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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

ABSTRACT: Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

SUBMITTER: Horikoshi M

PROVIDER: S-EPMC3605762 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Horikoshi Momoko M Yaghootkar Hanieh H Mook-Kanamori Dennis O DO Sovio Ulla U Taal H Rob HR Hennig Branwen J BJ Bradfield Jonathan P JP St Pourcain Beate B Evans David M DM Charoen Pimphen P Kaakinen Marika M Cousminer Diana L DL Lehtimäki Terho T Kreiner-Møller Eskil E Warrington Nicole M NM Bustamante Mariona M Feenstra Bjarke B Berry Diane J DJ Thiering Elisabeth E Pfab Thiemo T Barton Sheila J SJ Shields Beverley M BM Kerkhof Marjan M van Leeuwen Elisabeth M EM Fulford Anthony J AJ Kutalik Zoltán Z Zhao Jing Hua JH den Hoed Marcel M Mahajan Anubha A Lindi Virpi V Goh Liang-Kee LK Hottenga Jouke-Jan JJ Wu Ying Y Raitakari Olli T OT Harder Marie N MN Meirhaeghe Aline A Ntalla Ioanna I Salem Rany M RM Jameson Karen A KA Zhou Kaixin K Monies Dorota M DM Lagou Vasiliki V Kirin Mirna M Heikkinen Jani J Adair Linda S LS Alkuraya Fowzan S FS Al-Odaib Ali A Amouyel Philippe P Andersson Ehm Astrid EA Bennett Amanda J AJ Blakemore Alexandra I F AI Buxton Jessica L JL Dallongeville Jean J Das Shikta S de Geus Eco J C EJ Estivill Xavier X Flexeder Claudia C Froguel Philippe P Geller Frank F Godfrey Keith M KM Gottrand Frédéric F Groves Christopher J CJ Hansen Torben T Hirschhorn Joel N JN Hofman Albert A Hollegaard Mads V MV Hougaard David M DM Hyppönen Elina E Inskip Hazel M HM Isaacs Aaron A Jørgensen Torben T Kanaka-Gantenbein Christina C Kemp John P JP Kiess Wieland W Kilpeläinen Tuomas O TO Klopp Norman N Knight Bridget A BA Kuzawa Christopher W CW McMahon George G Newnham John P JP Niinikoski Harri H Oostra Ben A BA Pedersen Louise L Postma Dirkje S DS Ring Susan M SM Rivadeneira Fernando F Robertson Neil R NR Sebert Sylvain S Simell Olli O Slowinski Torsten T Tiesler Carla M T CM Tönjes Anke A Vaag Allan A Viikari Jorma S JS Vink Jacqueline M JM Vissing Nadja Hawwa NH Wareham Nicholas J NJ Willemsen Gonneke G Witte Daniel R DR Zhang Haitao H Zhao Jianhua J Wilson James F JF Stumvoll Michael M Prentice Andrew M AM Meyer Brian F BF Pearson Ewan R ER Boreham Colin A G CA Cooper Cyrus C Gillman Matthew W MW Dedoussis George V GV Moreno Luis A LA Pedersen Oluf O Saarinen Maiju M Mohlke Karen L KL Boomsma Dorret I DI Saw Seang-Mei SM Lakka Timo A TA Körner Antje A Loos Ruth J F RJ Ong Ken K KK Vollenweider Peter P van Duijn Cornelia M CM Koppelman Gerard H GH Hattersley Andrew T AT Holloway John W JW Hocher Berthold B Heinrich Joachim J Power Chris C Melbye Mads M Guxens Mònica M Pennell Craig E CE Bønnelykke Klaus K Bisgaard Hans H Eriksson Johan G JG Widén Elisabeth E Hakonarson Hakon H Uitterlinden André G AG Pouta Anneli A Lawlor Debbie A DA Smith George Davey GD Frayling Timothy M TM McCarthy Mark I MI Grant Struan F A SF Jaddoe Vincent W V VW Jarvelin Marjo-Riitta MR Timpson Nicholas J NJ Prokopenko Inga I Freathy Rachel M RM

Nature genetics 20121202 1

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysi ...[more]

PMID: 23202124

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Project description:ImportanceBile acids play essential roles in metabolic modulation. Excessive serum total bile acid (sTBA) levels during pregnancy are associated with adverse perinatal outcomes; however, their association with the risk of intrauterine growth restriction (IUGR) remains unclear.ObjectiveTo investigate the association between maternal sTBA concentration during pregnancy and the risk of IUGR.Design, setting, and participantsThis retrospective cohort study included pregnant individuals who delivered live singleton neonates and had regular antenatal examination records available at a hospital-based center in Shanghai, China, from 2014 to 2018. Data were analyzed from July to November 2020.ExposuresMaternal sTBA concentration during pregnancy.Main outcomes and measuresFetal birth weight and probability of low birth weight (LBW) and IUGR.ResultsThis study included 68 245 singleton pregnancies with live births for analysis. The mean (SD) age of the pregnant individuals was 30.5 (3.8) years, 67 168 patients (98.4%) were Han, and 50 155 (73.5%) were nulliparous. Nonlinear regression models suggested that there was an inverted J-shaped association between maternal sTBA level during pregnancy and fetal birth weight, with a steep decrease in birth weight at high sTBA levels (estimated mean [SE] birth weight for sTBA of 40.8 ug/mL, 2879 [39.9] g) and greater birth weights at lower sTBA levels (estimated mean [SE] birth weight for sTBA 0.4 μg/mL, 3290 [3.9] g; and for 4.1 μg/mL, 3334 [1.6] g). Lower birth weight and a higher incidence of IUGR were observed in patients with gestational hypercholanemia (sTBA ≥4.08 μg/mL) compared with those without gestational hypercholanemia (birth weight: estimated adjusted mean [SE], 3309 [3.32] vs 3338 [0.80] g; P = .005; incidence of IUGR: 62 of 4467 [1.4%] vs 312 of 63 778 [0.5%]; P < .001). Moreover, compared with patients with sTBA concentrations of less than 4.08 μg/mL, those with gestational hypercholanemia had an increased risk of LBW (adjusted odds ratio [aOR], 1.29; 95% CI, 1.09-1.53) and IUGR (aOR, 2.18; 95% CI, 1.62-2.91). In addition, there was an additive interaction between hypertensive disorders in pregnancy (HDP) and hypercholanemia on LBW and IUGR risk. The highest risks of LBW and IUGR were found in pregnant individuals with both HDP and hypercholanemia compared with those with normotensive pregnancies with sTBA concentrations less than 4.08 μg/mL (LBW: aOR, 9.13; 95% CI, 6.88-12.12; IUGR: aOR, 19.14; 95% CI, 12.09-30.28).Conclusions and relevanceThis study found that gestational hypercholanemia was associated with an increased risk of LBW and IUGR, especially in pregnant individuals with HDP. Therefore, it would be meaningful to monitor sTBA concentration during the follow-up of pregnancies with potential IUGR.

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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Publications

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

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