Objective: While multiple lines of evidence suggest the importance of genetic contributors to risk of preterm birth, the nature of the genetic component has not been identified. We perform segregation analyses to identify the best fitting genetic model for gestational age, a quantitative proxy for preterm birth. Methods: Because either mother or infant can be considered the proband from a preterm delivery and there is evidence to suggest that genetic factors in either one or both may influence the trait, we performed segregation analysis for gestational age either attributed to the infant (infant’s gestational age), or the mother (by averaging the gestational ages at which her children were delivered), using 96 multiplex preterm families. Results: These data lend further support to a genetic component contributing to birth timing since sporadic (i.e. no familial resemblance) and nontransmission (i.e. environmental factors alone contribute to gestational age) models are strongly rejected. Analyses of gestational age attributed to the infant support a model in which mother’s genome and/or maternally-inherited genes acting in the fetus are largely responsible for birth timing, with a smaller contribution from the paternally-inherited alleles in the fetal genome. Conclusion: Our findings suggest that genetic influences on birth timing are important and likely complex.
© 2009 S. Karger AG, Basel
- Preterm birth
- Gestational age
- Segregation analysis
- Maternal effects
- Genetic model
- Martin JA, Kung HC, Mathews TJ, Hoyert DL, Strobino DM, Guyer B, Sutton SR: Annual summary of vital statistics: 2006. Pediatrics 2008;121:788–801.
- Esplin MS: Preterm birth: A review of genetic factors and future directions for genetic study. Obstet Gynecol Surv 2006;61:800–806.
- Green NS, Damus K, Simpson JL, Iams J, Reece EA, Hobel CJ, Merkatz IR, Greene MF, Schwarz RH: Research agenda for preterm birth: Recommendations from the march of dimes. Am J Obstet Gynecol 2005;193:626–635.
- Adams MM, Elam-Evans LD, Wilson HG, Gilbertz DA: Rates of and factors associated with recurrence of preterm delivery. JAMA 2000;283:1591–1596.
- Basso O, Olsen J, Christensen K: Study of environmental, social, and paternal factors in preterm delivery using sibs and half sibs. A population-based study in denmark. J Epidemiol Community Health 1999;53:20–23.
- Kistka ZA, Palomar L, Boslaugh SE, DeBaun MR, DeFranco EA, Muglia LJ: Risk for postterm delivery after previous postterm delivery. Am J Obstet Gynecol 2007;196:241.e1–e6.
- Kistka ZA, Palomar L, Lee KA, Boslaugh SE, Wangler MF, Cole FS, DeBaun MR, Muglia LJ: Racial disparity in the frequency of recurrence of preterm birth. Am J Obstet Gynecol 2007;196:131.e1–e6.
- Mercer BM, Goldenberg RL, Moawad AH, Meis PJ, Iams JD, Das AF, Caritis SN, Miodovnik M, Menard MK, Thurnau GR, Dombrowski MP, Roberts JM, McNellis D: The preterm prediction study: Effect of gestational age and cause of preterm birth on subsequent obstetric outcome. National institute of child health and human development maternal-fetal medicine units network. Am J Obstet Gynecol 1999;181:1216–1221.
- Winkvist A, Mogren I, Hogberg U: Familial patterns in birth characteristics: Impact on individual and population risks. Int J Epidemiol 1998;27:248–254.
- Melve KK, Skjaerven R, Gjessing HK, Oyen N: Recurrence of gestational age in sibships: Implications for perinatal mortality. Am J Epidemiol 1999;150:756–762.
- Porter TF, Fraser AM, Hunter CY, Ward RH, Varner MW: The risk of preterm birth across generations. Obstet Gynecol 1997;90:63–67.
- 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.
- Treloar SA, Macones GA, Mitchell LE, Martin NG: Genetic influences on premature parturition in an australian twin sample. Twin Res 2000;3:80–82.
- Kistka ZA, Defranco EA, Ligthart L, Willemsen G, Plunkett J, Muglia LJ, Boomsma DI: Heritability of parturition timing: An extended twin design analysis. Am J Obstet Gynecol 2008;199;43.e1–5.
- Lunde A, Melve KK, Gjessing HK, Skjaerven R, Irgens LM: 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.
- Ananth CV, Wilcox AJ: Placental abruption and perinatal mortality in the United States. Am J Epidemiol 2001;153:332–337.
- Li DK: Changing paternity and the risk of preterm delivery in the subsequent pregnancy. Epidemiology 1999;10:148–152.
- Vatten LJ, Skjaerven R: Effects on pregnancy outcome of changing partner between first two births: Prospective population study. BMJ 2003;327:1138.
- Palomar L, DeFranco EA, Lee KA, Allsworth JE, Muglia LJ: Paternal race is a risk factor for preterm birth. Am J Obstet Gynecol 2007;197:152.e1–e7.
- Tan H, Wen SW, Walker M, Demissie K: Parental race, birth weight, gestational age, and fetal growth among twin infants in the united states. Early Hum Dev 2004;80:153–160.
- Lie RT, Wilcox AJ, Skjaerven R: Maternal and paternal influences on length of pregnancy. Obstet Gynecol 2006;107:880–885.
- Wilcox AJ, Skaerven R, Lie RT: Familial patterns of preterm delivery: Maternal and fetal contributions. Am J Epidemiol 2008;167:474–479.
- Plunkett J, Borecki I, Morgan T, Stamilio D, Muglia LJ: Population-based estimate of sibling risk for preterm birth, preterm premature rupture of membranes, placental abruption and pre-eclampsia. BMC Genet 2008;9:44.
- Altmuller J, Palmer LJ, Fischer G, Scherb H, Wjst M: Genomewide scans of complex human diseases: True linkage is hard to find. Am J Hum Genet 2001;69:936–950.
- Kalish RB, Vardhana S, Normand NJ, Gupta M, Witkin SS: Association of a maternal cd14–159 gene polymorphism with preterm premature rupture of membranes and spontaneous preterm birth in multi-fetal pregnancies. J Reprod Immunol 2006;70:109–117.
- Menon R, Velez DR, Simhan H, Ryckman K, Jiang L, Thorsen P, Vogel I, Jacobsson B, Merialdi M, Williams SM, Fortunato SJ: Multilocus interactions at maternal tumor necrosis factor-alpha, tumor necrosis factor receptors, interleukin-6 and interleukin-6 receptor genes predict spontaneous preterm labor in European-American women. Am J Obstet Gynecol 2006;194:1616–1624.
- Engel SA, Erichsen HC, Savitz DA, Thorp J, Chanock SJ, Olshan AF: Risk of spontaneous preterm birth is associated with common proinflammatory cytokine polymorphisms. Epidemiology 2005;16:469–477.
- Macones GA, Parry S, Elkousy M, Clothier B, Ural SH, Strauss JF 3rd: A polymorphism in the promoter region of tnf and bacterial vaginosis: Preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth. Am J Obstet Gynecol 2004;190:1504–1508.
- Velez DR, Menon R, Thorsen P, Jiang L, Simhan H, Morgan N, Fortunato SJ, Williams SM: Ethnic differences in interleukin 6 (il-6) and il6 receptor genes in spontaneous preterm birth and effects on amniotic fluid protein levels. Ann Hum Genet 2007;71:586–600.
- World Health Organization WHO: International statistical classification of diseases and related health problems. Geneva, Switzerland, World Health Organization, 1992, 1 and 2.
- Hasstedt S: Pedigree Analysis Package. Salt Lake City, Department of Human Genetics, University of Utah, 2002.
- Akaike H: A new look at the statistical model identification. IEEE Trans Automat Control 1974;19:716–723.
- Cannings C, Thompson EA: Ascertainment in the sequential sampling of pedigrees. Clin Genet 1977;12:208–212.
- Comuzzie AG, Williams JT: Correcting for ascertainment bias in the coga data set. Genet Epidemiol 1999;17(suppl 1):S109–S114.
- Elston R, Olson J, Palmer L: Ascertainment; Biostatistical genetics and genetic epidemiology. Chichester, John Wiley and Sons, 2002.
- Khoury MJ, James LM: Population and familial relative risks of disease associated with environmental factors in the presence of gene-environment interaction. Am J Epidemiol 1993;137:1241–1250.
- Williams WR, Anderson DE: Genetic epidemiology of breast cancer: Segregation analysis of 200 danish pedigrees. Genet Epidemiol 1984;1:7–20.
- Hager R, Cheverud JM, Wolf JB: Maternal effects as the cause of parent-of-origin effects that mimic genomic imprinting. Genetics 2008;178:1755–1762.
- Crews DH Jr: Age of dam and sex of calf adjustments and genetic parameters for gestation length in charolais cattle. J Anim Sci 2006;84:25–31.
- Jamrozik J, Fatehi J, Kistemaker GJ, Schaeffer LR: Estimates of genetic parameters for Canadian Holstein female reproduction traits. J Dairy Sci 2005;88:2199–2208.
- Heath SC: Markov chain Monte Carlo segregation and linkage analysis for oligogenic models. Am J Hum Genet 1997;61:748–760.
- Thompson: Monte Carlo in Genetic Analysis: Technical Report No 294. Seattle, Department of Statistics, University of Washington, 1995.
- Snow GL, Wijsman EM: Pedigree analysis package (pap) vs. Morgan: Model selection and hypothesis testing on a large pedigree. Genet Epidemiol 1998;15:355–369.
- Boehnke M, Greenberg DA: The effects of conditioning on probands to correct for multiple ascertainment. Am J Hum Genet 1984;36:1298–1308.
Louis J. Muglia, MD, PhD
Vanderbilt University Medical Center
2215 Garland Avenue
Nashville, TN 37232-0007 (USA)
Tel. +1 615 322 5893, Fax +1 615 936 6852, E-Mail Louis.Muglia@Vanderbilt.Edu
Received: December 9, 2008
Accepted after revision: February 26, 2009
Published online: June 11, 2009
Number of Print Pages : 11
Number of Figures : 1, Number of Tables : 5, Number of References : 44
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 68, No. 3, Year 2009 (Cover Date: July 2009)
Journal Editor: Devoto M. (Philadelphia, Pa.)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)
For additional information: http://www.karger.com/HHE
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