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A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.

ABSTRACT: BACKGROUND:Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS:To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n?=?95] and Genotype-Tissue Expression v7 [n?=?174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n?=?74-421 samples). RESULTS:We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS:By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

SUBMITTER: Zhong J

PROVIDER: S-EPMC7566474 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.

Zhong Jun J Jermusyk Ashley A Wu Lang L Hoskins Jason W JW Collins Irene I Mocci Evelina E Zhang Mingfeng M Song Lei L Chung Charles C CC Zhang Tongwu T Xiao Wenming W Albanes Demetrius D Andreotti Gabriella G Arslan Alan A AA Babic Ana A Bamlet William R WR Beane-Freeman Laura L Berndt Sonja S Borgida Ayelet A Bracci Paige M PM Brais Lauren L Brennan Paul P Bueno-de-Mesquita Bas B Buring Julie J Canzian Federico F Childs Erica J EJ Cotterchio Michelle M Du Mengmeng M Duell Eric J EJ Fuchs Charles C Gallinger Steven S Gaziano J Michael JM Giles Graham G GG Giovannucci Edward E Goggins Michael M Goodman Gary E GE Goodman Phyllis J PJ Haiman Christopher C Hartge Patricia P Hasan Manal M Helzlsouer Kathy J KJ Holly Elizabeth A EA Klein Eric A EA Kogevinas Manolis M Kurtz Robert J RJ LeMarchand Loic L Malats Núria N Männistö Satu S Milne Roger R Neale Rachel E RE Ng Kimmie K Obazee Ofure O Oberg Ann L AL Orlow Irene I Patel Alpa V AV Peters Ulrike U Porta Miquel M Rothman Nathaniel N Scelo Ghislaine G Sesso Howard D HD Severi Gianluca G Sieri Sabina S Silverman Debra D Sund Malin M Tjønneland Anne A Thornquist Mark D MD Tobias Geoffrey S GS Trichopoulou Antonia A Van Den Eeden Stephen K SK Visvanathan Kala K Wactawski-Wende Jean J Wentzensen Nicolas N White Emily E Yu Herbert H Yuan Chen C Zeleniuch-Jacquotte Anne A Hoover Robert R Brown Kevin K Kooperberg Charles C Risch Harvey A HA Jacobs Eric J EJ Li Donghui D Yu Kai K Shu Xiao-Ou XO Chanock Stephen J SJ Wolpin Brian M BM Stolzenberg-Solomon Rachael Z RZ Chatterjee Nilanjan N Klein Alison P AP Smith Jill P JP Kraft Peter P Shi Jianxin J Petersen Gloria M GM Zheng Wei W Amundadottir Laufey T LT

Journal of the National Cancer Institute 20201001 10

<h4>Background</h4>Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown.<h4>Methods</h4>To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integr ...[more]

PMID: 31917448

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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 Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.

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A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.

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