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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

ABSTRACT: Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

SUBMITTER: Ferreira MA

PROVIDER: S-EPMC6465407 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

Ferreira Manuel A MA Gamazon Eric R ER Al-Ejeh Fares F Aittomäki Kristiina K Andrulis Irene L IL Anton-Culver Hoda H Arason Adalgeir A Arndt Volker V Aronson Kristan J KJ Arun Banu K BK Asseryanis Ella E Azzollini Jacopo J Balmaña Judith J Barnes Daniel R DR Barrowdale Daniel D Beckmann Matthias W MW Behrens Sabine S Benitez Javier J Bermisheva Marina M Białkowska Katarzyna K Blomqvist Carl C Bogdanova Natalia V NV Bojesen Stig E SE Bolla Manjeet K MK Borg Ake A Brauch Hiltrud H Brenner Hermann H Broeks Annegien A Burwinkel Barbara B Caldés Trinidad T Caligo Maria A MA Campa Daniele D Campbell Ian I Canzian Federico F Carter Jonathan J Carter Brian D BD 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 Czene Kamila K Daly Mary B MB de la Hoya Miguel M Dennis Joe J Devilee Peter P Diez Orland O Dörk Thilo T 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 Friedman Eitan E Frost Debra D Gabrielson Marike M Gago-Dominguez Manuela 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 He Wei W Heyworth Jane J Hogervorst Frans B L FBL Hollestelle Antoinette A Hoover Robert N RN Hopper John L JL Hulick Peter J PJ Humphreys Keith K Imyanitov Evgeny N EN Isaacs Claudine C Jakimovska Milena M Jakubowska Anna A James Paul A PA Janavicius Ramunas R Jankowitz Rachel C RC John Esther M EM Johnson Nichola N Joseph Vijai V Karlan Beth Y BY Khusnutdinova Elza E Kiiski Johanna I JI Ko Yon-Dschun YD Jones Michael E ME Konstantopoulou Irene I Kristensen Vessela N VN Laitman Yael Y Lambrechts Diether D Lazaro Conxi C Leslie Goska G Lester Jenny J Lesueur Fabienne F Lindström Sara S Long Jirong J Loud Jennifer T JT Lubiński Jan J Makalic Enes E Mannermaa Arto A Manoochehri Mehdi M Margolin Sara S Maurer Tabea T Mavroudis Dimitrios D McGuffog Lesley L Meindl Alfons A Menon Usha U Michailidou Kyriaki K Miller Austin A Montagna Marco M Moreno Fernando F Moserle Lidia L Mulligan Anna Marie AM Nathanson Katherine L KL Neuhausen Susan L SL Nevanlinna Heli H Nevelsteen Ines I Nielsen Finn C FC Nikitina-Zake Liene L Nussbaum Robert L RL 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 Sokilde IS Peixoto Ana A Peterlongo Paolo P Pharoah Paul D P PDP Plaseska-Karanfilska Dijana D Poppe Bruce B Presneau Nadege N Radice Paolo P Rantala Johanna J Rennert Gad G Risch Harvey A HA Saloustros Emmanouil E Sanden Kristin K Sawyer Elinor J EJ Schmidt Marjanka K MK Schmutzler Rita K RK Sharma Priyanka P Shu Xiao-Ou XO Simard Jacques J Singer Christian F CF 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 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 Wang Qin Q Wappenschmidt Barbara B Weitzel Jeffrey N JN Wendt Camilla C Winqvist Robert R Yang Xiaohong R XR Yannoukakos Drakoulis D Ziogas Argyrios A Kraft Peter P Antoniou Antonis C AC Zheng Wei W Easton Douglas F DF Milne Roger L RL Beesley Jonathan J Chenevix-Trench Georgia G

Nature communications 20190415 1

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several w ...[more]

PMID: 30988301

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Project description:Plants synthesize specialized metabolites to facilitate environmental and ecological interactions. During evolution, plants diversified in their potential to synthesize these metabolites. Quantitative differences in metabolite levels of natural Arabidopsis (Arabidopsis thaliana) accessions can be employed to unravel the genetic basis for metabolic traits using genome-wide association studies (GWAS). Here, we performed metabolic GWAS on seeds of a panel of 315 A. thaliana natural accessions, including the reference genotypes C24 and Col-0, for polar and semi-polar seed metabolites using untargeted ultra-performance liquid chromatography-mass spectrometry. As a complementary approach, we performed quantitative trait locus (QTL) mapping of near-isogenic introgression lines between C24 and Col-0 for specific seed specialized metabolites. Besides common QTL between seeds and leaves, GWAS revealed seed-specific QTL for specialized metabolites, indicating differences in the genetic architecture of seeds and leaves. In seeds, aliphatic methylsulfinylalkyl and methylthioalkyl glucosinolates associated with the ALKENYL HYDROXYALKYL PRODUCING loci (GS-ALK and GS-OHP) on chromosome 4 containing alkenyl hydroxyalkyl producing 2 (AOP2) and 3 (AOP3) or with the GS-ELONG locus on chromosome 5 containing methylthioalkyl malate synthase (MAM1) and MAM3. We detected two unknown sulfur-containing compounds that were also mapped to these loci. In GWAS, some of the annotated flavonoids (kaempferol 3-O-rhamnoside-7-O-rhamnoside, quercetin 3-O-rhamnoside-7-O-rhamnoside) were mapped to transparent testa 7 (AT5G07990), encoding a cytochrome P450 75B1 monooxygenase. Three additional mass signals corresponding to quercetin-containing flavonols were mapped to UGT78D2 (AT5G17050). The association of the loci and associating metabolic features were functionally verified in knockdown mutant lines. By performing GWAS and QTL mapping, we were able to leverage variation of natural populations and parental lines to study seed specialized metabolism. The GWAS data set generated here is a high-quality resource that can be investigated in further studies.

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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

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Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

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