Assessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysis.
BACKGROUND
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.


RESULTS
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.
Human Genetics Division, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America; Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, United States of America.
Ge
G
Zhang
Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Jonas
J
Bacelis
Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, United States of America.
Candice
C
Lengyel
Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Kari
K
Teramo
PEDEGO Research Center, University of Oulu and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
Mikko
M
Hallman
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
Øyvind
Ø
Helgeland
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
Stefan
S
Johansson
Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.
Ronny
R
Myhre
Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Verena
V
Sengpiel
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
Pål Rasmus
PR
Njølstad
Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway; Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
Bo
B
Jacobsson
Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, United States of America.
Louis
L
Muglia
D001827:Body Height; D001835:Body Weight; D015984:Causality; D003718:Denmark; D005260:Female; D005387:Finland; D005865:Gestational Age; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D057182:Mendelian Randomization Analysis; D009035:Mothers; D009664:Norway; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy