IJMEG Copyright © 2010-present. All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Mol Epidemiol Genet 2013;4(3):128-139

Original Article
Genome-wide and candidate gene association studies of placental abruption

Tsegaselassie Workalemahu, Daniel A Enquobahrie, Amy Moore, Sixto E Sanchez, Cande V Ananth, Percy N Pacora, Liming
Liang, Manuel Salazar, Michelle A Williams

Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, Massachusetts; Center for Perinatal
Studies, Swedish Medical Center, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle,
Washington; Sección de Post Grado, Facultad de Medicina Humana, Universidad San Martín de Porres, Lima, Peru; A.C.
PROESA, Lima, Peru; Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University
Medical Center, New York; Department of Epidemiology, Joseph L. Mailman School of Public Health, Columbia University, New
York; Department of Obstetrics and Gynecology, San Marcos University, Lima, Peru

Received August 26, 2013; Accepted September 10, 2013; Epub September 12, 2013; Published September 15, 2013

Abstract: Placental abruption (PA), a pregnancy-related vascular disorder, is a leading cause of maternal and perinatal
morbidity and mortality. The success of identifying genetic susceptibility loci for PA, a multi-factorial heritable disorder, has
been limited. We conducted a genome-wide association study (GWAS) and candidate gene association study using 470 PA
cases and 473 controls from Lima, Peru. Genotyping for common genetic variations (single nucleotide polymorphisms, SNPs)
was conducted using the Illumina Cardio-Metabo Chip platform. Common variations in 35 genes that participate in
mitochondrial biogenesis (MB) and oxidative phosphorylation (OS) were selected for the candidate gene study. Regression
models were fit to examine associations of each SNP with risk of PA. In pathway analyses, we examined functions and
functional relationships of genes represented by the top GWAS hits. Genetic risk scores (GRS), based on top hits of the GWAS
and candidate gene analyses, respectively, were computed using the risk allele counting method. The top hit in the GWAS
analyses was rs1238566 (empirical P-value=1.04e-4 and FDR-adjusted P-value=5.65E-04) in FLI-1 gene, a
megakaryocyte-specific transcription factor. Networks of genes involved in lipid metabolism and cell signaling were
significantly enriched by the 51 genes whose SNPs were among the top 200 GWAS hits (P-value <2.1e-3). SNPs known to
regulate MB (e.g. CAMK2B, NR1H3, PPARG, PRKCA, and THRB) and OP (e.g., COX5A, and NDUF family of genes) were
associated with PA risk (P-value <0.05). GRS was significantly associated with PA risk (trend P-value <0.001 and 0.01 for
GWAS and candidate gene based GRS, respectively). Our study suggests that integrating multiple analytical strategies in
genetic association studies can provide opportunities for identifying genetic risk factors and novel molecular mechanisms that
underlie PA. (IJMEG1308006).

Keywords: Placental abruption, genome-wide association study, pathway analyses, candidate gene, genetic risk score

Address correspondence to: Tsegaselassie Workalemahu, Department of Epidemiology, Harvard School of Public Health,
Harvard University, Boston, Massachusetts. E-mail: tsw988@mail.harvard.edu