AIMS/HYPOTHESIS: The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies. METHODS: Midwife records from the Danish State Archives provided information on mother's age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes. RESULTS: Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (beta = -33 g [95% CI -55, -10], p = 0.004) and CDKAL1 rs7756992 (beta = -22 g [95% CI -43, -1], p = 0.04). The association for the latter locus was confirmed in a meta-analysis (n = 24,885) (beta = -20 g [95% CI -29, -11], p = 5 x 10(-6)). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p = 0.09); however, in a meta-analysis (n = 25,164) this type 2 diabetes risk allele was associated with lower birthweight (beta = -16 g [95% CI -24, -8], p = 8 x 10(-5)). On average, individuals with high genetic risk (>or=25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (beta = -35 g [95% CI -69, -2], p = 0.037). CONCLUSIONS/ INTERPRETATION: We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.
AIMS/HYPOTHESIS: The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies. METHODS: Midwife records from the Danish State Archives provided information on mother's age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes. RESULTS: Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5rs11708067 (beta = -33 g [95% CI -55, -10], p = 0.004) and CDKAL1rs7756992 (beta = -22 g [95% CI -43, -1], p = 0.04). The association for the latter locus was confirmed in a meta-analysis (n = 24,885) (beta = -20 g [95% CI -29, -11], p = 5 x 10(-6)). The HHEX-IDErs1111875 variant showed no significant association among Danes (p = 0.09); however, in a meta-analysis (n = 25,164) this type 2 diabetes risk allele was associated with lower birthweight (beta = -16 g [95% CI -24, -8], p = 8 x 10(-5)). On average, individuals with high genetic risk (>or=25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (beta = -35 g [95% CI -69, -2], p = 0.037). CONCLUSIONS/ INTERPRETATION: We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.
Authors: Struan F A Grant; Gudmar Thorleifsson; Inga Reynisdottir; Rafn Benediktsson; Andrei Manolescu; Jesus Sainz; Agnar Helgason; Hreinn Stefansson; Valur Emilsson; Anna Helgadottir; Unnur Styrkarsdottir; Kristinn P Magnusson; G Bragi Walters; Ebba Palsdottir; Thorbjorg Jonsdottir; Thorunn Gudmundsdottir; Arnaldur Gylfason; Jona Saemundsdottir; Robert L Wilensky; Muredach P Reilly; Daniel J Rader; Yu Bagger; Claus Christiansen; Vilmundur Gudnason; Gunnar Sigurdsson; Unnur Thorsteinsdottir; Jeffrey R Gulcher; Augustine Kong; Kari Stefansson Journal: Nat Genet Date: 2006-01-15 Impact factor: 38.330
Authors: Rachel M Freathy; Dennis O Mook-Kanamori; Ulla Sovio; Inga Prokopenko; Nicholas J Timpson; Diane J Berry; Nicole M Warrington; Elisabeth Widen; Jouke Jan Hottenga; Marika Kaakinen; Leslie A Lange; Jonathan P Bradfield; Marjan Kerkhof; Julie A Marsh; Reedik Mägi; Chih-Mei Chen; Helen N Lyon; Mirna Kirin; Linda S Adair; Yurii S Aulchenko; Amanda J Bennett; Judith B Borja; Nabila Bouatia-Naji; Pimphen Charoen; Lachlan J M Coin; Diana L Cousminer; Eco J C de Geus; Panos Deloukas; Paul Elliott; David M Evans; Philippe Froguel; Beate Glaser; Christopher J Groves; Anna-Liisa Hartikainen; Neelam Hassanali; Joel N Hirschhorn; Albert Hofman; Jeff M P Holly; Elina Hyppönen; Stavroula Kanoni; Bridget A Knight; Jaana Laitinen; Cecilia M Lindgren; Wendy L McArdle; Paul F O'Reilly; Craig E Pennell; Dirkje S Postma; Anneli Pouta; Adaikalavan Ramasamy; Nigel W Rayner; Susan M Ring; Fernando Rivadeneira; Beverley M Shields; David P Strachan; Ida Surakka; Anja Taanila; Carla Tiesler; Andre G Uitterlinden; Cornelia M van Duijn; Alet H Wijga; Gonneke Willemsen; Haitao Zhang; Jianhua Zhao; James F Wilson; Eric A P Steegers; Andrew T Hattersley; Johan G Eriksson; Leena Peltonen; Karen L Mohlke; Struan F A Grant; Hakon Hakonarson; Gerard H Koppelman; George V Dedoussis; Joachim Heinrich; Matthew W Gillman; Lyle J Palmer; Timothy M Frayling; Dorret I Boomsma; George Davey Smith; Chris Power; Vincent W V Jaddoe; Marjo-Riitta Jarvelin; Mark I McCarthy Journal: Nat Genet Date: 2010-04-06 Impact factor: 38.330
Authors: Richa Saxena; Benjamin F Voight; Valeriya Lyssenko; Noël P Burtt; Paul I W de Bakker; Hong Chen; Jeffrey J Roix; Sekar Kathiresan; Joel N Hirschhorn; Mark J Daly; Thomas E Hughes; Leif Groop; David Altshuler; Peter Almgren; Jose C Florez; Joanne Meyer; Kristin Ardlie; Kristina Bengtsson Boström; Bo Isomaa; Guillaume Lettre; Ulf Lindblad; Helen N Lyon; Olle Melander; Christopher Newton-Cheh; Peter Nilsson; Marju Orho-Melander; Lennart Råstam; Elizabeth K Speliotes; Marja-Riitta Taskinen; Tiinamaija Tuomi; Candace Guiducci; Anna Berglund; Joyce Carlson; Lauren Gianniny; Rachel Hackett; Liselotte Hall; Johan Holmkvist; Esa Laurila; Marketa Sjögren; Maria Sterner; Aarti Surti; Margareta Svensson; Malin Svensson; Ryan Tewhey; Brendan Blumenstiel; Melissa Parkin; Matthew Defelice; Rachel Barry; Wendy Brodeur; Jody Camarata; Nancy Chia; Mary Fava; John Gibbons; Bob Handsaker; Claire Healy; Kieu Nguyen; Casey Gates; Carrie Sougnez; Diane Gage; Marcia Nizzari; Stacey B Gabriel; Gung-Wei Chirn; Qicheng Ma; Hemang Parikh; Delwood Richardson; Darrell Ricke; Shaun Purcell Journal: Science Date: 2007-04-26 Impact factor: 47.728
Authors: Valeriya Lyssenko; Cecilia L F Nagorny; Michael R Erdos; Nils Wierup; Anna Jonsson; Peter Spégel; Marco Bugliani; Richa Saxena; Malin Fex; Nicolo Pulizzi; Bo Isomaa; Tiinamaija Tuomi; Peter Nilsson; Johanna Kuusisto; Jaakko Tuomilehto; Michael Boehnke; David Altshuler; Frank Sundler; Johan G Eriksson; Anne U Jackson; Markku Laakso; Piero Marchetti; Richard M Watanabe; Hindrik Mulder; Leif Groop Journal: Nat Genet Date: 2008-12-07 Impact factor: 38.330
Authors: Eleftheria Zeggini; Michael N Weedon; Cecilia M Lindgren; Timothy M Frayling; Katherine S Elliott; Hana Lango; Nicholas J Timpson; John R B Perry; Nigel W Rayner; Rachel M Freathy; Jeffrey C Barrett; Beverley Shields; Andrew P Morris; Sian Ellard; Christopher J Groves; Lorna W Harries; Jonathan L Marchini; Katharine R Owen; Beatrice Knight; Lon R Cardon; Mark Walker; Graham A Hitman; Andrew D Morris; Alex S F Doney; Mark I McCarthy; Andrew T Hattersley Journal: Science Date: 2007-04-26 Impact factor: 47.728