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.
<h4>Background</h4>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 feta...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2020
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/b5bb6856719c4cbca033102f463bf5c0 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:b5bb6856719c4cbca033102f463bf5c0 |
|---|---|
| record_format |
dspace |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R |
| spellingShingle |
Medicine R Jing Chen Jonas Bacelis Pol Sole-Navais Amit Srivastava Julius Juodakis Amy Rouse Mikko Hallman Kari Teramo Mads Melbye Bjarke Feenstra Rachel M Freathy George Davey Smith Deborah A Lawlor Jeffrey C Murray Scott M Williams Bo Jacobsson Louis J Muglia Ge Zhang 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. |
| description |
<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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 |
article |
| author |
Jing Chen Jonas Bacelis Pol Sole-Navais Amit Srivastava Julius Juodakis Amy Rouse Mikko Hallman Kari Teramo Mads Melbye Bjarke Feenstra Rachel M Freathy George Davey Smith Deborah A Lawlor Jeffrey C Murray Scott M Williams Bo Jacobsson Louis J Muglia Ge Zhang |
| author_facet |
Jing Chen Jonas Bacelis Pol Sole-Navais Amit Srivastava Julius Juodakis Amy Rouse Mikko Hallman Kari Teramo Mads Melbye Bjarke Feenstra Rachel M Freathy George Davey Smith Deborah A Lawlor Jeffrey C Murray Scott M Williams Bo Jacobsson Louis J Muglia Ge Zhang |
| author_sort |
Jing Chen |
| 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_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_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_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. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2020 |
| url |
https://doaj.org/article/b5bb6856719c4cbca033102f463bf5c0 |
| work_keys_str_mv |
AT jingchen dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT jonasbacelis dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT polsolenavais dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT amitsrivastava dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT juliusjuodakis dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT amyrouse dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT mikkohallman dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT kariteramo dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT madsmelbye dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT bjarkefeenstra dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT rachelmfreathy dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT georgedaveysmith dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT deborahalawlor dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT jeffreycmurray dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT scottmwilliams dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT bojacobsson dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT louisjmuglia dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs AT gezhang dissectingmaternalandfetalgeneticeffectsunderlyingtheassociationsbetweenmaternalphenotypesbirthoutcomesandadultphenotypesamendelianrandomizationandhaplotypebasedgeneticscoreanalysisin10734motherinfantpairs |
| _version_ |
1718375861708652544 |
| spelling |
oai:doaj.org-article:b5bb6856719c4cbca033102f463bf5c02021-12-02T19:55:40ZDissecting 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.1549-12771549-167610.1371/journal.pmed.1003305https://doaj.org/article/b5bb6856719c4cbca033102f463bf5c02020-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pmed.1003305https://doaj.org/toc/1549-1277https://doaj.org/toc/1549-1676<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.Jing ChenJonas BacelisPol Sole-NavaisAmit SrivastavaJulius JuodakisAmy RouseMikko HallmanKari TeramoMads MelbyeBjarke FeenstraRachel M FreathyGeorge Davey SmithDeborah A LawlorJeffrey C MurrayScott M WilliamsBo JacobssonLouis J MugliaGe ZhangPublic Library of Science (PLoS)articleMedicineRENPLoS Medicine, Vol 17, Iss 8, p e1003305 (2020) |