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

Pervjakova, Natalia ; Moen, Gunn-Helen ; Borges, Maria-Carolina ; Ferreira, Teresa ; Cook, James P ; Allard, Catherine ; Beaumont, Robin N ; Canouil, Mickaël ; Hatem, Gad LU and Heiskala, Anni , et al. (2022) In Human Molecular Genetics 31(19). p.3377-3391
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 (GenDIP) Consortium assembled genome-wide association studies (GWAS) 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 < 5x10-8) with GDM, mapping... (More)

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 (GenDIP) Consortium assembled genome-wide association studies (GWAS) 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 < 5x10-8) with GDM, mapping to/near MTNR1B (p = 4.3x10-54), TCF7L2 (p = 4.0x10-16), CDKAL1 (p = 1.6 × 10-14), CDKN2A-CDKN2B (p = 4.1x10-9) and HKDC1 (p = 2.9x10-8). 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 randomisation 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
31
issue
19
pages
3377 - 3391
publisher
Oxford University Press
external identifiers
  • pmid:35220425
  • scopus:85133653659
ISSN
0964-6906
DOI
10.1093/hmg/ddac050
language
English
LU publication?
yes
additional info
© The Author(s) 2022. Published by Oxford University Press.
id
6183ba7b-3d2b-4a89-8014-4f75405582aa
date added to LUP
2022-08-12 16:12:44
date last changed
2024-05-18 22:07:31
@article{6183ba7b-3d2b-4a89-8014-4f75405582aa,
  abstract     = {{<p>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 (GenDIP) Consortium assembled genome-wide association studies (GWAS) 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 &lt; 5x10-8) with GDM, mapping to/near MTNR1B (p = 4.3x10-54), TCF7L2 (p = 4.0x10-16), CDKAL1 (p = 1.6 × 10-14), CDKN2A-CDKN2B (p = 4.1x10-9) and HKDC1 (p = 2.9x10-8). 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 randomisation 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.</p>}},
  author       = {{Pervjakova, Natalia and Moen, Gunn-Helen and Borges, Maria-Carolina and Ferreira, Teresa and Cook, James P and Allard, Catherine and Beaumont, Robin N and Canouil, Mickaël and Hatem, Gad and Heiskala, Anni and Joensuu, Anni and Karhunen, Ville and Kwak, Soo Heon and Lin, Frederick T J and Liu, Jun and Rifas-Shiman, Sheryl and Tam, Claudia H and Tam, Wing Hung and Thorleifsson, Gudmar and Andrew, Toby and Auvinen, Juha and Bhowmik, Bishwajit and Bonnefond, Amélie and Delahaye, Fabien and Demirkan, Ayse and Froguel, Philippe and Haller-Kikkatalo, Kadri and Hardardottir, Hildur and Hummel, Sandra and Hussain, Akhtar and Kajantie, Eero and Keikkala, Elina and Khamis, Amna and Lahti, Jari and Lekva, Tove and Mustaniemi, Sanna and Sommer, Christine and Tagoma, Aili and Tzala, Evangelia and Uibo, Raivo and Vääräsmäki, Marja and Villa, Pia M and Birkeland, Kåre I and Bouchard, Luigi and Duijn, Cornelia M and Finer, Sarah and Groop, Leif and Hämäläinen, Esa and Hayes, Geoffrey M and Hitman, Graham A and Jang, Hak C and Järvelin, Marjo-Riitta and Jenum, Anne Karen and Laivuori, Hannele and Ma, Ronald C and Melander, Olle and Oken, Emily and Park, Kyong Soo and Perron, Patrice and Prasad, Rashmi B and Qvigstad, Elisabeth and Sebert, Sylvain and Stefansson, Kari and Steinthorsdottir, Valgerdur and Tuomi, Tiinamaija and Hivert, Marie-France and Franks, Paul W and McCarthy, Mark I and Lindgren, Cecilia M and Freathy, Rachel M and Lawlor, Deborah A and Morris, Andrew P and Mägi, Reedik}},
  issn         = {{0964-6906}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{19}},
  pages        = {{3377--3391}},
  publisher    = {{Oxford University Press}},
  series       = {{Human Molecular Genetics}},
  title        = {{Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes}},
  url          = {{http://dx.doi.org/10.1093/hmg/ddac050}},
  doi          = {{10.1093/hmg/ddac050}},
  volume       = {{31}},
  year         = {{2022}},
}