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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

ABSTRACT: Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10-54), TCF7L2 (P = 4.0 × 10-16), CDKAL1 (P = 1.6 × 10-14), CDKN2A-CDKN2B (P = 4.1 × 10-9) and HKDC1 (P = 2.9 × 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

SUBMITTER: Pervjakova N

PROVIDER: S-EPMC9523562 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

Pervjakova Natalia N Moen Gunn-Helen GH Borges Maria-Carolina MC Ferreira Teresa T Cook James P JP Allard Catherine C Beaumont Robin N RN Canouil Mickaël M Hatem Gad G Heiskala Anni A Joensuu Anni A Karhunen Ville V Kwak Soo Heon SH Lin Frederick T J FTJ Liu Jun J Rifas-Shiman Sheryl S Tam Claudia H CH Tam Wing Hung WH Thorleifsson Gudmar G Andrew Toby T Auvinen Juha J Bhowmik Bishwajit B Bonnefond Amélie A Delahaye Fabien F Demirkan Ayse A Froguel Philippe P Haller-Kikkatalo Kadri K Hardardottir Hildur H Hummel Sandra S Hussain Akhtar A Kajantie Eero E Keikkala Elina E Khamis Amna A Lahti Jari J Lekva Tove T Mustaniemi Sanna S Sommer Christine C Tagoma Aili A Tzala Evangelia E Uibo Raivo R Vääräsmäki Marja M Villa Pia M PM Birkeland Kåre I KI Bouchard Luigi L Duijn Cornelia M CM Finer Sarah S Groop Leif L Hämäläinen Esa E Hayes Geoffrey M GM Hitman Graham A GA Jang Hak C HC Järvelin Marjo-Riitta MR Jenum Anne Karen AK Laivuori Hannele H Ma Ronald C RC Melander Olle O Oken Emily E Park Kyong Soo KS Perron Patrice P Prasad Rashmi B RB Qvigstad Elisabeth E Sebert Sylvain S Stefansson Kari K Steinthorsdottir Valgerdur V Tuomi Tiinamaija T Hivert Marie-France MF Franks Paul W PW McCarthy Mark I MI Lindgren Cecilia M CM Freathy Rachel M RM Lawlor Deborah A DA Morris Andrew P AP Mägi Reedik R

Human molecular genetics 20220901 19

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association ...[more]

PMID: 35220425

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Project description:Type 2 diabetes mellitus (DM) is a common metabolic disorder predisposing to diabetic cardiomyopathy and atherosclerotic cardiovascular disease (CVD), which could lead to heart failure through a variety of mechanisms, including myocardial infarction and chronic pressure overload. Pathogenetic mechanisms, mainly linked to hyperglycemia and chronic sustained hyperinsulinemia, include changes in metabolic profiles, intracellular signaling pathways, energy production, redox status, increased susceptibility to ischemia, and extracellular matrix remodeling. The close relationship between type 2 DM and CVD has led to the common soil hypothesis, postulating that both conditions share common genetic and environmental factors influencing this association. However, although the common risk factors of both CVD and type 2 DM, such as obesity, insulin resistance, dyslipidemia, inflammation, and thrombophilia, can be identified in the majority of affected patients, less is known about how these factors influence both conditions, so that efforts are still needed for a more comprehensive understanding of this relationship. The genetic, epigenetic, and environmental backgrounds of both type 2 DM and CVD have been more recently studied and updated. However, the underlying pathogenetic mechanisms have seldom been investigated within the broader shared background, but rather studied in the specific context of type 2 DM or CVD, separately. As the precise pathophysiological links between type 2 DM and CVD are not entirely understood and many aspects still require elucidation, an integrated description of the genetic, epigenetic, and environmental influences involved in the concomitant development of both diseases is of paramount importance to shed new light on the interlinks between type 2 DM and CVD. This review addresses the current knowledge of overlapping genetic and epigenetic aspects in type 2 DM and CVD, including microRNAs and long non-coding RNAs, whose abnormal regulation has been implicated in both disease conditions, either etiologically or as cause for their progression. Understanding the links between these disorders may help to drive future research toward an integrated pathophysiological approach and to provide future directions in the field.

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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.

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