Chen J, Bacelis J, Sole-Navais P, Srivastava A, Juodakis J, Rouse A, et al. (2020) 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): e1003305. https://doi.org/10.1371/journal.pmed.1003305
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
|Author:||Chen, Jing1; Bacelis, Jonas2,3; Sole-Navais, Pol2;|
1Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
2Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
3Region Västra Götaland, Sahlgrenska University Hospital, Department of Obstetrics and Gynecology, Gothenburg, Sweden
4Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
5Center 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, Cincinnati, Ohio, United States of America
6PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
7Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
8Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
9Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
10Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America
11Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, United Kingdom
12MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom
13Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom
14Bristol NIHR Biomedical Research Centre, United Kingdom
15Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States of America
16Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
17Department of Genetics and Bioinformatics, Domain of Health Data and Digitalisation, Institute of Public Health, Oslo, Norway
|Online Access:||PDF Full Text (PDF, 2.3 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2020092170221
Public Library of Science,
|Publish Date:|| 2020-09-21
Background/Objectives: 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.
Conclusions: 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.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
3123 Gynaecology and paediatrics
This work is supported by a grant from the Burroughs Wellcome Fund (10172896) and a grant from the Cincinnati Children's Hospital Medical Center (GAP/RIP) to GZ and a grant from the March of Dimes (22-FY17-889) and a grant from the Bill and Melinda Gates Foundation (OPP1175128) to LJM and GZ. The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), and NIH/NINDS (grant no. 1: UO1 NS 047537-01 and grant no. 2: UO1 NS 047537-06A1). The genotyping and analyses were supported by grants from Jane and Dan Olsson Foundation (Gothenburg, Sweden), Swedish Medical Research Council (2015-02559), Norwegian Research Council/FUGE (grant no. 151918/S10; FRI-MEDBIO 249779), March of Dimes (21-FY16-121), and the Burroughs Wellcome Fund Preterm Birth Research Grant (10172896) and by Swedish government grants to researchers in the public health sector (ALFGBG-717501, ALFGBG-507701, ALFGBG-426411) to BJ. RMF is supported by a Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). BF was supported by a grant from the Oak Foundation. DAL and GDS work in a unit that is supported by the University of Bristol and Medical Research Council (MC_UU_00011/1 and MC_UU_00011/6). DAL is supported by a grant from the US National Institute of Health (R01 DK10324), an NIHR Senior Investigator Award (NF-0616-10102), a grant from the European Research Council (DevelopObese; 669545) and a grant from the British Heart Foundation (AA/18/7/34219). The UK Medical Research Council and Wellcome (grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The DNBC data sets used for the analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/gap/ through dbGaP accession number phs000103.v1.p1. The GWAS of Prematurity and its Complications study is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under the Genes, Environment and Health Initiative (GEI). The HAPO data sets used for the analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/gap/ through dbGaP accession number phs000096.v4.p1. This study is part of the Gene Environment Association Studies initiative (GENEVA) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The GPN datasets used for the analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/gap/ through dbGaP accession number phs000714.v1.p1. Samples and associated were provided by the NICHD-funded Genomic and Proteomic Network for Preterm Birth Research (GPN-PBR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© 2020 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.