Dataset Information

High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19.

ABSTRACT:

Objective

To refine a previously reported linkage peak for endometriosis on chromosome 10q26, and conduct follow-up analyses and a fine-mapping association study across the region to identify new candidate genes for endometriosis.

Design

Case-control study.

Setting

Academic research.

Patient(s)

Cases=3,223 women with surgically confirmed endometriosis; controls=1,190 women without endometriosis and 7,060 population samples.

Intervention(s)

Analysis of 11,984 single nucleotide polymorphisms on chromosome 10.

Main outcome measure(s)

Allele frequency differences between cases and controls.

Result(s)

Linkage analyses on families grouped by endometriosis symptoms (primarily subfertility) provided increased evidence for linkage (logarithm of odds score=3.62) near a previously reported linkage peak. Three independent association signals were found at 96.59 Mb (rs11592737), 105.63 Mb (rs1253130), and 124.25 Mb (rs2250804). Analyses including only samples from linkage families supported the association at all three regions. However, only rs11592737 in the cytochrome P450 subfamily C (CYP2C19) gene was replicated in an independent sample of 2,079 cases and 7,060 population controls.

Conclusion(s)

The role of the CYP2C19 gene in conferring risk for endometriosis warrants further investigation.

SUBMITTER: Painter JN

PROVIDER: S-EPMC3125525 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19.

Painter Jodie N JN Nyholt Dale R DR Morris Andrew A Zhao Zhen Z ZZ Henders Anjali K AK Lambert Ann A Wallace Leanne L Martin Nicholas G NG Kennedy Stephen H SH Treloar Susan A SA Zondervan Krina T KT Montgomery Grant W GW

Fertility and sterility 20110416 7

<h4>Objective</h4>To refine a previously reported linkage peak for endometriosis on chromosome 10q26, and conduct follow-up analyses and a fine-mapping association study across the region to identify new candidate genes for endometriosis.<h4>Design</h4>Case-control study.<h4>Setting</h4>Academic research.<h4>Patient(s)</h4>Cases=3,223 women with surgically confirmed endometriosis; controls=1,190 women without endometriosis and 7,060 population samples.<h4>Intervention(s)</h4>Analysis of 11,984 s ...[more]

PMID: 21497341

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Project description:Coronary artery disease (CAD), and one of its intermediate risk factors, dyslipidemia, possess a demonstrable genetic component, although the genetic architecture is incompletely defined. We previously reported a linkage peak on chromosome 5q31-33 for early-onset CAD where the strength of evidence for linkage was increased in families with higher mean low density lipoprotein-cholesterol (LDL-C). Therefore, we sought to fine-map the peak using association mapping of LDL-C as an intermediate disease-related trait to further define the etiology of this linkage peak. The study populations consisted of 1908 individuals from the CATHGEN biorepository of patients undergoing cardiac catheterization; 254 families (N = 827 individuals) from the GENECARD familial study of early-onset CAD; and 162 aorta samples harvested from deceased donors. Linkage disequilibrium-tagged SNPs were selected with an average of one SNP per 20 kb for 126.6-160.2 MB (region of highest linkage) and less dense spacing (one SNP per 50 kb) for the flanking regions (117.7-126.6 and 160.2-167.5 MB) and genotyped on all samples using a custom Illumina array. Association analysis of each SNP with LDL-C was performed using multivariable linear regression (CATHGEN) and the quantitative trait transmission disequilibrium test (QTDT; GENECARD). SNPs associated with the intermediate quantitative trait, LDL-C, were then assessed for association with CAD (i.e., a qualitative phenotype) using linkage and association in the presence of linkage (APL; GENECARD) and logistic regression (CATHGEN and aortas).We identified four genes with SNPs that showed the strongest and most consistent associations with LDL-C and CAD: EBF1, PPP2R2B, SPOCK1, and PRELID2. The most significant results for association of SNPs with LDL-C were: EBF1, rs6865969, p = 0.01; PPP2R2B, rs2125443, p = 0.005; SPOCK1, rs17600115, p = 0.003; and PRELID2, rs10074645, p = 0.0002). The most significant results for CAD were EBF1, rs6865969, p = 0.007; PPP2R2B, rs7736604, p = 0.0003; SPOCK1, rs17170899, p = 0.004; and PRELID2, rs7713855, p = 0.003.Using an intermediate disease-related quantitative trait of LDL-C we have identified four novel CAD genes, EBF1, PRELID2, SPOCK1, and PPP2R2B. These four genes should be further examined in future functional studies as candidate susceptibility loci for cardiovascular disease mediated through LDL-cholesterol pathways.

Dataset Information

High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19.

Objective

Design

Setting

Patient(s)

Intervention(s)

Main outcome measure(s)

Result(s)

Conclusion(s)

Publications

High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19.

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