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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

ABSTRACT: The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P?

SUBMITTER: Wu L

PROVIDER: S-EPMC6314198 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

Wu Lang L Shi Wei W Long Jirong J Guo Xingyi X Michailidou Kyriaki K Beesley Jonathan J Bolla Manjeet K MK Shu Xiao-Ou XO Lu Yingchang Y Cai Qiuyin Q Al-Ejeh Fares F Rozali Esdy E Wang Qin Q Dennis Joe J Li Bingshan B Zeng Chenjie C Feng Helian H Gusev Alexander A Barfield Richard T RT Andrulis Irene L IL Anton-Culver Hoda H Arndt Volker V Aronson Kristan J KJ Auer Paul L PL Barrdahl Myrto M Baynes Caroline C Beckmann Matthias W MW Benitez Javier J Bermisheva Marina M Blomqvist Carl C Bogdanova Natalia V NV Bojesen Stig E SE Brauch Hiltrud H Brenner Hermann H Brinton Louise L Broberg Per P Brucker Sara Y SY Burwinkel Barbara B Caldés Trinidad T Canzian Federico F Carter Brian D BD Castelao J Esteban JE Chang-Claude Jenny J Chen Xiaoqing X Cheng Ting-Yuan David TD Christiansen Hans H Clarke Christine L CL Collée Margriet M Cornelissen Sten S Couch Fergus J FJ Cox David D Cox Angela A Cross Simon S SS Cunningham Julie M JM Czene Kamila K Daly Mary B MB Devilee Peter P Doheny Kimberly F KF Dörk Thilo T Dos-Santos-Silva Isabel I Dumont Martine M Dwek Miriam M Eccles Diana M DM Eilber Ursula U Eliassen A Heather AH Engel Christoph C Eriksson Mikael M Fachal Laura L Fasching Peter A PA Figueroa Jonine J Flesch-Janys Dieter D Fletcher Olivia O Flyger Henrik H Fritschi Lin L Gabrielson Marike M Gago-Dominguez Manuela M Gapstur Susan M SM García-Closas Montserrat M Gaudet Mia M MM Ghoussaini Maya M Giles Graham G GG Goldberg Mark S MS Goldgar David E DE González-Neira Anna A Guénel Pascal P Hahnen Eric E Haiman Christopher A CA Håkansson Niclas N Hall Per P Hallberg Emily E Hamann Ute U Harrington Patricia P Hein Alexander A Hicks Belynda B Hillemanns Peter P Hollestelle Antoinette A Hoover Robert N RN Hopper John L JL Huang Guanmengqian G Humphreys Keith K Hunter David J DJ Jakubowska Anna A Janni Wolfgang W John Esther M EM Johnson Nichola N Jones Kristine K Jones Michael E ME Jung Audrey A Kaaks Rudolf R Kerin Michael J MJ Khusnutdinova Elza E Kosma Veli-Matti VM Kristensen Vessela N VN Lambrechts Diether D Le Marchand Loic L Li Jingmei J Lindström Sara S Lissowska Jolanta J Lo Wing-Yee WY Loibl Sibylle S Lubinski Jan J Luccarini Craig C Lux Michael P MP MacInnis Robert J RJ Maishman Tom T Kostovska Ivana Maleva IM Mannermaa Arto A Manson JoAnn E JE Margolin Sara S Mavroudis Dimitrios D Meijers-Heijboer Hanne H Meindl Alfons A Menon Usha U Meyer Jeffery J Mulligan Anna Marie AM Neuhausen Susan L SL Nevanlinna Heli H Neven Patrick P Nielsen Sune F SF Nordestgaard Børge G BG Olopade Olufunmilayo I OI Olson Janet E JE Olsson Håkan H Peterlongo Paolo P Peto Julian J Plaseska-Karanfilska Dijana D Prentice Ross R Presneau Nadege N Pylkäs Katri K Rack Brigitte B Radice Paolo P Rahman Nazneen N Rennert Gad G Rennert Hedy S HS Rhenius Valerie V Romero Atocha A Romm Jane J Rudolph Anja A Saloustros Emmanouil E Sandler Dale P DP Sawyer Elinor J EJ Schmidt Marjanka K MK Schmutzler Rita K RK Schneeweiss Andreas A Scott Rodney J RJ Scott Christopher G CG Seal Sheila S Shah Mitul M Shrubsole Martha J MJ Smeets Ann A Southey Melissa C MC Spinelli John J JJ Stone Jennifer J Surowy Harald H Swerdlow Anthony J AJ Tamimi Rulla M RM Tapper William W Taylor Jack A JA Terry Mary Beth MB Tessier Daniel C DC Thomas Abigail A Thöne Kathrin K Tollenaar Rob A E M RAEM Torres Diana D Truong Thérèse T Untch Michael M Vachon Celine C Van Den Berg David D Vincent Daniel D Waisfisz Quinten Q Weinberg Clarice R CR Wendt Camilla C Whittemore Alice S AS Wildiers Hans H Willett Walter C WC Winqvist Robert R Wolk Alicja A Xia Lucy L Yang Xiaohong R XR Ziogas Argyrios A Ziv Elad E Dunning Alison M AM Pharoah Paul D P PDP Simard Jacques J Milne Roger L RL Edwards Stacey L SL Kraft Peter P Easton Douglas F DF Chenevix-Trench Georgia G Zheng Wei W

Nature genetics 20180618 7

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tis ...[more]

PMID: 29915430

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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.

Project description:AimsDegenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive.MethodsPredicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis.ResultsThe TWAS detected 420 DCS genes with p < 0.05 in skeletal muscle, such as ribosomal protein S15A (RPS15A) (PTWAS = 0.001), and 110 genes in whole blood, such as selectin L (SELL) (PTWAS = 0.001). Comparison with the DCS RNA expression profile identified 12 common genes, including Apelin Receptor (APLNR) (PTWAS = 0.001, PDEG = 0.025). In total, 148 DCS-enriched Gene Ontology (GO) terms were identified, such as mast cell degranulation (GO:0043303); 15 DCS-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified, such as the sphingolipid signalling pathway (ko04071). Nine terms, such as degradation of the extracellular matrix (R-HSA-1474228), were common to the TWAS enrichment results and the RNA expression profile.ConclusionOur results identify putative susceptibility genes; these findings provide new ideas for exploration of the genetic mechanism of DCS development and new targets for preclinical intervention and clinical treatment.Cite this article: Bone Joint Res 2023;12(1):80-90.

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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

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