology of youth-onset type 2 diabetes

Soo Heon Kwak^1,2, Shylaja Srinivasan³, Ling Chen⁴, Jennifer Todd⁵, Josep M. Mercader^2,4,6, Elizabeth T. Jensen⁷, Jasmin Divers⁸, Amy K. Mottl⁹, Catherine Pihoker¹⁰, Rachelle G. Gandica¹¹, Lori M. Laffel¹², Elvira Isganaitis¹², Morey W. Haymond¹³, Lynne L. Levitsky¹⁴, Toni I. Pollin¹⁵, Jose C. Florez^2,4,6, Jason Flannick^2,16,17 & Progress in Diabetes Genetics in Youth (ProDiGY) consortium^*

¹Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

²Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

³Division of Pediatric Endocrinology, University of California at San Francisco, San Francisco, CA, USA.

⁴Center for Genomic Medicine, and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

⁵Division of Pediatric Endocrinology, Department of Pediatrics, University of Vermont, Burlington, VT, USA.

⁶Department of Medicine, Harvard Medical School, Boston, MA, USA.

⁷Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, USA.

⁸Department of Foundations of Medicine, NYU Langone Health, New York, NY, USA.

⁹Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, NC, USA.

¹⁰Department of Pediatrics, University of Washington, Seattle, WA, USA.

¹¹Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY, USA.

¹²Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.

¹³Department of Pediatrics, Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.

¹⁴Pediatric Endocrine Division, Department of Pediatrics, Massachusetts General Hospital for Children and Harvard Medical School, Boston, MA, USA.

¹⁵Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.

¹⁶Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA.

¹⁷Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA.

Corresponding author : Correspondence to Jason Flannick.

Abstract

The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily ¹, producing a growing public health concern ¹ that disproportionately affects minority groups ². The genetic basis of youth-onset T2D and its relationship to other forms of diabetes are unclear ³. 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.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-02-15)
연구진국내+국외 연구진
분야 의약학 > 유전 및 유전체의학

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