Transmitted genes, rather than growth limitations caused by actual differences in maternal height, are the key means by which a mother's height influences her baby's birth weight and length, according to a new study published this week in PLOS Medicine. The report from Ge Zhang and Louis Muglia of Cincinnati Children's Hospital Medical Center and the March of Dimes Prematurity Research Center Ohio Collaborative and colleagues does, however, suggest that maternal height can directly mediate duration of gestation.
Compared to tall mothers, short mothers tend to deliver their babies at earlier gestational ages, with lower birth weights and lengths. To understand whether these associations were causative, Zhang and colleagues analyzed infant size and genetic data, including single nucleotide polymorphisms (SNPs), which mark differences between individuals in genes related to specific characteristics (such as height) obtained from 3,485 Nordic mother/baby pairs. The researchers conducted a type of analysis called Mendelian Randomization, which probed for associations between genetically predicted maternal height and duration of gestation, newborn length, and newborn weight. Birth length and weight were significantly associated with the maternal transmitted height-associated SNPs (p-values 8.08E-05 and 4.02E-12), but the associations with the non-transmitted SNPs were far less significant (p-values 0.0405 and 0.404). However, gestational age was significantly but modestly associated with the maternal non-transmitted SNPs (p-value 0.0424).
The use of the mother's non-transmitted alleles (specific variants of genes) in causal inference is an important advantage of the study. Because non-transmitted alleles will influence fetal growth exclusively via the characteristics of the mother, while transmitted alleles act within both mother and fetus, the study of non-transmitted alleles is central to teasing out the direct role of maternal height in fetal growth. However, confirmation in additional cohorts is warranted, as the study participants here may not have been broadly representative of their populations. Additionally, these findings may not be generalizable to low- and middle- income countries, where nutrition-related factors may substantially restrict growth. The authors state, "[d]isentangling these different mechanisms underlying the association between maternal height and pregnancy outcomes is important, as the knowledge may enhance our understanding of the genetic and environmental etiology of these important pregnancy outcomes and how they impact health."
Funding: This work was supported by grants from the March of Dimes (22-FY14-470, National Institutes of Health, Cincinnati Children's Hospital Medical Center, Fifth Third Foundation, Norwegian Research Council, Swedish Medical Society, Jane and Dan Olsson Foundations, Swedish Government Grants to Researchers in the Public Health Service, European Community's Seventh Framework Programme, ENGAGE Consortium, the European Research Council, the University of Bergen, Helse Vest, and the KG Jebsen Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Citation: Zhang G, Bacelis J, Lengyel C, Teramo K, Hallman M, Helgeland Ø, et al. (2015) Assessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysis. PLoS Med 12(8): e1001865. doi:10.1371/journal.pmed.1001865
Human Genetics Division, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, United States of America
Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg, Sweden
Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
PEDEGO Research Center, University of Oulu and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
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Dr Ge Zhang: Ge.Zhang@cchmc.org
Dr. Louis Muglia: Louis.Muglia@cchmc.orgs