Cargando…

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

BACKGROUND: 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...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Jing, Bacelis, Jonas, Sole-Navais, Pol, Srivastava, Amit, Juodakis, Julius, Rouse, Amy, Hallman, Mikko, Teramo, Kari, Melbye, Mads, Feenstra, Bjarke, Freathy, Rachel M., Smith, George Davey, Lawlor, Deborah A., Murray, Jeffrey C., Williams, Scott M., Jacobsson, Bo, Muglia, Louis J., Zhang, Ge
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447062/
https://www.ncbi.nlm.nih.gov/pubmed/32841251
http://dx.doi.org/10.1371/journal.pmed.1003305
_version_ 1783574237321101312
author Chen, Jing
Bacelis, Jonas
Sole-Navais, Pol
Srivastava, Amit
Juodakis, Julius
Rouse, Amy
Hallman, Mikko
Teramo, Kari
Melbye, Mads
Feenstra, Bjarke
Freathy, Rachel M.
Smith, George Davey
Lawlor, Deborah A.
Murray, Jeffrey C.
Williams, Scott M.
Jacobsson, Bo
Muglia, Louis J.
Zhang, Ge
author_facet Chen, Jing
Bacelis, Jonas
Sole-Navais, Pol
Srivastava, Amit
Juodakis, Julius
Rouse, Amy
Hallman, Mikko
Teramo, Kari
Melbye, Mads
Feenstra, Bjarke
Freathy, Rachel M.
Smith, George Davey
Lawlor, Deborah A.
Murray, Jeffrey C.
Williams, Scott M.
Jacobsson, Bo
Muglia, Louis J.
Zhang, Ge
author_sort Chen, Jing
collection PubMed
description BACKGROUND: 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.
format Online
Article
Text
id pubmed-7447062
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-74470622020-08-31 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 Chen, Jing Bacelis, Jonas Sole-Navais, Pol Srivastava, Amit Juodakis, Julius Rouse, Amy Hallman, Mikko Teramo, Kari Melbye, Mads Feenstra, Bjarke Freathy, Rachel M. Smith, George Davey Lawlor, Deborah A. Murray, Jeffrey C. Williams, Scott M. Jacobsson, Bo Muglia, Louis J. Zhang, Ge PLoS Med Research Article BACKGROUND: 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. Public Library of Science 2020-08-25 /pmc/articles/PMC7447062/ /pubmed/32841251 http://dx.doi.org/10.1371/journal.pmed.1003305 Text en © 2020 Chen et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Chen, Jing
Bacelis, Jonas
Sole-Navais, Pol
Srivastava, Amit
Juodakis, Julius
Rouse, Amy
Hallman, Mikko
Teramo, Kari
Melbye, Mads
Feenstra, Bjarke
Freathy, Rachel M.
Smith, George Davey
Lawlor, Deborah A.
Murray, Jeffrey C.
Williams, Scott M.
Jacobsson, Bo
Muglia, Louis J.
Zhang, Ge
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447062/
https://www.ncbi.nlm.nih.gov/pubmed/32841251
http://dx.doi.org/10.1371/journal.pmed.1003305
work_keys_str_mv AT chenjing dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT bacelisjonas dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT solenavaispol dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT srivastavaamit dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT juodakisjulius dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT rouseamy dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT hallmanmikko dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT teramokari dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT melbyemads dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT feenstrabjarke dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT freathyrachelm dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT smithgeorgedavey dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT lawlordeboraha dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT murrayjeffreyc dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT williamsscottm dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT jacobssonbo dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT muglialouisj dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs
AT zhangge dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs