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dc.contributor.authorZhang, Geen_US
dc.contributor.authorBacelis, Jonasen_US
dc.contributor.authorLengyel, Candiceen_US
dc.contributor.authorTeramo, Karien_US
dc.contributor.authorHallman, Mikkoen_US
dc.contributor.authorHelgeland, Øyvinden_US
dc.contributor.authorJohansson, Stefanen_US
dc.contributor.authorMyhre, Ronnyen_US
dc.contributor.authorSengpiel, Verenaen_US
dc.contributor.authorNjølstad, Pål Rasmusen_US
dc.contributor.authorJacobsson, Boen_US
dc.contributor.authorMuglia, Louisen_US
dc.date.accessioned2015-12-31T10:05:44Z
dc.date.available2015-12-31T10:05:44Z
dc.date.issued2015-08-18
dc.PublishedPLoS Medicine 2015, 12(8): e1001865eng
dc.identifier.issn1549-1676
dc.identifier.urihttps://hdl.handle.net/1956/10844
dc.description.abstractBackground: Observational epidemiological studies indicate that maternal height is associated with gestational age at birth and fetal growth measures (i.e., shorter mothers deliver infants at earlier gestational ages with lower birth weight and birth length). Different mechanisms have been postulated to explain these associations. This study aimed to investigate the casual relationships behind the strong association of maternal height with fetal growth measures (i.e., birth length and birth weight) and gestational age by a Mendelian randomization approach. Methods and Findings: We conducted a Mendelian randomization analysis using phenotype and genome-wide single nucleotide polymorphism (SNP) data of 3,485 mother/infant pairs from birth cohorts collected from three Nordic countries (Finland, Denmark, and Norway). We constructed a genetic score based on 697 SNPs known to be associated with adult height to index maternal height. To avoid confounding due to genetic sharing between mother and infant, we inferred parental transmission of the height-associated SNPs and utilized the haplotype genetic score derived from nontransmitted alleles as a valid genetic instrument for maternal height. In observational analysis, maternal height was significantly associated with birth length (p = 6.31 × 10−9), birth weight (p = 2.19 × 10−15), and gestational age (p = 1.51 × 10−7). Our parental-specific haplotype score association analysis revealed that birth length and birth weight were significantly associated with the maternal transmitted haplotype score as well as the paternal transmitted haplotype score. Their association with the maternal nontransmitted haplotype score was far less significant, indicating a major fetal genetic influence on these fetal growth measures. In contrast, gestational age was significantly associated with the nontransmitted haplotype score (p = 0.0424) and demonstrated a significant (p = 0.0234) causal effect of every 1 cm increase in maternal height resulting in ~0.4 more gestational d. Limitations of this study include potential influences in causal inference by biological pleiotropy, assortative mating, and the nonrandom sampling of study subjects. Conclusions: Our results demonstrate that the observed association between maternal height and fetal growth measures (i.e., birth length and birth weight) is mainly defined by fetal genetics. In contrast, the association between maternal height and gestational age is more likely to be causal. In addition, our approach that utilizes the genetic score derived from the nontransmitted maternal haplotype as a genetic instrument is a novel extension to the Mendelian randomization methodology in casual inference between parental phenotype (or exposure) and outcomes in offspring.en_US
dc.language.isoengeng
dc.publisherPLOSeng
dc.relation.urihttp://www.plosmedicine.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pmed.1001865&representation=PDF
dc.rightsAttribution CC BYeng
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/eng
dc.titleAssessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysisen_US
dc.typePeer reviewed
dc.typeJournal article
dc.date.updated2015-09-28T10:49:07Z
dc.description.versionpublishedVersionen_US
dc.rights.holderCopyright 2015 The Authors
dc.identifier.doihttps://doi.org/10.1371/journal.pmed.1001865
dc.identifier.cristin1275988


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