title: Placental genetic variations in circadian clock-related genes increase the risk of placental abruption.
abstract: The genetic architecture of placental abruption (PA) remains poorly understood. We examined variations in SNPs of circadian clock-related genes in placenta with PA risk. We also explored placental and maternal genomic contributions to PA risk. Placental genomic DNA samples were isolated from 280 PA cases and 244 controls. Genotyping was performed using the Illumina Cardio-MetaboChip. We examined 116 SNPs in 13 genes known to moderate circadian rhythms. Logistic regression models were fit to estimate odds ratios (ORs). The combined effect of multiple SNPs on PA risk was estimated using a weighted genetic risk score. We examined independent and joint associations of wGRS derived from placental and maternal genomes with PA. Seven SNPs in five genes (ARNTL2, CRY2, DEC1, PER3 and RORA), in the placental genome, were associated with PA risk. Each copy of the minor allele (G) of a SNP in the RORA gene (rs2899663) was associated with a 30% reduced odds of PA (95% CI 0.52-0.95). The odds of PA increased with increasing placental-wGRS (Ptrend<0.001). The ORs were 1.00, 2.16, 3.24 and 4.48 across quartiles. Associations persisted after the maternal-wGRS was included in the model. There was evidence of an additive contribution of placental and maternal genetic contributions to PA risk. Participants with placental- and maternal-wGRS in the highest quartile, compared with those in the lowest quartile, had a 15.57-fold (95% CI 3.34-72.60) increased odds of PA. Placental variants in circadian clock-related genes are associated with PA risk; and the association persists after control of genetic variants in the maternal genome.
authors.affiliation: Center for Perinatal Studies, Swedish Medical Center Seattle, WA, USA.
authors.forename: Chunfang
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health Boston, MA, USA.
authors.forename: Bizu
authors.initials: B
authors.lastname: Gelaye
authors.affiliation: UMR Amélioration Génétique et Adaptation des Plantes Méditerranéennes et Tropicales (AGAP), CIRAD Montpellier, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Denis
authors.affiliation: Department of Mathematics and Statistics, Georgetown University Washington, DC, USA.
authors.forename: Mahlet G
authors.initials: MG
authors.lastname: Tadesse
authors.affiliation: Center for Perinatal Studies, Swedish Medical CenterSeattle, WA, USA; Department of Epidemiology, School of Public Health, University of WashingtonSeattle, WA, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Enquobahrie
authors.affiliation: Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University Medical CenterNew York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia UniversityNew York, NY, USA.
authors.forename: Cande V
authors.initials: CV
authors.lastname: Ananth
authors.affiliation: Department of Obstetrics and Gynecology, San Marcos University Lima, Peru.
authors.forename: Percy N
authors.initials: PN
authors.lastname: Pacora
authors.affiliation: Department of Obstetrics and Gynecology, San Marcos University Lima, Peru.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salazar
authors.affiliation: Facultad de Medicina Humana, Universidad Peruana de Ciencias AplicadasPeru; A.C. PROESALima, Peru.
authors.forename: Sixto E
authors.initials: SE
authors.lastname: Sanchez
authors.affiliation: Department of Epidemiology, Harvard T.H. Chan School of Public Health Boston, MA, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Williams
keywords: Circadian gene; SNPs; placentae; placental abruption; pregnancy