Elliott A, Walters R K, Pirinen M, Kurki M, Junna N, Goldstein J, Reeve M P, Siirtola H, Lemmelä S, Turley P, Palotie A, Daly M, Widén E
Analytic and Translational Genetics Unit, Massachusetts Gen. Hosp., Boston, MA.
Stanley Ctr. for Psychiatric Res., Broad Inst. of Harvard and MIT, Cambridge, MA.
medRxiv. 2023 Feb 23:2023.02.16.23286014. doi: 10.1101/2023.02.16.23286014.
Gestational diabetes mellitus (GDM) affects more than 16 million pregnancies annually worldwide and is related to an increased lifetime risk of Type 2 diabetes (T2D). The diseases are hypothesized to share a genetic predisposition, but there are few GWAS studies of GDM and none of them is sufficiently powered to assess whether any variants or biological pathways are specific to GDM. We conducted the largest genome-wide association study of GDM to date in 12,332 cases and 131,109 parous female controls in the FinnGen Study and identified 13 GDM-associated loci including 8 novel loci. Genetic features distinct from T2D were identified both at the locus and genomic scale. Our results suggest that the genetics of GDM risk falls into two distinct categories - one part conventional T2D polygenic risk and one part predominantly influencing mechanisms disrupted in pregnancy. Loci with GDM-predominant effects map to genes related to islet cells, central glucose homeostasis, steroidogenesis, and placental expression. These results pave the way for an improved biological understanding of GDM pathophysiology and its role in the development and course of T2D.
妊娠期糖尿病（GDM）每年在全球影响超过1600万次妊娠，并且与2型糖尿病（T2D）的终生风险增加有关。据推测，这两种疾病具有共同的遗传易感性，但针对GDM的全基因组关联研究（GWAS）较少，而且没有一项研究有足够的效力来评估是否存在任何特定于GDM的变异或生物学途径。我们在芬兰基因研究中对12332例病例和131109例经产女性对照进行了迄今为止最大规模的GDM全基因组关联研究，确定了13个与GDM相关的基因座，其中包括8个新基因座。在基因座和基因组水平上都发现了与T2D不同的遗传特征。我们的结果表明，GDM风险的遗传学可分为两个不同的类别——一部分是传统的T2D多基因风险，另一部分主要影响妊娠中受到干扰的机制。具有GDM主要效应的基因座映射到与胰岛细胞、中枢葡萄糖稳态、类固醇生成和胎盘表达相关 的基因。这些结果为更好地从生物学角度理解GDM病理生理学及其在T2D发生发展过程中的作用铺平了道路。
