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Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

ABSTRACT: Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n?=?321,223) and offspring birth weight (n?=?230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

SUBMITTER: Warrington NM

PROVIDER: S-EPMC6522365 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Warrington Nicole M NM Beaumont Robin N RN Horikoshi Momoko M Day Felix R FR Helgeland Øyvind Ø Laurin Charles C Bacelis Jonas J Peng Shouneng S Hao Ke K Feenstra Bjarke B Wood Andrew R AR Mahajan Anubha A Tyrrell Jessica J Robertson Neil R NR Rayner N William NW Qiao Zhen Z Moen Gunn-Helen GH Vaudel Marc M Marsit Carmen J CJ Chen Jia J Nodzenski Michael M Schnurr Theresia M TM Zafarmand Mohammad H MH Bradfield Jonathan P JP Grarup Niels N Kooijman Marjolein N MN Li-Gao Ruifang R Geller Frank F Ahluwalia Tarunveer S TS Paternoster Lavinia L Rueedi Rico R Huikari Ville V Hottenga Jouke-Jan JJ Lyytikäinen Leo-Pekka LP Cavadino Alana A Metrustry Sarah S Cousminer Diana L DL Wu Ying Y Thiering Elisabeth E Wang Carol A CA Have Christian T CT Vilor-Tejedor Natalia N Joshi Peter K PK Painter Jodie N JN Ntalla Ioanna I Myhre Ronny R Pitkänen Niina N van Leeuwen Elisabeth M EM Joro Raimo R Lagou Vasiliki V Richmond Rebecca C RC Espinosa Ana A Barton Sheila J SJ Inskip Hazel M HM Holloway John W JW Santa-Marina Loreto L Estivill Xavier X Ang Wei W Marsh Julie A JA Reichetzeder Christoph C Marullo Letizia L Hocher Berthold B Lunetta Kathryn L KL Murabito Joanne M JM Relton Caroline L CL Kogevinas Manolis M Chatzi Leda L Allard Catherine C Bouchard Luigi L Hivert Marie-France MF Zhang Ge G Muglia Louis J LJ Heikkinen Jani J Morgen Camilla S CS van Kampen Antoine H C AHC van Schaik Barbera D C BDC Mentch Frank D FD Langenberg Claudia C Luan Jian'an J Scott Robert A RA Zhao Jing Hua JH Hemani Gibran G Ring Susan M SM Bennett Amanda J AJ Gaulton Kyle J KJ Fernandez-Tajes Juan J van Zuydam Natalie R NR Medina-Gomez Carolina C de Haan Hugoline G HG Rosendaal Frits R FR Kutalik Zoltán Z Marques-Vidal Pedro P Das Shikta S Willemsen Gonneke G Mbarek Hamdi H Müller-Nurasyid Martina M Standl Marie M Appel Emil V R EVR Fonvig Cilius E CE Trier Caecilie C van Beijsterveldt Catharina E M CEM Murcia Mario M Bustamante Mariona M Bonas-Guarch Sílvia S Hougaard David M DM Mercader Josep M JM Linneberg Allan A Schraut Katharina E KE Lind Penelope A PA Medland Sarah E SE Shields Beverley M BM Knight Bridget A BA Chai Jin-Fang JF Panoutsopoulou Kalliope K Bartels Meike M Sánchez Friman F Stokholm Jakob J Torrents David D Vinding Rebecca K RK Willems Sara M SM Atalay Mustafa M Chawes Bo L BL Kovacs Peter P Prokopenko Inga I Tuke Marcus A MA Yaghootkar Hanieh H Ruth Katherine S KS Jones Samuel E SE Loh Po-Ru PR Murray Anna A Weedon Michael N MN Tönjes Anke A Stumvoll Michael M Michaelsen Kim F KF Eloranta Aino-Maija AM Lakka Timo A TA van Duijn Cornelia M CM Kiess Wieland W Körner Antje A Niinikoski Harri H Pahkala Katja K Raitakari Olli T OT Jacobsson Bo B Zeggini Eleftheria E Dedoussis George V GV Teo Yik-Ying YY Saw Seang-Mei SM Montgomery Grant W GW Campbell Harry H Wilson James F JF Vrijkotte Tanja G M TGM Vrijheid Martine M de Geus Eco J C N EJCN Hayes M Geoffrey MG Kadarmideen Haja N HN Holm Jens-Christian JC Beilin Lawrence J LJ Pennell Craig E CE Heinrich Joachim J Adair Linda S LS Borja Judith B JB Mohlke Karen L KL Eriksson Johan G JG Widén Elisabeth E EE Hattersley Andrew T AT Spector Tim D TD Kähönen Mika M Viikari Jorma S JS Lehtimäki Terho T Boomsma Dorret I DI Sebert Sylvain S Vollenweider Peter P Sørensen Thorkild I A TIA Bisgaard Hans H Bønnelykke Klaus K Murray Jeffrey C JC Melbye Mads M Nohr Ellen A EA Mook-Kanamori Dennis O DO Rivadeneira Fernando F Hofman Albert A Felix Janine F JF Jaddoe Vincent W V VWV Hansen Torben T Pisinger Charlotta C Vaag Allan A AA Pedersen Oluf O Uitterlinden André G AG Järvelin Marjo-Riitta MR Power Christine C Hyppönen Elina E Scholtens Denise M DM Lowe William L WL Davey Smith George G Timpson Nicholas J NJ Morris Andrew P AP Wareham Nicholas J NJ Hakonarson Hakon H Grant Struan F A SFA Frayling Timothy M TM Lawlor Debbie A DA Njølstad Pål R PR Johansson Stefan S Ong Ken K KK McCarthy Mark I MI Perry John R B JRB Evans David M DM Freathy Rachel M RM

Nature genetics 20190501 5

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effect ...[more]

PMID: 31043758

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Project description:Birth weight is considered not only to undermine future growth, but also to induce lifelong diseases; the aim of this study is to explore the relationship between birth weight and adult bone mass. We performed multivariable regression analyses to assess the association of birth weight with bone parameters measured by dual-energy X-ray absorptiometry (DXA) and by quantitative ultrasound (QUS), independently. We also implemented a systemic Mendelian randomization (MR) analysis to explore the causal association between them with both fetal-specific and maternal-specific instrumental variables. In the observational analyses, we found that higher birth weight could increase the adult bone area (lumbar spine, β-coefficient= 0.17, P < 2.00 × 10-16; lateral spine, β-coefficient = 0.02, P = 0.04), decrease bone mineral content-adjusted bone area (BMCadjArea) (lumbar spine, β-coefficient= - 0.01, P = 2.27 × 10-14; lateral spine, β-coefficient = - 0.05, P = 0.001), and decrease adult bone mineral density (BMD) (lumbar spine, β-coefficient = - 0.04, P = 0.007; lateral spine; β-coefficient = - 0.03, P = 0.02; heel, β-coefficient = - 0.06, P < 2.00 × 10-16), and we observed that the effect of birth weight on bone size was larger than that on BMC. In MR analyses, the higher fetal-specific genetically determined birth weight was identified to be associated with higher bone area (lumbar spine; β-coefficient = 0.15, P = 1.26 × 10-6, total hip, β-coefficient = 0.15, P = 0.005; intertrochanteric area, β-coefficient = 0.13, P = 0.0009; trochanter area, β-coefficient = 0.11, P = 0.03) but lower BMD (lumbar spine, β-coefficient = - 0.10, P = 0.01; lateral spine, β-coefficient = - 0.12, P = 0.0003, and heel β-coefficient = - 0.11, P = 3.33 × 10-13). In addition, we found that the higher maternal-specific genetically determined offspring birth weight was associated with lower offspring adult heel BMD (β-coefficient = - 0.001, P = 0.04). The observational analyses suggested that higher birth weight was associated with the increased adult bone area but decreased BMD. By leveraging the genetic instrumental variables with maternal- and fetal-specific effects on birth weight, the observed relationship could be reflected by both the direct fetal and indirect maternal genetic effects.

Project description:Fetal alcohol-related growth restriction persists through infancy, but its impact later in life is less clear. Animal studies have demonstrated important roles for maternal nutrition in fetal alcohol spectrum disorders, but the impact of prenatal maternal body composition has not been studied in humans. This study examined the effects of prenatal alcohol exposure on longitudinal growth from birth through young adulthood and the degree to which maternal weight and body mass index (BMI) moderate these effects.Nearly 480 mothers were recruited at their first prenatal clinic visit to overrepresent moderate-to-heavy use of alcohol during pregnancy, including a 5% random sample of low-level drinkers and abstainers. They were interviewed at every prenatal visit about their alcohol consumption using a timeline follow-back approach. Their children were examined for weight, length/height, and head circumference at birth, 6.5 and 13 months, and 7.5, 14, and 19 years.In multiple regression models with repeated measures (adjusted for confounders), prenatal alcohol exposure was associated with longitudinal reductions in weight, height, and weight-for-length/BMI that were largely determined at birth. At low-to-moderate levels of exposure, these effects were more severe in infancy than in later childhood. By contrast, effects persisted among children whose mothers drank at least monthly and among those born to women with alcohol abuse and/or dependence who had consumed ? 4 drinks/occasion. In addition, effects on weight, height, and head circumference were markedly stronger among children born to mothers with lower prepregnancy weight.These findings confirm prior studies demonstrating alcohol-related reductions in weight, height, weight-for-height/BMI, and head circumference that persist through young adulthood. Stronger effects were seen among children born to mothers with smaller prepregnancy weight, which may have been because of attainment of higher blood alcohol concentrations in smaller mothers for a given amount of alcohol intake or to increased vulnerability in infants born to women with poorer nutrition.

Project description:BackgroundClinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.Participants and methodsA genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight).ResultsApproximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG.ConclusionsWe found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

Dataset Information

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Publications

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

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