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Genome-wide and candidate gene association studies of placental abruption.

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.

SUBMITTER: Workalemahu T

PROVIDER: S-EPMC3773564 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Genome-wide and candidate gene association studies of placental abruption.

Workalemahu Tsegaselassie T Enquobahrie Daniel A DA Moore Amy A Sanchez Sixto E SE Ananth Cande V CV Pacora Percy N PN Liang Liming L Salazar Manuel M Williams Michelle A MA

International journal of molecular epidemiology and genetics 20130912 3

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 ...[more]

PMID: 24046805

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Project description:While available evidence supports the role of genetics in the pathogenesis of placental abruption (PA), PA-related placental genome variations and maternal-placental genetic interactions have not been investigated. Maternal blood and placental samples collected from participants in the Peruvian Abruptio Placentae Epidemiology study were genotyped using Illumina's Cardio-Metabochip platform. We examined 118,782 genome-wide SNPs and 333 SNPs in 32 candidate genes from mitochondrial biogenesis and oxidative phosphorylation pathways in placental DNA from 280 PA cases and 244 controls. We assessed maternal-placental interactions in the candidate gene SNPS and two imprinted regions (IGF2/H19 and C19MC). Univariate and penalized logistic regression models were fit to estimate odds ratios. We examined the combined effect of multiple SNPs on PA risk using weighted genetic risk scores (WGRS) with repeated ten-fold cross-validations. A multinomial model was used to investigate maternal-placental genetic interactions. In placental genome-wide and candidate gene analyses, no SNP was significant after false discovery rate correction. The top genome-wide association study (GWAS) hits were rs544201, rs1484464 (CTNNA2), rs4149570 (TNFRSF1A) and rs13055470 (ZNRF3) (p-values: 1.11e-05 to 3.54e-05). The top 200 SNPs of the GWAS overrepresented genes involved in cell cycle, growth and proliferation. The top candidate gene hits were rs16949118 (COX10) and rs7609948 (THRB) (p-values: 6.00e-03 and 8.19e-03). Participants in the highest quartile of WGRS based on cross-validations using SNPs selected from the GWAS and candidate gene analyses had a 8.40-fold (95% CI: 5.8-12.56) and a 4.46-fold (95% CI: 2.94-6.72) higher odds of PA compared to participants in the lowest quartile. We found maternal-placental genetic interactions on PA risk for two SNPs in PPARG (chr3:12313450 and chr3:12412978) and maternal imprinting effects for multiple SNPs in the C19MC and IGF2/H19 regions. Variations in the placental genome and interactions between maternal-placental genetic variations may contribute to PA risk. Larger studies may help advance our understanding of PA pathogenesis.

Project description:BackgroundGenome-wide association (GWA) studies have led to a paradigm shift in how researchers study the genetics underlying disease. Many GWA studies are now publicly available and can be used to examine whether or not previously proposed candidate genes are supported by GWA data. This approach is particularly important for the field of alcoholism because the contribution of many candidate genes remains controversial.MethodsUsing the Human Genome Epidemiology (HuGE) Navigator, we selected candidate genes for alcoholism that have been frequently examined in scientific articles in the past decade. Specific candidate loci as well as all the reported single nucleotide polymorphisms (SNPs) in candidate genes were examined in the Study of Addiction: Genetics and Environment (SAGE), a GWA study comparing alcohol-dependent and nondependent subjects.ResultsSeveral commonly reported candidate loci, including rs1800497 in DRD2, rs698 in ADH1C, rs1799971 in OPRM1, and rs4680 in COMT, are not replicated in SAGE (p > 0.05). Among candidate loci available for analysis, only rs279858 in GABRA2 (p = 0.0052, OR = 1.16) demonstrated a modest association. Examination of all SNPs reported in SAGE in over 50 candidate genes revealed no SNPs with large frequency differences between cases and controls, and the lowest p-value of any SNP was 0.0006.ConclusionsWe provide evidence that several extensively studied candidate loci do not have a strong contribution to risk of developing alcohol dependence in European and African ancestry populations. Owing to the lack of coverage, we were unable to rule out the contribution of other variants, and these genes and particular loci warrant further investigation. Our analysis demonstrates that publicly available GWA results can be used to better understand which if any of previously proposed candidate genes contribute to disease. Furthermore, we illustrate how examining the convergence of candidate gene and GWA studies can help elucidate the genetic architecture of alcoholism and more generally complex diseases.

Project description:BACKGROUND: The high-throughput genotyping chips have contributed greatly to genome-wide association (GWA) studies to identify novel disease susceptibility single nucleotide polymorphisms (SNPs). The high-density chips are designed using two different SNP selection approaches, the direct gene-centric approach, and the indirect quasi-random SNPs or linkage disequilibrium (LD)-based tagSNPs approaches. Although all these approaches can provide high genome coverage and ascertain variants in genes, it is not clear to which extent these approaches could capture the common genic variants. It is also important to characterize and compare the differences between these approaches. METHODOLOGY/PRINCIPAL FINDINGS: In our study, by using both the Phase II HapMap data and the disease variants extracted from OMIM, a gene-centric evaluation was first performed to evaluate the ability of the approaches in capturing the disease variants in Caucasian population. Then the distribution patterns of SNPs were also characterized in genic regions, evolutionarily conserved introns and nongenic regions, ontologies and pathways. The results show that, no mater which SNP selection approach is used, the current high-density SNP chips provide very high coverage in genic regions and can capture most of known common disease variants under HapMap frame. The results also show that the differences between the direct and the indirect approaches are relatively small. Both have similar SNP distribution patterns in these gene-centric characteristics. CONCLUSIONS/SIGNIFICANCE: This study suggests that the indirect approaches not only have the advantage of high coverage but also are useful for studies focusing on various functional SNPs either in genes or in the conserved regions that the direct approach supports. The study and the annotation of characteristics will be helpful for designing and analyzing GWA studies that aim to identify genetic risk factors involved in common diseases, especially variants in genes and conserved regions.

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Genome-wide and candidate gene association studies of placental abruption.

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Genome-wide and candidate gene association studies of placental abruption.

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