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Article: A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk

TitleA transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk
Authors
Issue Date2018
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2018, v. 78, p. 5419-5430 How to Cite?
AbstractLarge-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.
Persistent Identifierhttp://hdl.handle.net/10722/265152
ISSN
2017 Impact Factor: 9.13
2015 SCImago Journal Rankings: 5.372
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLu, Y-
dc.contributor.authorBeeghly-Fadiel, A-
dc.contributor.authorWu, L-
dc.contributor.authorGuo, XI-
dc.contributor.authorLi, BS-
dc.contributor.authorSchildkraut, JM-
dc.contributor.authorIm, HK-
dc.contributor.authorChen, YA-
dc.contributor.authorPermuth, JB-
dc.contributor.authorReid, BM-
dc.contributor.authorTeer, JK-
dc.contributor.authorDomchek, SM-
dc.contributor.authorDörk, T-
dc.contributor.authorEaston, DF-
dc.contributor.authorEccles, DM-
dc.contributor.authorHøgdall, CK-
dc.contributor.authorHollestelle, A-
dc.contributor.authorHulick, PJ-
dc.contributor.authorHuntsman, DG-
dc.contributor.authorImyanitov, EN-
dc.contributor.authorIsaacs, C-
dc.contributor.authorJakubowska, A-
dc.contributor.authorJames, P-
dc.contributor.authorKarlan, BY-
dc.contributor.authorKelemen, LE-
dc.contributor.authorKiemeney, LA-
dc.contributor.authorKjaer, SK-
dc.contributor.authorKwong, A-
dc.date.accessioned2018-11-20T02:01:11Z-
dc.date.available2018-11-20T02:01:11Z-
dc.date.issued2018-
dc.identifier.citationCancer Research, 2018, v. 78, p. 5419-5430-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/265152-
dc.description.abstractLarge-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.titleA transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk-
dc.typeArticle-
dc.identifier.emailKwong, A: avakwong@hku.hk-
dc.identifier.authorityKwong, A=rp01734-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1158/0008-5472.CAN-18-0951-
dc.identifier.pmcidPMC6139053-
dc.identifier.hkuros295922-
dc.identifier.volume78-
dc.identifier.spage5419-
dc.identifier.epage5430-
dc.identifier.isiWOS:000444803700020-
dc.publisher.placeUnited States-

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