Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 377, Issue 12, Pages 1156-1167Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1612665
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Funding
- March of Dimes [22-FY15-003, 21-FY16-121]
- National Institutes of Health
- Cincinnati Children's Hospital Medical Center
- Fifth Third Foundation
- Bill and Melinda Gates Foundation [OPP1113966]
- Jane and Aatos Erkko Foundation
- Norwegian Research Council [FUGE 183220/S10, FRIMEDKLI-05 ES236011]
- Jane Foundation
- Dan Olsson Foundation
- Swedish government [ALFGBG-507701]
- FP7 from European Community's Seventh Framework Program [HEALTH-F4-2007-201413]
- John Templeton Foundation [54860]
- Oak Foundation fellowship
- Nordic Center of Excellence in Health-Related e-Sciences
- Norwegian Mother and Child Cohort Study
- Norwegian Ministry of Health
- Ministry of Education and Research
- National Institute of Environmental Health Sciences [N01-ES-75558]
- National Institute of Neurological Disorders and Stroke [UO1 NS 047537-01, UO1 NS 047537-06A1]
- Norwegian Research Council/FUGE [151918/S10, FRI-MEDBIO 249779]
- Swedish Research Council [2015-02559]
- Academy of Finland
- March of Dimes
- Bill and Melinda Gates Foundation
- John Templeton Foundation
- National Institutes of Health Genes, Environment, and Health Initiative
- Danish Council for Independent Research, Medical Sciences
- National Institute of Arthritis and Musculoskeletal and Skin Diseases [P30 AR070549]
- Swedish Research Council [2015-02559] Funding Source: Swedish Research Council
- Medical Research Council [MC_UU_12013/1] Funding Source: researchfish
- MRC [MC_UU_12013/1] Funding Source: UKRI
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BACKGROUND Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (< 37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P< 5.0x10(-8)) or an association with suggestive significance (P< 1.0x10(-6)) in the discovery set. RESULTS In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement.
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