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

  title={Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors},
  author={Nicole M. Warrington and Robin N. Beaumont and Momoko Horikoshi and Felix R. Day and {\O}yvind Helgeland and Charles Laurin and Jonas Bacelis and Shouneng Peng and Ke Hao and Bjarke Feenstra and Andrew R. Wood and Anubha Mahajan and Jessica Tyrrell and Neil R. Robertson and Nigel William Rayner and Zhen Qiao and Gunn-Helen {\O}iseth Moen and Marc Vaudel and Carmen J. Marsit and Jia Chen and Michael Nodzenski and Theresia M. Schnurr and Mohammad H. Zafarmand and Jonathan P. Bradfield and Niels Grarup and Marjolein N. Kooijman and Ruifang Li-Gao and Frank Geller and Tarunveer Singh Ahluwalia and Lavinia Paternoster and Rico Rueedi and Ville Huikari and Jouke- Jan Hottenga and Leo-Pekka Lyytik{\"a}inen and Alana Cavadino and Sarah Jane Metrustry and Diana L. Cousminer and Ying Wu and Elisabeth Thiering and Carol A. Wang and Christian Theil Have and Nat{\`a}lia Vilor-Tejedor and Peter K. Joshi and Jodie N. Painter and Ioanna Ntalla and Ronny Myhre and Niina Pitk{\"a}nen and Elisabeth M. van Leeuwen and Raimo Joro and Vasiliki Lagou and Rebecca C. Richmond and Ana Espinosa and Sheila J Barton and Hazel M. Inskip and John W. Holloway and Loreto Santa-Marina and Xavier Estivill and Wei Q. Ang and Julie A. Marsh and Christoph Reichetzeder and Letizia Marullo and Berthold Hocher and Kathryn L. Lunetta and Joanne M. Murabito and Caroline L. Relton and Manolis Kogevinas and Leda Chatzi and Catherine Allard and Luigi Bouchard and Marie-France Hivert and Ge Zhang and Louis J. Muglia and Jani Heikkinen and Camilla S Morgen and Antoine H. C. van Kampen and Barbera D. C. van Schaik and Frank D. Mentch and Claudia Langenberg and Jian’an Luan and Robert A. Scott and Jing Hua Zhao and Gibran Hemani and Susan M. Ring and Amanda Bennett and Kyle J. Gaulton and Juan Fern{\'a}ndez-Tajes and Natalie R. van Zuydam and Carolina Medina-Gomez and Hugoline G de Haan and Frits Richard Rosendaal and Zolt{\'a}n Kutalik and Pedro Marques‐Vidal and Shikta Das and Gonneke Willemsen and Hamdi Mbarek and Martina M{\"u}ller-Nurasyid and Marie Standl and Emil Vincent R Appel and Cilius Esmann Fonvig and C{\ae}cilie Trier and Catharina E M van Beijsterveldt and Mario Murcia and Mariona Bustamante and S{\'i}lvia Bon{\`a}s-Guarch and David Michael Hougaard and Josep Maria Mercader and Allan Linneberg and Katharina E. Schraut and Penelope A. Lind and Sarah E. Medland and Beverley M. Shields and Bridget A. Knight and Jin-Fang Chai and Kalliope Panoutsopoulou and Meike Bartels and Friman S{\'a}nchez and J. Stokholm and David Torrents and Rebecca Kofod Vinding and Sara M. Willems and Mustafa Atalay and Bo Lund Chawes and Peter Kovacs and Inga Prokopenko and Marcus A. Tuke and Hanieh Yaghootkar and Katherine S. Ruth and Samuel E. Jones and Po-Ru Loh and Anna Murray and Michael N. Weedon and Anke Tönjes and Michael Stumvoll and Kim F. Michaelsen and Aino-Maija Eloranta and Timo A. Lakka and Cornelia M. van Duijn and Wieland Kiess and Antje K{\"o}rner and Harri Niinikoski and Katja Pahkala and Olli T. Raitakari and Bo Jacobsson and Eleftheria Zeggini and George V. Dedoussis and Yik Ying Teo and Seang-Mei Saw and Grant W. Montgomery and Harry Campbell and James F. Wilson and Tanja G. M. Vrijkotte and Martine Vrijheid and Eco J. C. de Geus and M. Geoffrey Hayes and Haja N. Kadarmideen and Jens-Christian Holm and Lawrence J. Beilin and Craig E. Pennell and Joachim Heinrich and Linda S Adair and Judith B. Borja and Karen L. Mohlke and Johan Gunnar Eriksson and Elisabeth Wid{\'e}n and Andrew T. Hattersley and Tim D. Spector and Mika K{\"a}h{\"o}nen and Jorma S.A. Viikari and Terho Lehtim{\"a}ki and Dorret I. Boomsma and Sylvain Sebert and Peter Vollenweider and Thorkild I. A. S{\o}rensen and Hans Bisgaard and Klaus B{\o}nnelykke and Jeffrey C. Murray and Mads Melbye and Ellen Aagaard N{\o}hr and Dennis O. Mook-Kanamori and Fernando Rivadeneira and Albert Hofman and Janine F. Felix and Vincent W. V. Jaddoe and Torben Hansen and Charlotta Pisinger and Allan Arthur Vaag and Oluf Pedersen and Andr{\'e} G. Uitterlinden and Marjo-Riitta J{\"a}rvelin and Christine Power and Elina Hypp{\"o}nen and Denise M. Scholtens and William L. Lowe and George Davey Smith and Nicholas John Timpson and Andrew P. Morris and Nicholas J. Wareham and Hakon H. Hakonarson and Struan F. A. Grant and Timothy M. Frayling and Deborah A. Lawlor and P{\aa}l Rasmus Nj{\o}lstad and Stefan Johansson and Ken K. Ong and Mark I. McCarthy and John R. B. Perry and David M. Evans and Rachel M. Freathy},
  journal={Nature Genetics},
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… 

Placenta mediates the effect of maternal hypertension polygenic score on offspring birth weight: a study of birth cohort with fetal growth velocity data

This study suggests that maternal hypertension genes are strongly associated with placental growth and that fetal growth inhibition is induced through the intrauterine environment established by the placenta.

Mendelian randomization study of maternal influences on birthweight and future cardiometabolic risk in the HUNT cohort

The results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals.

Distinction between the effects of parental and fetal genomes on fetal growth.

The results indicate that the maternal genome contributes to increased birth weight through blood-glucose-raising alleles while blood-pressure- raising alleles reduce birth weight largely through the fetal genome.

Haplotype genetic score analysis in 10,734 mother/infant pairs reveals complex maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes and adult phenotypes

It was showed that maternal height and fetal growth jointly affect the duration of gestation – maternal height positively influences the gestational duration, while faster fetal growth reduces Gestational duration.

Influence of genetic variants for birth weight on fetal growth and placental haemodynamics

The results suggest that genetic variants related to birth weight exert their combined effect on fetal growth from second half of pregnancy onwards and have no effect on placental haemodynamics.

Do maternal intrauterine environmental influences that lower offspring birthweight causally increase offspring cardiometabolic risk factors in later life? A Mendelian randomization study of 45,849 genotyped parent offspring pairs in the HUNT study

The results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals.

Investigating a Potential Causal Relationship Between Maternal Blood Pressure During Pregnancy and Future Offspring Cardiometabolic Health

Little evidence is found to support the notion that maternal BP is a major causal risk factor for adverse offspring cardiometabolic outcomes in later life.

Dissecting maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes, and adult phenotypes: A mendelian-randomization and haplotype-based genetic score analysis in 10,734 mother–infant pairs

Both maternal height and Fetal growth are important factors in shaping the duration of gestation: genetically elevated maternal height is associated with longer gestational duration, whereas alleles that increase fetal growth are associated with shorter gestationalduration.

Using a two-sample Mendelian randomization design to investigate a possible causal effect of maternal lipid concentrations on offspring birth weight

These findings suggest that maternal gestational HDL-C, LDL-C and triglyceride concentrations play a limited role in determining offspring BW, and illustrates the power and flexibility of two-sample MR in assessing the causal effect of maternal environmental exposures on offspring outcomes.

Associations of maternal blood pressure-raising polygenic risk scores with fetal weight

It is shown that pregnant women’s genetic susceptibility to high BP contributes to reduced fetal growth, suggesting a potential future clinical application in perinatal health.



Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.

For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.

Genome-wide associations for birth weight and correlations with adult disease

It is demonstrated that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and some of the pathways through which these causal genetic effects are mediated.

Assessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysis

The results demonstrate that the observed association between maternal height and fetal growth measures (i.e., birth length and birth weight) is mainly defined by fetal genetics, and the association betweenaternal height and gestational age is more likely to be causal.

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth.

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

The number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking, are extended and highlight genetic links between fetal growth and postnatal growth and metabolism.

Differential parental weight and height contributions to offspring birthweight and weight gain in infancy.

The influences of parental height and weight on birthweight and infant weight gain are similar for the two parents, with the exception of the influence of weight onBirthweight where the mother is much more influential than the father.

Relationship of paternal factors to birth weight.

Paternal height explains an independent portion of the variance in term birth weight among normal newborns of up to 250 g that cannot be explained by other maternal or pregnancy-specific factors.

Can genetic evidence help us to understand the fetal origins of type 2 diabetes?

The results of the Mendelian randomisation study carried out by Wang et al are discussed, in relation to the study design and its limitations, and challenges and opportunities for future studies are outlined.

Using Mendelian randomization to determine causal effects of maternal pregnancy (intrauterine) exposures on offspring outcomes: Sources of bias and methods for assessing them

Recommendations that researchers should use when applying MR to test the effects of intrauterine exposures on postnatal offspring outcomes are provided and an illustrative example with real data is used to demonstrate how these can be applied and subsequent results appropriately interpreted.