Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
29 09 2022
29 09 2022
Historique:
received:
11
11
2021
revised:
09
02
2022
accepted:
23
02
2022
pubmed:
28
2
2022
medline:
4
10
2022
entrez:
27
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35220425
pii: 6537590
doi: 10.1093/hmg/ddac050
pmc: PMC9523562
doi:
Substances chimiques
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3377-3391Subventions
Organisme : NIH HHS
ID : UH3 OD023286
Pays : United States
Organisme : British Heart Foundation
ID : CH/F/20/90003
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00011/6
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N024397/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CS/16/4/32482
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NICHD NIH HHS
ID : R01 HD034568
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press.
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