The contribution of genetic and environmental factors to the duration of pregnancy

  • Timothy P. York
    Reprints: Timothy P. York, PhD, Virginia Institute for Psychiatric and Behavioral Genetics, Department of Human and Molecular Genetics & OB/GYN, Virginia Commonwealth University, Box 980003, Richmond, VA 23298-0003.
    Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA

    Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA

    Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Richmond, VA
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  • Lindon J. Eaves
    Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA

    Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA

    Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA
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  • Michael C. Neale
    Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA

    Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA

    Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA
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  • Jerome F. Strauss III
    Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA

    Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Richmond, VA
    Search for articles by this author
Published:October 04, 2013DOI:
      This review describes how improvements in biometric-genetic studies of twin kinships, half-sibships, and cousinships have now demonstrated a sizeable fetal genetic and maternal genetic contribution to the spontaneous onset of labor. This is an important development because previous literature for the most part reports only an influence of the maternal genome. Current estimates of the percent of variation that is attributable to fetal genetic factors range from 11–35%; the range for the maternal genetic contribution is 13–20%. These same studies demonstrate an even larger influence of environmental sources over and above the influence of genetic sources and previously identified environmental risk factors. With these estimates in hand, a major goal for research on pregnancy duration is to identify specific allelic variation and environmental risk to account for this estimated genetic and environmental variation. A review of the current literature can serve as a guide for future research efforts.

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        • Magnus P.
        • Bakketeig L.S.
        • Skjaerven R.
        Correlations of birth weight and gestational age across generations.
        Ann Hum Biol. 1993; 20: 231-238
        • Goldenberg R.L.
        The management of preterm labor.
        Obstet Gynecol. 2002; 100: 1020-1037
        • Lawn J.E.
        • Wilczynska-Ketende K.
        • Cousens S.N.
        Estimating the causes of 4 million neonatal deaths in the year 2000.
        Int J Epidemiol. 2006; 35: 706-718
        • Narang I.
        Review series: what goes around, comes around: childhood influences on later lung health? Long-term follow-up of infants with lung disease of prematurity.
        Chron Respir Dis. 2010; 7: 259-269
        • Crump C.
        • Sundquist K.
        • Winkleby M.A.
        • Sundquist J.
        Preterm birth and risk of epilepsy in Swedish adults.
        Neurology. 2011; 77: 1376-1382
        • Wehkalampi K.
        • Hovi P.
        • Dunkel L.
        • et al.
        Advanced pubertal growth spurt in subjects born preterm: the Helsinki study of very low birth weight adults.
        J Clin Endocrinol Metab. 2011; 96: 525-533
        • Santos I.S.
        • Matijasevich A.
        • Domingues M.R.
        • Barros A.J.
        • Victora C.G.
        • Barros F.C.
        Late preterm birth is a risk factor for growth faltering in early childhood: a cohort study.
        BMC Pediatr. 2009; 9: 71
        • Crump C.
        • Winkleby M.A.
        • Sundquist K.
        • Sundquist J.
        Risk of hypertension among young adults who were born preterm: a Swedish national study of 636,000 births.
        Am J Epidemiol. 2011; 173: 797-803
        • Manzardo A.M.
        • Madarasz W.V.
        • Penick E.C.
        • et al.
        Effects of premature birth on the risk for alcoholism appear to be greater in males than females.
        J Stud Alcohol Drugs. 2011; 72: 390-398
        • Swamy G.K.
        • Ostbye T.
        • Skjaerven R.
        Association of preterm birth with long-term survival, reproduction, and next-generation preterm birth.
        JAMA. 2008; 299: 1429-1436
        • Skilton M.R.
        • Viikari J.S.
        • Juonala M.
        • et al.
        Fetal growth and preterm birth influence cardiovascular risk factors and arterial health in young adults: the Cardiovascular Risk in Young Finns Study.
        Arterioscler Thromb Vasc Biol. 2011; 31: 2975-2981
        • Lye S.J.
        • Tsui P.
        • Dong X.
        • et al.
        Myometrial programming: a new concept underlying the regulation of myometrial function during pregnancy.
        Taylor and Francis, Boca Raton, FL2007
        • Chaudhari B.P.
        • Plunkett J.
        • Ratajczak C.K.
        • Shen T.T.
        • DeFranco E.A.
        • Muglia L.J.
        The genetics of birth timing: insights into a fundamental component of human development.
        Clin Genet. 2008; 74: 493-501
        • Mendelson C.R.
        Minireview: fetal-maternal hormonal signaling in pregnancy and labor.
        Mol Endocrinol. 2009; 23: 947-954
        • Smith R.
        • Paul J.
        • Maiti K.
        • Tolosa J.
        • Madsen G.
        Recent advances in understanding the endocrinology of human birth.
        Trends Endocrinol Metab. 2012; 23: 516-523
        • Clausson B.
        • Lichtenstein P.
        • Cnattingius S.
        Genetic influence on birthweight and gestational length determined by studies in offspring of twins.
        BJOG. 2000; 107: 375-381
        • van Dongen J.
        • Slagboom P.E.
        • Draisma H.H.
        • Martin N.G.
        • Boomsma D.I.
        The continuing value of twin studies in the omics era.
        Nat Rev Genet. 2012; 13: 640-653
        • Posthuma D.
        • Boomsma D.I.
        A note on the statistical power in extended twin designs.
        Behav Genet. 2000; 30: 147-158
        • York T.P.
        • Eaves L.J.
        • Lichtenstein P.
        • et al.
        Fetal and maternal genes' influence on gestational age in a quantitative genetic analysis of 244,000 Swedish births.
        Am J Epidemiol. 2013; 178: 543-550
        • Neale M.C.
        • Cardon L.R.
        Methodology for genetic studies of twins and families.
        Kluwer Academic Publishers, Dordrecht, The Netherlands1992
        • Silventoinen K.
        • Sammalisto S.
        • Perola M.
        • et al.
        Heritability of adult body height: a comparative study of twin cohorts in eight countries.
        Twin Res. 2003; 6: 399-408
        • Silventoinen K.
        Determinants of variation in adult body height.
        J Biosoc Sci. 2003; 35: 263-285
        • Lunde A.
        • Melve K.K.
        • Gjessing H.K.
        • Skjaerven R.
        • Irgens L.M.
        Genetic and environmental influences on birth weight, birth length, head circumference, and gestational age by use of population-based parent-offspring data.
        Am J Epidemiol. 2007; 165: 734-741
        • York T.P.
        • Strauss 3rd, J.F.
        • Neale M.C.
        • Eaves L.J.
        Racial differences in genetic and environmental risk to preterm birth.
        PLoS One. 2010; 5: e12391
        • Svensson A.C.
        • Sandin S.
        • Cnattingius S.
        • et al.
        Maternal effects for preterm birth: a genetic epidemiologic study of 630,000 families.
        Am J Epidemiol. 2009; 170: 1365-1372
        • Oberg A.S.
        • Frisell T.
        • Svensson A.C.
        • Iliadou A.N.
        Maternal and fetal genetic contributions to postterm birth: familial clustering in a population-based sample of 475,429 Swedish births.
        Am J Epidemiol. 2013; 177: 531-537
        • Neale M.C.
        • Eaves L.J.
        • Kendler K.S.
        The power of the classical twin study to resolve variation in threshold traits.
        Behav Genet. 1994; 24: 239-258
        • Ragland D.R.
        Dichotomizing continuous outcome variables: dependence of the magnitude of association and statistical power on the cutpoint.
        Epidemiology. 1992; 3: 434-440
        • MacCallum R.C.
        • Zhang S.
        • Preacher K.J.
        • Rucker D.D.
        On the practice of dichotomization of quantitative variables.
        Psychol Methods. 2002; 7: 19-40
        • Boyd H.A.
        • Poulsen G.
        • Wohlfahrt J.
        • Murray J.C.
        • Feenstra B.
        • Melbye M.
        Maternal contributions to preterm delivery.
        Am J Epidemiol. 2009; 170: 1358-1364
        • Wilcox A.J.
        • Skjaerven R.
        • Lie R.T.
        Familial patterns of preterm delivery: maternal and fetal contributions.
        Am J Epidemiol. 2008; 167: 474-479
        • Treloar S.A.
        • Macones G.A.
        • Mitchell L.E.
        • Martin N.G.
        Genetic influences on premature parturition in an Australian twin sample.
        Twin Res. 2000; 3: 80-82
        • Plunkett J.
        • Feitosa M.F.
        • Trusgnich M.
        • et al.
        Mother's genome or maternally-inherited genes acting in the fetus influence gestational age in familial preterm birth.
        Hum Hered. 2009; 68: 209-219
        • Visscher P.M.
        • Hill W.G.
        • Wray N.R.
        Heritability in the genomics era: concepts and misconceptions.
        Nat Rev Genet. 2008; 9: 255-266
        • Crider K.S.
        • Whitehead N.
        • Buus R.M.
        Genetic variation associated with preterm birth: a HuGE review.
        Genet Med. 2005; 7: 593-604
        • Anum E.A.
        • Springel E.H.
        • Shriver M.D.
        • Strauss 3rd, J.F.
        Genetic contributions to disparities in preterm birth.
        Pediatr Res. 2009; 65: 1-9
        • Plunkett J.
        • Muglia L.J.
        Genetic contributions to preterm birth: implications from epidemiological and genetic association studies.
        Ann Med. 2008; 40: 167-195
        • Hill L.D.
        • York T.P.
        • Kusanovic J.P.
        • et al.
        Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia.
        PLoS One. 2011; 6: e16681
        • Haataja R.
        • Karjalainen M.K.
        • Luukkonen A.
        • et al.
        Mapping a new spontaneous preterm birth susceptibility gene, IGF1R, using linkage, haplotype sharing, and association analysis.
        PLoS Genet. 2011; 7: e1001293
        • Karjalainen M.K.
        • Huusko J.M.
        • Ulvila J.
        • et al.
        A potential novel spontaneous preterm birth gene, AR, identified by linkage and association analysis of X chromosomal markers.
        PLoS One. 2012; 7: e51378
        • Mann P.C.
        • Cooper M.E.
        • Ryckman K.K.
        • et al.
        Polymorphisms in the fetal progesterone receptor and a calcium-activated potassium channel isoform are associated with preterm birth in an Argentinian population.
        J Perinatol. 2013; 33: 336-340
        • Wang H.
        • Parry S.
        • Macones G.
        • et al.
        A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans.
        Proc Natl Acad Sci U S A. 2006; 103: 13463-13467
        • Dolan S.M.
        • Hollegaard M.V.
        • Merialdi M.
        • et al.
        Synopsis of preterm birth genetic association studies: the preterm birth genetics knowledge base (PTBGene).
        Public Health Genomics. 2010; 13: 514-523
        • Bezold K.Y.
        • Karjalainen M.K.
        • Hallman M.
        • Teramo K.
        • Muglia L.J.
        The genomics of preterm birth: from animal models to human studies.
        Genome Med. 2013; 5: 34
        • Kim Y.
        • Zerwas S.
        • Trace S.E.
        • Sullivan P.F.
        Schizophrenia genetics: where next?.
        Schizophr Bull. 2011; 37: 456-463
        • Yang J.
        • Benyamin B.
        • McEvoy B.P.
        • et al.
        Common SNPs explain a large proportion of the heritability for human height.
        Nat Genet. 2010; 42: 565-569
        • Ku C.S.
        • Loy E.Y.
        • Pawitan Y.
        • Chia K.S.
        The pursuit of genome-wide association studies: where are we now?.
        J Hum Genet. 2010; 55: 195-206
        • Singleton A.B.
        • Hardy J.
        • Traynor B.J.
        • Houlden H.
        Towards a complete resolution of the genetic architecture of disease.
        Trends Genet. 2010; 26: 438-442
        • Eberle M.A.
        • Ng P.C.
        • Kuhn K.
        • et al.
        Power to detect risk alleles using genome-wide tag SNP panels.
        PLoS Genet. 2007; 3: 1827-1837
        • Hindorff L.A.
        • Sethupathy P.
        • Junkins H.A.
        • et al.
        Potential etiologic and functional implications of genome-wide association loci for human diseases and traits.
        Proc Natl Acad Sci U S A. 2009; 106: 9362-9367
        • Uzun A.
        • Dewan A.T.
        • Istrail S.
        • Padbury J.F.
        Pathway-based genetic analysis of preterm birth.
        Genomics. 2013; 101: 163-170
        • Manolio T.A.
        • Collins F.S.
        • Cox N.J.
        • et al.
        Finding the missing heritability of complex diseases.
        Nature. 2009; 461: 747-753
        • Button K.S.
        • Ioannidis J.P.
        • Mokrysz C.
        • et al.
        Power failure: why small sample size undermines the reliability of neuroscience.
        Nat Rev Neurosci. 2013; 14: 365-376
        • Lango Allen H.
        • Estrada K.
        • Lettre G.
        • et al.
        Hundreds of variants clustered in genomic loci and biological pathways affect human height.
        Nature. 2010; 467: 832-838
        • Speliotes E.K.
        • Willer C.J.
        • Berndt S.I.
        • et al.
        Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.
        Nat Genet. 2010; 42: 937-948
        • Maher B.
        Personal genomes: the case of the missing heritability.
        Nature. 2008; 456: 18-21
        • Pennell C.E.
        • Jacobsson B.
        • Williams S.M.
        • et al.
        Genetic epidemiologic studies of preterm birth: guidelines for research.
        Am J Obstet Gynecol. 2007; 196: 107-118
        • Cirulli E.T.
        • Goldstein D.B.
        Uncovering the roles of rare variants in common disease through whole-genome sequencing.
        Nat Rev Genet. 2010; 11: 415-425
        • Kaufman J.S.
        • Cooper R.S.
        • McGee D.L.
        Socioeconomic status and health in blacks and whites: the problem of residual confounding and the resiliency of race.
        Epidemiology. 1997; 8: 621-628
        • Lu M.C.
        • Chen B.
        Racial and ethnic disparities in preterm birth: the role of stressful life events.
        Am J Obstet Gynecol. 2004; 191: 691-699
        • Goldenberg R.L.
        • Cliver S.P.
        • Mulvihill F.X.
        • et al.
        Medical, psychosocial, and behavioral risk factors do not explain the increased risk for low birth weight among black women.
        Am J Obstet Gynecol. 1996; 175: 1317-1324
        • Gravlee C.C.
        How race becomes biology: embodiment of social inequality.
        Am J Phys Anthropol. 2009; 139: 47-57
        • Burris H.H.
        • Collins Jr., J.W.
        Race and preterm birth: the case for epigenetic inquiry.
        Ethn Dis. 2010; 20: 296-299
        • McGowan P.O.
        • Sasaki A.
        • D'Alessio A.C.
        • et al.
        Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.
        Nat Neurosci. 2009; 12: 342-348
        • McGowan P.O.
        • Meaney M.J.
        • Szyf M.
        Diet and the epigenetic (re)programming of phenotypic differences in behavior.
        Brain Res. 2008; 1237: 12-24
        • Waterland R.A.
        Early environmental effects on epigenetic regulation in humans.
        Epigenetics. 2009; 4: 523-525
        • Rutten B.P.
        • Mill J.
        Epigenetic mediation of environmental influences in major psychotic disorders.
        Schizophr Bull. 2009; 35: 1045-1056
        • Champagne F.A.
        Epigenetic influence of social experiences across the lifespan.
        Dev Psychobiol. 2010; 52: 299-311
        • Jaenisch R.
        • Bird A.
        Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.
        Nat Genet. 2003; 33: 245-254
        • Miller G.
        • Chen E.
        • Cole S.W.
        Health psychology: developing biologically plausible models linking the social world and physical health.
        Annu Rev Psychol. 2009; 60: 501-524
        • Hunter R.G.
        • McEwen B.S.
        Stress and anxiety across the lifespan: structural plasticity and epigenetic regulation.
        Epigenomics. 2013; 5: 177-194
        • Dolinoy D.C.
        • Weidman J.R.
        • Jirtle R.L.
        Epigenetic gene regulation: linking early developmental environment to adult disease.
        Reprod Toxicol. 2007; 23: 297-307
        • Wang H.
        • Ogawa M.
        • Wood J.R.
        • et al.
        Genetic and epigenetic mechanisms combine to control MMP1 expression and its association with preterm premature rupture of membranes.
        Hum Mol Genet. 2008; 17: 1087-1096
        • Adkins R.M.
        • Krushkal J.
        • Tylavsky F.A.
        • Thomas F.
        Racial differences in gene-specific DNA methylation levels are present at birth.
        Birth Defects Res A Clin Mol Teratol. 2011; 91: 728-736
        • Parets S.E.
        • Conneely K.N.
        • Kilaru V.
        • et al.
        Fetal DNA methylation associates with early spontaneous preterm birth and gestational age.
        PLoS One. 2013; 8: e67489
        • Romero R.
        • Espinoza J.
        • Gotsch F.
        • et al.
        The use of high-dimensional biology (genomics, transcriptomics, proteomics, and metabolomics) to understand the preterm parturition syndrome.
        BJOG. 2006; 113: 118-135
        • Parimi N.
        • Tromp G.
        • Kuivaniemi H.
        • et al.
        Analytical approaches to detect maternal/fetal genotype incompatibilities that increase risk of pre-eclampsia.
        BMC Med Genet. 2008; 9: 60
        • Manuck T.A.
        • Lai Y.
        • Meis P.J.
        • et al.
        Admixture mapping to identify spontaneous preterm birth susceptibility loci in African Americans.
        Obstet Gynecol. 2011; 117: 1078-1084
        • Pasaniuc B.
        • Zaitlen N.
        • Lettre G.
        • et al.
        Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium.
        PLoS Genet. 2011; 7: e1001371
        • Kang G.
        • Gao G.
        • Shete S.
        • et al.
        Capitalizing on admixture in genome-wide association studies: a two-stage testing procedure and application to height in African-Americans.
        Front Genet. 2011; 2
        • Tsai H.J.
        • Yu Y.
        • Zhang S.
        • et al.
        Association of genetic ancestry with preterm delivery and related traits among African American mothers.
        Am J Obstet Gynecol. 2009; 201 (94.e1-10)
        • Glymour M.M.
        • Tchetgen E.J.
        • Robins J.M.
        Credible Mendelian randomization studies: approaches for evaluating the instrumental variable assumptions.
        Am J Epidemiol. 2012; 175: 332-339
        • Smith G.D.
        • Ebrahim S.
        “Mendelian randomization”: can genetic epidemiology contribute to understanding environmental determinants of disease?.
        Int J Epidemiol. 2003; 32: 1-22
        • Kramer M.R.
        • Hogue C.R.
        What causes racial disparities in very preterm birth? A biosocial perspective.
        Epidemiol Rev. 2009; 31: 84-98
        • York T.P.
        • Strauss 3rd, J.F.
        • Neale M.C.
        • Eaves L.J.
        Estimating fetal and maternal genetic contributions to premature birth from multiparous pregnancy histories of twins using MCMC and maximum-likelihood approaches.
        Twin Res Hum Genet. 2009; 12: 333-342