Dataset Information

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

ABSTRACT: Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.

SUBMITTER: Feng H

PROVIDER: S-EPMC7987299 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Feng Helian H Gusev Alexander A Pasaniuc Bogdan B Wu Lang L Long Jirong J Abu-Full Zomoroda Z Aittomäki Kristiina K Andrulis Irene L IL Anton-Culver Hoda H Antoniou Antonis C AC Arason Adalgeir A Arndt Volker V Aronson Kristan J KJ Arun Banu K BK Asseryanis Ella E Auer Paul L PL Azzollini Jacopo J Balmaña Judith J Barkardottir Rosa B RB Barnes Daniel R DR Barrowdale Daniel D Beckmann Matthias W MW Behrens Sabine S Benitez Javier J Bermisheva Marina M Białkowska Katarzyna K Blanco Ana A Blomqvist Carl C Boeckx Bram B Bogdanova Natalia V NV Bojesen Stig E SE Bolla Manjeet K MK Bonanni Bernardo B Borg Ake A Brauch Hiltrud H Brenner Hermann H Briceno Ignacio I Broeks Annegien A Brüning Thomas T Burwinkel Barbara B Cai Qiuyin Q Caldés Trinidad T Caligo Maria A MA Campbell Ian I Canisius Sander S Campa Daniele D Carter Brian D BD Carter Jonathan J Castelao Jose E JE Chang-Claude Jenny J Chanock Stephen J SJ Christiansen Hans H Chung Wendy K WK Claes Kathleen B M KBM Clarke Christine L CL Couch Fergus J FJ Cox Angela A Cross Simon S SS Cybulski Cezary C Czene Kamila K Daly Mary B MB de la Hoya Miguel M De Leeneer Kim K Dennis Joe J Devilee Peter P Diez Orland O Domchek Susan M SM Dörk Thilo T Dos-Santos-Silva Isabel I Dunning Alison M AM Dwek Miriam M Eccles Diana M DM Ejlertsen Bent B Ellberg Carolina C Engel Christoph C Eriksson Mikael M Fasching Peter A PA Fletcher Olivia O Flyger Henrik H Fostira Florentia F Friedman Eitan E Fritschi Lin L Frost Debra D Gabrielson Marike M Ganz Patricia A PA Gapstur Susan M SM Garber Judy J García-Closas Montserrat M García-Sáenz José A JA Gaudet Mia M MM Giles Graham G GG Glendon Gord G Godwin Andrew K AK Goldberg Mark S MS Goldgar David E DE González-Neira Anna A Greene Mark H MH Gronwald Jacek J Guénel Pascal P Haiman Christopher A CA Hall Per P Hamann Ute U Hake Christopher C He Wei W Heyworth Jane J Hogervorst Frans B L FBL Hollestelle Antoinette A Hooning Maartje J MJ Hoover Robert N RN Hopper John L JL Huang Guanmengqian G Hulick Peter J PJ Humphreys Keith K Imyanitov Evgeny N EN Isaacs Claudine C Jakimovska Milena M Jakubowska Anna A James Paul P Janavicius Ramunas R Jankowitz Rachel C RC John Esther M EM Johnson Nichola N Joseph Vijai V Jung Audrey A Karlan Beth Y BY Khusnutdinova Elza E Kiiski Johanna I JI Konstantopoulou Irene I Kristensen Vessela N VN Laitman Yael Y Lambrechts Diether D Lazaro Conxi C Leroux Dominique D Leslie Goska G Lester Jenny J Lesueur Fabienne F Lindor Noralane N Lindström Sara S Lo Wing-Yee WY Loud Jennifer T JT Lubiński Jan J Makalic Enes E Mannermaa Arto A Manoochehri Mehdi M Manoukian Siranoush S Margolin Sara S Martens John W M JWM Martinez Maria E ME Matricardi Laura L Maurer Tabea T Mavroudis Dimitrios D McGuffog Lesley L Meindl Alfons A Menon Usha U Michailidou Kyriaki K Kapoor Pooja M PM Miller Austin A Montagna Marco M Moreno Fernando F Moserle Lidia L Mulligan Anna M AM Muranen Taru A TA Nathanson Katherine L KL Neuhausen Susan L SL Nevanlinna Heli H Nevelsteen Ines I Nielsen Finn C FC Nikitina-Zake Liene L Offit Kenneth K Olah Edith E Olopade Olufunmilayo I OI Olsson Håkan H Osorio Ana A Papp Janos J Park-Simon Tjoung-Won TW Parsons Michael T MT Pedersen Inge S IS Peixoto Ana A Peterlongo Paolo P Peto Julian J Pharoah Paul D P PDP Phillips Kelly-Anne KA Plaseska-Karanfilska Dijana D Poppe Bruce B Pradhan Nisha N Prajzendanc Karolina K Presneau Nadege N Punie Kevin K Pylkäs Katri K Radice Paolo P Rantala Johanna J Rashid Muhammad Usman MU Rennert Gad G Risch Harvey A HA Robson Mark M Romero Atocha A Saloustros Emmanouil E Sandler Dale P DP Santos Catarina C Sawyer Elinor J EJ Schmidt Marjanka K MK Schmidt Daniel F DF Schmutzler Rita K RK Schoemaker Minouk J MJ Scott Rodney J RJ Sharma Priyanka P Shu Xiao-Ou XO Simard Jacques J Singer Christian F CF Skytte Anne-Bine AB Soucy Penny P Southey Melissa C MC Spinelli John J JJ Spurdle Amanda B AB Stone Jennifer J Swerdlow Anthony J AJ Tapper William J WJ Taylor Jack A JA Teixeira Manuel R MR Terry Mary Beth MB Teulé Alex A Thomassen Mads M Thöne Kathrin K Thull Darcy L DL Tischkowitz Marc M Toland Amanda E AE Tollenaar Rob A E M RAEM Torres Diana D Truong Thérèse T Tung Nadine N Vachon Celine M CM van Asperen Christi J CJ van den Ouweland Ans M W AMW van Rensburg Elizabeth J EJ Vega Ana A Viel Alessandra A Vieiro-Balo Paula P Wang Qin Q Wappenschmidt Barbara B Weinberg Clarice R CR Weitzel Jeffrey N JN Wendt Camilla C Winqvist Robert R Yang Xiaohong R XR Yannoukakos Drakoulis D Ziogas Argyrios A Milne Roger L RL Easton Douglas F DF Chenevix-Trench Georgia G Zheng Wei W Kraft Peter P Jiang Xia X

Genetic epidemiology 20200301 5

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). W ...[more]

PMID: 32115800

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Project description:Large genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with increased risk of prostate cancer (PrCa), and many of these risk loci is presumed to confer regulatory effects on gene expression. While eQTL studies of long RNAs has yielded many potential risk genes, the relationship between PrCa risk genetics and microRNA expression dysregulation is understudied. We performed an microRNA transcriptome-wide association study of PrCa risk using small RNA sequencing and genome-wide genotyping data from N = 441 normal prostate epithelium tissue samples along with N = 411 prostate adenocarcinoma tumor samples from the Cancer Genome Atlas (TCGA). Genetically regulated expression prediction models were trained for all expressed microRNAs using the FUSION TWAS software. TWAS for PrCa risk was performed with both sets of models using single-SNP summary statistics from the recent PRACTICAL consortium PrCa case-control OncoArray GWAS meta-analysis. A total of 613 and 571 distinct expressed microRNAs were identified in the normal and tumor tissue datasets, respectively (overlap: 480). Among these, 79 (13%) normal tissue microRNAs demonstrated significant cis-heritability (median cis-h2 = 0.15, range: 0.03-0.79) for model training. Similar results were obtained from TCGA tumor samples, with 48 (9%) microRNA expression models successfully trained (median cis-h2 = 0.14, range: 0.06-0.60). Using normal tissue models, we identified two significant TWAS microRNA associations with PrCa risk: over-expression of mir-941 family microRNAs (PTWAS = 2.9E-04) and reduced expression of miR-3617-5p (PTWAS = 1.0E-03). The TCGA tumor TWAS also identified a significant association with miR-941 overexpression (PTWAS = 9.7E-04). Subsequent finemapping of the TWAS results using a multi-tissue database indicated limited evidence of causal status for each microRNA with PrCa risk (posterior inclusion probabilities <0.05). Future work will examine downstream regulatory effects of microRNA dysregulation as well as microRNA-mediated risk mechanisms via competing endogenous RNA relationships.

Dataset Information

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Publications

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

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