American Journal of Epidemiology Advance Access published online on October 23, 2009
American Journal of Epidemiology, doi:10.1093/aje/kwp325
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Original Contribution |
The Genetics of Preterm Birth: Using What We Know to Design Better Association Studies
* Correspondence to Dr. Clarice Weinberg, Biostatistics Branch, Mail Drop A3-03, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, NC 27709 (e-mail: weinber2{at}niehs.nih.gov).
Received for publication February 26, 2009. Accepted for publication July 15, 2009.
Women delivering preterm are at greatly increased risk of another preterm birth in subsequent pregnancies, reflecting effects of the environment, genetics, or both. Recent literature tells an increasingly coherent story about genetic susceptibility. Women who change partners after delivering preterm retain their elevated risk, whereas fathers who change partners do not. Women who themselves were preterm are at increased risk, an association not seen in fathers. Women with a half-sister who delivered preterm are at increased risk only if the shared parent was the mother. Concordance for preterm delivery is elevated in monozygotic compared with dizygotic twin mothers but not in monozygotic twin fathers. Several mechanisms could be operating: mitochondrial genes, maternal genes, or fetal genes expressing only the maternally derived copy. The authors compare 3 study designs for their ability to detect variants and to distinguish among mechanisms underlying heritability of this common outcome. The case-parent triad design offers robustness against self-selection and genetic population stratification, providing for estimation of genetic effects that are fetal, maternal, or that depend on the parent of origin. A case-base approach compares case-mothers with randomly sampled baby-mother pairs and permits estimation of the same relative risk parameters. Both designs offer important advantages over the commonly applied case-mother/control-mother design.
association analysis; genetics; logistic model; log-linear model; models, statistical; power comparisons; premature birth; study design
Abbreviations: EM, expectation maximization
Editor's note: Related articles appear on pages 000 and 000, an invited commentary on the 3 articles is published on page 000, and a response by the authors of the second article to the commentary is on page 000. In accordance with Journal policy, the authors of the first and third articles were asked whether they wanted to respond to the commentary but chose not to do so.
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