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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

ABSTRACT: Large-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.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

SUBMITTER: Lu Y

PROVIDER: S-EPMC6139053 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

Lu Yingchang Y Beeghly-Fadiel Alicia A Wu Lang L Guo Xingyi X Li Bingshan B Schildkraut Joellen M JM Im Hae Kyung HK Chen Yian A YA Permuth Jennifer B JB Reid Brett M BM Teer Jamie K JK Moysich Kirsten B KB Andrulis Irene L IL Anton-Culver Hoda H Arun Banu K BK Bandera Elisa V EV Barkardottir Rosa B RB Barnes Daniel R DR Benitez Javier J Bjorge Line L Brenton James J Butzow Ralf R Caldes Trinidad T Caligo Maria A MA Campbell Ian I Chang-Claude Jenny J Claes Kathleen B M KBM Couch Fergus J FJ Cramer Daniel W DW Daly Mary B MB deFazio Anna A Dennis Joe J Diez Orland O Domchek Susan M SM Dörk Thilo T Easton Douglas F DF Eccles Diana M DM Fasching Peter A PA Fortner Renée T RT Fountzilas George G Friedman Eitan E Ganz Patricia A PA Garber Judy J Giles Graham G GG Godwin Andrew K AK Goldgar David E DE Goodman Marc T MT Greene Mark H MH Gronwald Jacek J Hamann Ute U Heitz Florian F Hildebrandt Michelle A T MAT Høgdall Claus K CK Hollestelle Antoinette A Hulick Peter J PJ Huntsman David G DG Imyanitov Evgeny N EN Isaacs Claudine C Jakubowska Anna A James Paul P Karlan Beth Y BY Kelemen Linda E LE Kiemeney Lambertus A LA Kjaer Susanne K SK Kwong Ava A Le Nhu D ND Leslie Goska G Lesueur Fabienne F Levine Douglas A DA Mattiello Amalia A May Taymaa T McGuffog Lesley L McNeish Iain A IA Merritt Melissa A MA Modugno Francesmary F Montagna Marco M Neuhausen Susan L SL Nevanlinna Heli H Nielsen Finn C FC Nikitina-Zake Liene L Nussbaum Robert L RL Offit Kenneth K Olah Edith E Olopade Olufunmilayo I OI Olson Sara H SH Olsson Håkan H Osorio Ana A Park Sue K SK Parsons Michael T MT Peeters Petra H M PHM Pejovic Tanja T Peterlongo Paolo P Phelan Catherine M CM Pujana Miquel Angel MA Ramus Susan J SJ Rennert Gad G Risch Harvey H Rodriguez Gustavo C GC Rodríguez-Antona Cristina C Romieu Isabelle I Rookus Matti A MA Rossing Mary Anne MA Rzepecka Iwona K IK Sandler Dale P DP Schmutzler Rita K RK Setiawan Veronica W VW Sharma Priyanka P Sieh Weiva W Simard Jacques J Singer Christian F CF Song Honglin H Southey Melissa C MC Spurdle Amanda B AB Sutphen Rebecca R Swerdlow Anthony J AJ Teixeira Manuel R MR Teo Soo H SH Thomassen Mads M Tischkowitz Marc M Toland Amanda E AE Trichopoulou Antonia A Tung Nadine N Tworoger Shelley S SS van Rensburg Elizabeth J EJ Vanderstichele Adriaan A Vega Ana A Edwards Digna Velez DV Webb Penelope M PM Weitzel Jeffrey N JN Wentzensen Nicolas N White Emily E Wolk Alicja A Wu Anna H AH Yannoukakos Drakoulis D Zorn Kristin K KK Gayther Simon A SA Antoniou Antonis C AC Berchuck Andrew A Goode Ellen L EL Chenevix-Trench Georgia G Sellers Thomas A TA Pharoah Paul D P PDP Zheng Wei W Long Jirong J

Cancer research 20180727 18

Large-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 tis ...[more]

PMID: 30054336

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Project description:IntroductionCataract is the leading cause of blindness among the elderly worldwide. Twin and family studies support an important role for genetic factors in cataract susceptibility with heritability estimates up to 58%. To date, 55 loci for cataract have been identified by genome-wide association studies (GWAS), however, much work remains to identify the causal genes. Here, we conducted a transcriptome-wide association study (TWAS) of cataract to prioritize causal genes and identify novel ones, and examine the impact of their expression.MethodsWe performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 54 tissues (including 49 from the Genotype Tissue Expression (GTEx) Project v8) with cataract using FUSION software. Meta-analyzed GWAS summary statistics from 59,944 cataract cases and 478,571 controls, all of European ancestry and from two cohorts (GERA and UK Biobank) were used. We then examined the expression of the novel genes in the lens tissue using the iSyTE database.ResultsAcross tissue-specific and multi-tissue analyses, we identified 99 genes for which genetically predicted gene expression was associated with cataract after correcting for multiple testing. Of these 99 genes, 20 (AC007773.1, ANKH, ASIP, ATP13A2, CAPZB, CEP95, COQ6, CREB1, CROCC, DDX5, EFEMP1, EIF2S2, ESRRB, GOSR2, HERC4, INSRR, NIPSNAP2, PICALM, SENP3, and SH3YL1) did not overlap with previously reported cataract-associated loci. Tissue-specific analysis identified 202 significant gene-tissue associations for cataract, of which 166 (82.2%), representing 9 unique genes, were attributed to the previously reported 11q13.3 locus. Tissue-enrichment analysis revealed that gastrointestinal tissues represented one of the highest proportions of the Bonferroni-significant gene-tissue associations (21.3%). Moreover, this gastrointestinal tissue type was the only anatomical category significantly enriched in our results, after correcting for the number of tissue donors and imputable genes for each reference panel. Finally, most of the novel cataract genes (e.g., Capzb) were robustly expressed in iSyTE lens data.DiscussionOur results provide evidence of the utility of imputation-based TWAS approaches to characterize known GWAS risk loci and identify novel candidate genes that may increase our understanding of cataract etiology. Our findings also highlight the fact that expression of genes associated with cataract susceptibility is not necessarily restricted to lens tissue.

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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

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