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

Autoři: Jing Chen aff001;  Jonas Bacelis aff002;  Pol Sole-Navais aff002;  Amit Srivastava aff004;  Julius Juodakis aff002;  Amy Rouse aff005;  Mikko Hallman aff006;  Kari Teramo aff007;  Mads Melbye aff008;  Bjarke Feenstra aff008;  Rachel M. Freathy aff011;  George Davey Smith aff012;  Deborah A. Lawlor aff012;  Jeffrey C. Murray aff015;  Scott M. Williams aff016;  Bo Jacobsson aff002;  Louis J. Muglia aff004;  Ge Zhang aff004
Působiště autorů: Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America aff001;  Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden aff002;  Region Västra Götaland, Sahlgrenska University Hospital, Department of Obstetrics and Gynecology, Gothenburg, Sweden aff003;  Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America aff004;  Center for Prevention of Preterm Birth, Perinatal Institute and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnat aff005;  Center for Prevention of Preterm Birth, Perinatal Institute and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnat aff005;  Center for Prevention of Preterm Birth, Perinatal Institute and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnat aff005;  Center for Prevention of Preterm Birth, Perinatal Institute and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnat aff005;  PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland aff006;  Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland aff007;  Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark aff008;  Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark aff009;  Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America aff010;  Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, United Kingdom aff011;  MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom aff012;  Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom aff013;  Bristol NIHR Biomedical Research Centre, United Kingdom aff014;  Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America aff015;  Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America aff016;  Department of Genetics and Bioinformatics, Domain of Health Data and Digitalisation, Institute of Public Health, Oslo, Norway aff017
Vyšlo v časopise: 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. PLoS Med 17(8): e32767. doi:10.1371/journal.pmed.1003305
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003305



Many maternal traits are associated with a neonate’s gestational duration, birth weight, and birth length. These birth outcomes are subsequently associated with late-onset health conditions. The causal mechanisms and the relative contributions of maternal and fetal genetic effects behind these observed associations are unresolved.

Methods and findings

Based on 10,734 mother–infant duos of European ancestry from the UK, Northern Europe, Australia, and North America, we constructed haplotype genetic scores using single-nucleotide polymorphisms (SNPs) known to be associated with adult height, body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), and type 2 diabetes (T2D). Using these scores as genetic instruments, we estimated the maternal and fetal genetic effects underlying the observed associations between maternal phenotypes and pregnancy outcomes. We also used infant-specific birth weight genetic scores as instrument and examined the effects of fetal growth on pregnancy outcomes, maternal BP, and glucose levels during pregnancy. The maternal nontransmitted haplotype score for height was significantly associated with gestational duration (p = 2.2 × 10−4). Both maternal and paternal transmitted height haplotype scores were highly significantly associated with birth weight and length (p < 1 × 10−17). The maternal transmitted BMI scores were associated with birth weight with a significant maternal effect (p = 1.6 × 10−4). Both maternal and paternal transmitted BP scores were negatively associated with birth weight with a significant fetal effect (p = 9.4 × 10−3), whereas BP alleles were significantly associated with gestational duration and preterm birth through maternal effects (p = 3.3 × 10−2 and p = 4.5 × 10−3, respectively). The nontransmitted haplotype score for FPG was strongly associated with birth weight (p = 4.7 × 10−6); however, the glucose-increasing alleles in the fetus were associated with reduced birth weight through a fetal effect (p = 2.2 × 10−3). The haplotype scores for T2D were associated with birth weight in a similar way but with a weaker maternal effect (p = 6.4 × 10−3) and a stronger fetal effect (p = 1.3 × 10−5). The paternal transmitted birth weight score was significantly associated with reduced gestational duration (p = 1.8 × 10−4) and increased maternal systolic BP during pregnancy (p = 2.2 × 10−2). The major limitations of the study include missing and heterogenous phenotype data in some data sets and different instrumental strength of genetic scores for different phenotypic traits.


We found that 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 gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: taller maternal stature, higher maternal BMI, and higher maternal blood glucose are associated with larger birth size through maternal effects; in the fetus, the height- and metabolic-risk–increasing alleles are associated with increased and decreased birth size, respectively; alleles raising birth weight in the fetus are associated with shorter gestational duration and higher maternal BP. These maternal and fetal genetic effects may explain the observed associations between the studied maternal phenotypes and birth outcomes, as well as the life-course associations between these birth outcomes and adult phenotypes.

Klíčová slova:

Birth – Birth weight – Genetics – Haplotypes – Phenotypes – Pregnancy – Preterm birth – Type 2 diabetes


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