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

Pervjakova, Natalia (author): Tartu University Hospital

Moen, Gunn-Helen (author): University of Oslo

Borges, Maria-Carolina (author): University of Bristol

Ferreira, Teresa (author): University of Oxford

Cook, James P (author): University of Liverpool

Allard, Catherine (author): Sherbrooke University

Beaumont, Robin N (author): University of Exeter

Canouil, Mickaël (author): Pasteur Institute of Lille

Hatem, Gad (author): Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups

Heiskala, Anni (author): University of Oulu

Joensuu, Anni (author): Finnish National Institute for Health and Welfare

Karhunen, Ville (author): University of Oulu

Kwak, Soo Heon (author)

Lin, Frederick T J (author)

Liu, Jun (author)

Rifas-Shiman, Sheryl (author)

Tam, Claudia H (author)

Tam, Wing Hung (author)

Thorleifsson, Gudmar (author)

Andrew, Toby (author)

Auvinen, Juha (author)

Bhowmik, Bishwajit (author)

Bonnefond, Amélie (author)

Delahaye, Fabien (author)

Demirkan, Ayse (author)

Froguel, Philippe (author)

Haller-Kikkatalo, Kadri (author)

Hardardottir, Hildur (author)

Hummel, Sandra (author)

Hussain, Akhtar (author)

Kajantie, Eero (author)

Keikkala, Elina (author)

Khamis, Amna (author)

Lahti, Jari (author)

Lekva, Tove (author)

Mustaniemi, Sanna (author)

Sommer, Christine (author)

Tagoma, Aili (author)

Tzala, Evangelia (author)

Uibo, Raivo (author): University of Tartu

Vääräsmäki, Marja (author)

Villa, Pia M (author)

Birkeland, Kåre I (author)

Bouchard, Luigi (author)

Duijn, Cornelia M (author)

Finer, Sarah (author)

Groop, Leif (author): Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,University of Helsinki

Hämäläinen, Esa (author)

Hayes, Geoffrey M (author)

Hitman, Graham A (author)

Jang, Hak C (author)

Järvelin, Marjo-Riitta (author)

Jenum, Anne Karen (author)

Laivuori, Hannele (author)

Ma, Ronald C (author)

Melander, Olle (author): Lund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups

Oken, Emily (author)

Park, Kyong Soo (author)

Perron, Patrice (author)

Prasad, Rashmi B (author): Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups

Qvigstad, Elisabeth (author)

Sebert, Sylvain (author)

Stefansson, Kari (author)

Steinthorsdottir, Valgerdur (author)

Tuomi, Tiinamaija (author): Lund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,Folkhälsan Research Center,Helsinki University Central Hospital,University of Helsinki

Hivert, Marie-France (author)

Franks, Paul W (author): Lund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Harvard University

McCarthy, Mark I (author)

Lindgren, Cecilia M (author): Broad Institute,University of Oxford

Freathy, Rachel M (author)

Lawlor, Deborah A (author)

Morris, Andrew P (author)

Mägi, Reedik (author)

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(creator_code:org_t)

2022-02-26
2022
English.
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 31:19, s. 3377-3391

Related links:: http://dx.doi.org/10... (free); show more...; https://lup.lub.lu.s...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

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By the author/editor: Pervjakova, Nata ...; Moen, Gunn-Helen; Borges, Maria-Ca ...; Ferreira, Teresa; Cook, James P; Allard, Catherin ...; show more...; Beaumont, Robin ...; Canouil, Mickaël; Hatem, Gad; Heiskala, Anni; Joensuu, Anni; Karhunen, Ville; Kwak, Soo Heon; Lin, Frederick T ...; Liu, Jun; Rifas-Shiman, Sh ...; Tam, Claudia H; Tam, Wing Hung; Thorleifsson, Gu ...; Andrew, Toby; Auvinen, Juha; Bhowmik, Bishwaj ...; Bonnefond, Améli ...; Delahaye, Fabien; Demirkan, Ayse; Froguel, Philipp ...; Haller-Kikkatalo ...; Hardardottir, Hi ...; Hummel, Sandra; Hussain, Akhtar; Kajantie, Eero; Keikkala, Elina; Khamis, Amna; Lahti, Jari; Lekva, Tove; Mustaniemi, Sann ...; Sommer, Christin ...; Tagoma, Aili; Tzala, Evangelia; Uibo, Raivo; Vääräsmäki, Marj ...; Villa, Pia M; Birkeland, Kåre ...; Bouchard, Luigi; Duijn, Cornelia ...; Finer, Sarah; Groop, Leif; Hämäläinen, Esa; Hayes, Geoffrey ...; Hitman, Graham A; Jang, Hak C; Järvelin, Marjo- ...; Jenum, Anne Kare ...; Laivuori, Hannel ...; Ma, Ronald C; Melander, Olle; Oken, Emily; Park, Kyong Soo; Perron, Patrice; Prasad, Rashmi B; Qvigstad, Elisab ...; Sebert, Sylvain; Stefansson, Kari; Steinthorsdottir ...; Tuomi, Tiinamaij ...; Hivert, Marie-Fr ...; Franks, Paul W; McCarthy, Mark I; Lindgren, Cecili ...; Freathy, Rachel ...; Lawlor, Deborah ...; Morris, Andrew P; Mägi, Reedik; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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By the university: Lund University

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