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1.  The Importance of Integration of Stakeholder Views in Core Outcome Set Development: Otitis Media with Effusion in Children with Cleft Palate 
PLoS ONE  2015;10(6):e0129514.
Background
Approximately 75% of children with cleft palate (CP) have Otitis Media with Effusion (OME) histories. Evidence for the effective management of OME in these children is lacking. The inconsistency in outcome measurement in previous studies has led to a call for the development of a Core Outcome Set (COS). Despite the increase in the number of published COS, involvement of patients in the COS development process, and methods to integrate the views of patients and health professionals, to date have been limited.
Methods and Findings
A list of outcomes measured in previous research was identified through reviewing the literature. Opinion on the importance of each of these outcomes was then sought from key stakeholders: Ear, Nose and Throat (ENT) surgeons, audiologists, cleft surgeons, speech and language therapists, specialist cleft nurses, psychologists, parents and children. The opinion of health professionals was sought in a three round Delphi survey where participants were asked to score each outcome using a bespoke online system. Parents and children were also asked to score outcomes in a survey and provided an in-depth insight into having OME through semi-structured interviews. The results of the Delphi survey, interviews and parent/patient survey were brought together in a final consensus meeting with representation from all stakeholders. A final set of eleven outcomes reached the definition of “consensus in” to form the recommended COS: hearing; chronic otitis media (COM); OME; receptive language skills; speech development; psycho social development; acute otitis media (AOM); cholesteatoma; side effects of treatment; listening skills; otalgia.
Conclusions
We have produced a recommendation about the outcomes that should be measured, as a minimum, in studies of the management of OME in children with CP. The development process included input from key stakeholders and used novel methodology to integrate the opinion of healthcare professionals, parents and children.
doi:10.1371/journal.pone.0129514
PMCID: PMC4483230  PMID: 26115172
2.  Identification of two novel mammographic density loci at 6Q25.1 
Introduction
Mammographic density (MD) is a strong heritable and intermediate phenotype for breast cancer, but much of its genetic variation remains unexplained. We performed a large-scale genetic association study including 8,419 women of European ancestry to identify MD loci.
Methods
Participants of three Swedish studies were genotyped on a custom Illumina iSelect genotyping array and percent and absolute mammographic density were ascertained using semiautomated and fully automated methods from film and digital mammograms. Linear regression analysis was used to test for SNP-MD associations, adjusting for age, body mass index, menopausal status and six principal components. Meta-analyses were performed by combining P values taking sample size, study-specific inflation factor and direction of effect into account.
Results
Genome-wide significant associations were observed for two previously identified loci: ZNF365 (rs10995194, P = 2.3 × 10−8 for percent MD and P = 8.7 × 10−9 for absolute MD) and AREG (rs10034692, P = 6.7 × 10−9 for absolute MD). In addition, we found evidence of association for two variants at 6q25.1, both of which are known breast cancer susceptibility loci: rs9485370 in the TAB2 gene (P = 4.8 × 10−9 for percent MD and P = 2.5 × 10−8 for absolute MD) and rs60705924 in the CCDC170/ESR1 region (P = 2.2 × 10−8 for absolute MD). Both regions have been implicated in estrogen receptor signaling with TAB2 being a potential regulator of tamoxifen response.
Conclusions
We identified two novel MD loci at 6q25.1. These findings underscore the importance of 6q25.1 as a susceptibility region and provide more insight into the mechanisms through which MD influences breast cancer risk.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0591-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0591-2
PMCID: PMC4501298  PMID: 26036842
3.  Effects of statin use on volumetric mammographic density: results from the KARMA study 
BMC Cancer  2015;15:435.
Background
Epidemiological data on statins and breast cancer risk have been inconclusive. The aim of this study was to clarify the role of statins in breast cancer risk by studying their effect on mammographic density.
Methods
The KARolinska MAmmography project for risk prediction of breast cancer (KARMA) includes 70,877 women who underwent either a screening or clinical mammography from January 2011 to December 2013. In total, 41,102 women responded to a web-based questionnaire, and had raw digital mammograms stored. Volumetric mammographic density was measured using Volpara™ and information on statin use was obtained through linkage with the Swedish National Prescription Register. Analysis of covariance was used to study the effect of statin use on mammographic density, adjusting for a large set of potential confounders. We also studied the effects of statin class and treatment duration and tested for potential effect modification by hormone replacement therapy (HRT).
Results
Statin use was recorded in 3,337 women (8.1 %) of the study population and lipophilic statins was the most commonly prescribed type (93.4 % of all statin users). After multivariable adjustment, percent dense volume was lower in statin users than in non-users (P < 0.001). This association was explained by a larger absolute non-dense volume in statin users (P < 0.001). Overall, no difference in absolute dense volume was detected, but interaction analyses revealed a larger dense volume among statin users who reported ever HRT use (P = 0.03). No differential effects were observed according to statin lipophilicity and treatment duration.
Conclusions
We observed no overall effect of statin use on mammographic density in terms of absolute dense volume, although a larger absolute dense volume was observed in statin users who reported ever HRT use, which requires further investigation.
doi:10.1186/s12885-015-1457-9
PMCID: PMC4446081  PMID: 26016855
Volumetric mammographic density; Statins; Screening-based cohort; Epidemiology; Breast cancer
4.  Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer 
Purrington, Kristen S. | Slager, Susan | Eccles, Diana | Yannoukakos, Drakoulis | Fasching, Peter A. | Miron, Penelope | Carpenter, Jane | Chang-Claude, Jenny | Martin, Nicholas G. | Montgomery, Grant W. | Kristensen, Vessela | Anton-Culver, Hoda | Goodfellow, Paul | Tapper, William J. | Rafiq, Sajjad | Gerty, Susan M. | Durcan, Lorraine | Konstantopoulou, Irene | Fostira, Florentia | Vratimos, Athanassios | Apostolou, Paraskevi | Konstanta, Irene | Kotoula, Vassiliki | Lakis, Sotiris | Dimopoulos, Meletios A. | Skarlos, Dimosthenis | Pectasides, Dimitrios | Fountzilas, George | Beckmann, Matthias W. | Hein, Alexander | Ruebner, Matthias | Ekici, Arif B. | Hartmann, Arndt | Schulz-Wendtland, Ruediger | Renner, Stefan P. | Janni, Wolfgang | Rack, Brigitte | Scholz, Christoph | Neugebauer, Julia | Andergassen, Ulrich | Lux, Michael P. | Haeberle, Lothar | Clarke, Christine | Pathmanathan, Nirmala | Rudolph, Anja | Flesch-Janys, Dieter | Nickels, Stefan | Olson, Janet E. | Ingle, James N. | Olswold, Curtis | Slettedahl, Seth | Eckel-Passow, Jeanette E. | Anderson, S.Keith | Visscher, Daniel W. | Cafourek, Victoria L. | Sicotte, Hugues | Prodduturi, Naresh | Weiderpass, Elisabete | Bernstein, Leslie | Ziogas, Argyrios | Ivanovich, Jennifer | Giles, Graham G. | Baglietto, Laura | Southey, Melissa | Kosma, Veli-Matti | Fischer, Hans-Peter | Reed, Malcom W.R. | Cross, Simon S. | Deming-Halverson, Sandra | Shrubsole, Martha | Cai, Qiuyin | Shu, Xiao-Ou | Daly, Mary | Weaver, JoEllen | Ross, Eric | Klemp, Jennifer | Sharma, Priyanka | Torres, Diana | Rüdiger, Thomas | Wölfing, Heidrun | Ulmer, Hans-Ulrich | Försti, Asta | Khoury, Thaer | Kumar, Shicha | Pilarski, Robert | Shapiro, Charles L. | Greco, Dario | Heikkilä, Päivi | Aittomäki, Kristiina | Blomqvist, Carl | Irwanto, Astrid | Liu, Jianjun | Pankratz, Vernon Shane | Wang, Xianshu | Severi, Gianluca | Mannermaa, Arto | Easton, Douglas | Hall, Per | Brauch, Hiltrud | Cox, Angela | Zheng, Wei | Godwin, Andrew K. | Hamann, Ute | Ambrosone, Christine | Toland, Amanda Ewart | Nevanlinna, Heli | Vachon, Celine M. | Couch, Fergus J.
Carcinogenesis  2013;35(5):1012-1019.
Summary
In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10− 8) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10− 4] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10− 9) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46–4.70, P = 4.8 × 10− 69). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
doi:10.1093/carcin/bgt404
PMCID: PMC4004200  PMID: 24325915
5.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
6.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
7.  Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk 
Nature communications  2014;5:5303.
Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci.
doi:10.1038/ncomms6303
PMCID: PMC4320806  PMID: 25342443
8.  Common germline polymorphisms associated with breast cancer-specific survival 
Pirie, Ailith | Guo, Qi | Kraft, Peter | Canisius, Sander | Eccles, Diana M | Rahman, Nazneen | Nevanlinna, Heli | Chen, Constance | Khan, Sofia | Tyrer, Jonathan | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Lush, Michael | Dunning, Alison M | Shah, Mitul | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Lambrechts, Dieter | Weltens, Caroline | Leunen, Karin | van Ongeval, Chantal | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Blomqvist, Carl | Aittomäki, Kristiina | Fagerholm, Rainer | Muranen, Taru A | Olsen, Janet E | Hallberg, Emily | Vachon, Celine | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Broeks, Annegien | Cornelissen, Sten | Haiman, Christopher A | Henderson, Brian E | Schumacher, Frederick | Le Marchand, Loic | Hopper, John L | Tsimiklis, Helen | Apicella, Carmel | Southey, Melissa C | Cross, Simon S | Reed, Malcolm WR | Giles, Graham G | Milne, Roger L | McLean, Catriona | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Hooning, Maartje J | Hollestelle, Antoinette | Martens, John WM | van den Ouweland, Ans MW | Marme, Federick | Schneeweiss, Andreas | Yang, Rongxi | Burwinkel, Barbara | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Brenner, Hermann | Butterbach, Katja | Holleczek, Bernd | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Li, Jingmei | Brand, Judith S | Humphreys, Keith | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Ficarazzi, Filomena | Beckmann, Matthias W | Hein, Alexander | Ekici, Arif B | Balleine, Rosemary | Phillips, Kelly-Anne | Benitez, Javier | Zamora, M Pilar | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Jakubowska, Anna | Lubinski, Jan | Gronwald, Jacek | Durda, Katarzyna | Hamann, Ute | Kabisch, Maria | Ulmer, Hans Ulrich | Rüdiger, Thomas | Margolin, Sara | Kristensen, Vessela | Nord, Siljie | Evans, D Gareth | Abraham, Jean | Earl, Helena | Poole, Christopher J | Hiller, Louise | Dunn, Janet A | Bowden, Sarah | Yang, Rose | Campa, Daniele | Diver, W Ryan | Gapstur, Susan M | Gaudet, Mia M | Hankinson, Susan | Hoover, Robert N | Hüsing, Anika | Kaaks, Rudolf | Machiela, Mitchell J | Willett, Walter | Barrdahl, Myrto | Canzian, Federico | Chin, Suet-Feung | Caldas, Carlos | Hunter, David J | Lindstrom, Sara | Garcia-Closas, Montserrat | Couch, Fergus J | Chenevix-Trench, Georgia | Mannermaa, Arto | Andrulis, Irene L | Hall, Per | Chang-Claude, Jenny | Easton, Douglas F | Bojesen, Stig E | Cox, Angela | Fasching, Peter A | Pharoah, Paul DP | Schmidt, Marjanka K
Introduction
Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium.
Methods
A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect.
Results
Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease.
Conclusions
Although no variants reached genome-wide significance (P <5 x 10−8), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0570-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0570-7
PMCID: PMC4484708  PMID: 25897948
9.  The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients 
Oncotarget  2015;6(10):7390-7407.
We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518). Two SNPs were successfully validated: rs6500843 (any chemotherapy; per-allele HR 1.16, 95% C.I. 1.08-1.26, p=0.0001, p(adjusted)=0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p(adjusted)=0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p(interaction)=0.0009), with the rs6500843-GG genotype corresponding to the highest hazard among chemotherapy-treated cases (HR 1.47, 95% C.I. 1.20-1.80). Upon trans-eQTL analysis of public microarray data, the rs6500843 locus was found to associate with the expression of a group of genes involved in cell cycle control, notably AURKA, the expression of which also exhibited differential prognostic value between chemotherapy-treated and untreated cases in our analysis of microarray data. Based on previously published information, we propose that the eQTL genes may be connected to the rs6500843 locus via a RBFOX1-FOXM1-mediated regulatory pathway.
PMCID: PMC4480688  PMID: 25823661
breast cancer; survival; SNP; chemotherapy; cell cycle
10.  Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche 
Perry, John RB | Day, Felix | Elks, Cathy E | Sulem, Patrick | Thompson, Deborah J | Ferreira, Teresa | He, Chunyan | Chasman, Daniel I | Esko, Tõnu | Thorleifsson, Gudmar | Albrecht, Eva | Ang, Wei Q | Corre, Tanguy | Cousminer, Diana L | Feenstra, Bjarke | Franceschini, Nora | Ganna, Andrea | Johnson, Andrew D | Kjellqvist, Sanela | Lunetta, Kathryn L | McMahon, George | Nolte, Ilja M | Paternoster, Lavinia | Porcu, Eleonora | Smith, Albert V | Stolk, Lisette | Teumer, Alexander | Tšernikova, Natalia | Tikkanen, Emmi | Ulivi, Sheila | Wagner, Erin K | Amin, Najaf | Bierut, Laura J | Byrne, Enda M | Hottenga, Jouke-Jan | Koller, Daniel L | Mangino, Massimo | Pers, Tune H | Yerges-Armstrong, Laura M | Zhao, Jing Hua | Andrulis, Irene L | Anton-Culver, Hoda | Atsma, Femke | Bandinelli, Stefania | Beckmann, Matthias W | Benitez, Javier | Blomqvist, Carl | Bojesen, Stig E | Bolla, Manjeet K | Bonanni, Bernardo | Brauch, Hiltrud | Brenner, Hermann | Buring, Julie E | Chang-Claude, Jenny | Chanock, Stephen | Chen, Jinhui | Chenevix-Trench, Georgia | Collée, J. Margriet | Couch, Fergus J | Couper, David | Coveillo, Andrea D | Cox, Angela | Czene, Kamila | D’adamo, Adamo Pio | Smith, George Davey | De Vivo, Immaculata | Demerath, Ellen W | Dennis, Joe | Devilee, Peter | Dieffenbach, Aida K | Dunning, Alison M | Eiriksdottir, Gudny | Eriksson, Johan G | Fasching, Peter A | Ferrucci, Luigi | Flesch-Janys, Dieter | Flyger, Henrik | Foroud, Tatiana | Franke, Lude | Garcia, Melissa E | García-Closas, Montserrat | Geller, Frank | de Geus, Eco EJ | Giles, Graham G | Gudbjartsson, Daniel F | Gudnason, Vilmundur | Guénel, Pascal | Guo, Suiqun | Hall, Per | Hamann, Ute | Haring, Robin | Hartman, Catharina A | Heath, Andrew C | Hofman, Albert | Hooning, Maartje J | Hopper, John L | Hu, Frank B | Hunter, David J | Karasik, David | Kiel, Douglas P | Knight, Julia A | Kosma, Veli-Matti | Kutalik, Zoltan | Lai, Sandra | Lambrechts, Diether | Lindblom, Annika | Mägi, Reedik | Magnusson, Patrik K | Mannermaa, Arto | Martin, Nicholas G | Masson, Gisli | McArdle, Patrick F | McArdle, Wendy L | Melbye, Mads | Michailidou, Kyriaki | Mihailov, Evelin | Milani, Lili | Milne, Roger L | Nevanlinna, Heli | Neven, Patrick | Nohr, Ellen A | Oldehinkel, Albertine J | Oostra, Ben A | Palotie, Aarno | Peacock, Munro | Pedersen, Nancy L | Peterlongo, Paolo | Peto, Julian | Pharoah, Paul DP | Postma, Dirkje S | Pouta, Anneli | Pylkäs, Katri | Radice, Paolo | Ring, Susan | Rivadeneira, Fernando | Robino, Antonietta | Rose, Lynda M | Rudolph, Anja | Salomaa, Veikko | Sanna, Serena | Schlessinger, David | Schmidt, Marjanka K | Southey, Mellissa C | Sovio, Ulla | Stampfer, Meir J | Stöckl, Doris | Storniolo, Anna M | Timpson, Nicholas J | Tyrer, Jonathan | Visser, Jenny A | Vollenweider, Peter | Völzke, Henry | Waeber, Gerard | Waldenberger, Melanie | Wallaschofski, Henri | Wang, Qin | Willemsen, Gonneke | Winqvist, Robert | Wolffenbuttel, Bruce HR | Wright, Margaret J | Boomsma, Dorret I | Econs, Michael J | Khaw, Kay-Tee | Loos, Ruth JF | McCarthy, Mark I | Montgomery, Grant W | Rice, John P | Streeten, Elizabeth A | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Alizadeh, Behrooz Z | Bergmann, Sven | Boerwinkle, Eric | Boyd, Heather A | Crisponi, Laura | Gasparini, Paolo | Gieger, Christian | Harris, Tamara B | Ingelsson, Erik | Järvelin, Marjo-Riitta | Kraft, Peter | Lawlor, Debbie | Metspalu, Andres | Pennell, Craig E | Ridker, Paul M | Snieder, Harold | Sørensen, Thorkild IA | Spector, Tim D | Strachan, David P | Uitterlinden, André G | Wareham, Nicholas J | Widen, Elisabeth | Zygmunt, Marek | Murray, Anna | Easton, Douglas F | Stefansson, Kari | Murabito, Joanne M | Ong, Ken K
Nature  2014;514(7520):92-97.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
doi:10.1038/nature13545
PMCID: PMC4185210  PMID: 25231870
11.  Background risk of breast cancer and the association between physical activity and mammographic density 
Introduction
High physical activity has been shown to decrease the risk of breast cancer, potentially by a mechanism that also reduces mammographic density. We tested the hypothesis that the risk of developing breast cancer in the next 10 years according to the Tyrer-Cuzick prediction model influences the association between physical activity and mammographic density.
Methods
We conducted a population-based cross-sectional study of 38,913 Swedish women aged 40–74 years. Physical activity was assessed using the validated web-questionnaire Active-Q and mammographic density was measured by the fully automated volumetric Volpara method. The 10-year risk of breast cancer was estimated using the Tyrer-Cuzick (TC) prediction model. Linear regression analyses were performed to assess the association between physical activity and volumetric mammographic density and the potential interaction with the TC breast cancer risk.
Results
Overall, high physical activity was associated with lower absolute dense volume. As compared to women with the lowest total activity level (<40 metabolic equivalent hours [MET-h] per day), women with the highest total activity level (≥50 MET-h/day) had an estimated 3.4 cm3 (95% confidence interval, 2.3-4.7) lower absolute dense volume. The inverse association was seen for any type of physical activity among women with <3.0% TC 10-year risk, but only for total and vigorous activities among women with 3.0-4.9% TC risk, and only for vigorous activity among women with ≥5.0% TC risk. The association between total activity and absolute dense volume was modified by the TC breast cancer risk (Pinteraction = 0.05). As anticipated, high physical activity was also associated with lower non-dense volume. No consistent association was found between physical activity and percent dense volume.
Conclusions
Our results suggest that physical activity may decrease breast cancer risk through reducing mammographic density, and that the physical activity needed to reduce mammographic density may depend on background risk of breast cancer.
doi:10.1186/s13058-015-0565-4
PMCID: PMC4403929  PMID: 25888057
12.  A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium 
Milne, Roger L. | Herranz, Jesús | Michailidou, Kyriaki | Dennis, Joe | Tyrer, Jonathan P. | Zamora, M. Pilar | Arias-Perez, José Ignacio | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Wang, Qin | Bolla, Manjeet K. | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Li, Jingmei | Anton-Culver, Hoda | Neuhausen, Susan L. | Ziogas, Argyrios | Clarke, Christina A. | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Chenevix-Trench, Georgia | Swerdlow, Anthony | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Dunning, Alison M. | Shah, Mitul | Guénel, Pascal | Truong, Thérèse | Sanchez, Marie | Mulot, Claire | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Collée, J. Margriet | Jager, Agnes | Cox, Angela | Brock, Ian W. | Reed, Malcolm W.R. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Dumont, Martine | Soucy, Penny | Dörk, Thilo | Bogdanova, Natalia V. | Hamann, Ute | Försti, Asta | Rüdiger, Thomas | Ulmer, Hans-Ulrich | Fasching, Peter A. | Häberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Radice, Paolo | Peterlongo, Paolo | Peissel, Bernard | Mariani, Paolo | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Lambrechts, Diether | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Schmidt, Marjanka K. | Broeks, Annegien | Verhoef, Senno | Rutgers, Emiel J. | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Pharoah, Paul D.P. | Hall, Per | Benítez, Javier | Malats, Núria | Easton, Douglas F.
Human Molecular Genetics  2013;23(7):1934-1946.
Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10−8. Results from the second analytic approach were consistent with those from the first (P > 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
doi:10.1093/hmg/ddt581
PMCID: PMC3943524  PMID: 24242184
13.  A Genome-wide Association Study of Early-onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age 
Ahsan, Habibul | Halpern, Jerry | Kibriya, Muhammad G | Pierce, Brandon L | Tong, Lin | Gamazon, Eric | McGuire, Valerie | Felberg, Anna | Shi, Jianxin | Jasmine, Farzana | Roy, Shantanu | Brutus, Rachelle | Argos, Maria | Melkonian, Stephanie | Chang-Claude, Jenny | Andrulis, Irene | Hopper, John L | John, Esther M. | Malone, Kathi | Ursin, Giske | Gammon, Marilie D | Thomas, Duncan C | Seminara, Daniela | Casey, Graham | Knight, Julia A | Southey, Melissa C | Giles, Graham G | Santella, Regina M | Lee, Eunjung | Conti, David | Duggan, David | Gallinger, Steve | Haile, Robert | Jenkins, Mark | Lindor, Noralane M | Newcomb, Polly | Michailidou, Kyriaki | Apicella, Carmel | Park, Daniel J | Peto, Julian | Fletcher, Olivia | Silva, Isabel dos Santos | Lathrop, Mark | Hunter, David J | Chanock, Stephen J | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lochmann, Magdalena | Beckmann, Lars | Hein, Rebecca | Makalic, Enes | Schmidt, Daniel F | Bui, Quang Minh | Stone, Jennifer | Flesch-Janys, Dieter | Dahmen, Norbert | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Hall, Per | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Rahman, Nazneen | Turnbull, Clare | Dunning, Alison M. | Pharoah, Paul | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Uitterlinden, Andre G. | Rivadeneira, Fernando | Nicolae, Dan | Easton, Douglas F | Cox, Nancy J | Whittemore, Alice S
Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 SNPs among a discovery set of 3,523 EOBC incident case and 2,702 population control women aged <=51 years. The SNPs with smallest P-values were examined in a replication set of 3,470 EOBC case and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P-values to obtain a gene-based P-value. We examined the gene with smallest P-value for replication in 1,145 breast cancer case and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P<4×10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P<6×10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P<0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genomewide gene-based threshold of 2.5×10−6. In conclusion, EOBC and LOBC appear to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.
doi:10.1158/1055-9965.EPI-13-0340
PMCID: PMC3990360  PMID: 24493630
14.  Genetic studies of body mass index yield new insights for obesity biology 
Locke, Adam E. | Kahali, Bratati | Berndt, Sonja I. | Justice, Anne E. | Pers, Tune H. | Day, Felix R. | Powell, Corey | Vedantam, Sailaja | Buchkovich, Martin L. | Yang, Jian | Croteau-Chonka, Damien C. | Esko, Tonu | Fall, Tove | Ferreira, Teresa | Gustafsson, Stefan | Kutalik, Zoltán | Luan, Jian’an | Mägi, Reedik | Randall, Joshua C. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Faul, Jessica D. | Smith, Jennifer A. | Zhao, Jing Hua | Zhao, Wei | Chen, Jin | Fehrmann, Rudolf | Hedman, Åsa K. | Karjalainen, Juha | Schmidt, Ellen M. | Absher, Devin | Amin, Najaf | Anderson, Denise | Beekman, Marian | Bolton, Jennifer L. | Bragg-Gresham, Jennifer L. | Buyske, Steven | Demirkan, Ayse | Deng, Guohong | Ehret, Georg B. | Feenstra, Bjarke | Feitosa, Mary F. | Fischer, Krista | Goel, Anuj | Gong, Jian | Jackson, Anne U. | Kanoni, Stavroula | Kleber, Marcus E. | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Medland, Sarah E. | Nalls, Michael A. | Palmer, Cameron D. | Pasko, Dorota | Pechlivanis, Sonali | Peters, Marjolein J. | Prokopenko, Inga | Shungin, Dmitry | Stančáková, Alena | Strawbridge, Rona J. | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W. | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V. | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Isaacs, Aaron | Albrecht, Eva | Ärnlöv, Johan | Arscott, Gillian M. | Attwood, Antony P. | Bandinelli, Stefania | Barrett, Amy | Bas, Isabelita N. | Bellis, Claire | Bennett, Amanda J. | Berne, Christian | Blagieva, Roza | Blüher, Matthias | Böhringer, Stefan | Bonnycastle, Lori L. | Böttcher, Yvonne | Boyd, Heather A. | Bruinenberg, Marcel | Caspersen, Ida H. | Chen, Yii-Der Ida | Clarke, Robert | Daw, E. Warwick | de Craen, Anton J. M. | Delgado, Graciela | Dimitriou, Maria | Doney, Alex S. F. | Eklund, Niina | Estrada, Karol | Eury, Elodie | Folkersen, Lasse | Fraser, Ross M. | Garcia, Melissa E. | Geller, Frank | Giedraitis, Vilmantas | Gigante, Bruna | Go, Alan S. | Golay, Alain | Goodall, Alison H. | Gordon, Scott D. | Gorski, Mathias | Grabe, Hans-Jörgen | Grallert, Harald | Grammer, Tanja B. | Gräßler, Jürgen | Grönberg, Henrik | Groves, Christopher J. | Gusto, Gaëlle | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hartman, Catharina A. | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L. | Helmer, Quinta | Hengstenberg, Christian | Holmen, Oddgeir | Hottenga, Jouke-Jan | James, Alan L. | Jeff, Janina M. | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Kinnunen, Leena | Koenig, Wolfgang | Koskenvuo, Markku | Kratzer, Wolfgang | Laitinen, Jaana | Lamina, Claudia | Leander, Karin | Lee, Nanette R. | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lo, Ken Sin | Lobbens, Stéphane | Lorbeer, Roberto | Lu, Yingchang | Mach, François | Magnusson, Patrik K. E. | Mahajan, Anubha | McArdle, Wendy L. | McLachlan, Stela | Menni, Cristina | Merger, Sigrun | Mihailov, Evelin | Milani, Lili | Moayyeri, Alireza | Monda, Keri L. | Morken, Mario A. | Mulas, Antonella | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W. | Nagaraja, Ramaiah | Nöthen, Markus M. | Nolte, Ilja M. | Pilz, Stefan | Rayner, Nigel W. | Renstrom, Frida | Rettig, Rainer | Ried, Janina S. | Ripke, Stephan | Robertson, Neil R. | Rose, Lynda M. | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R. | Scott, William R. | Seufferlein, Thomas | Shi, Jianxin | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V. | Steinthorsdottir, Valgerdur | Stirrups, Kathleen | Stringham, Heather M. | Sundström, Johan | Swertz, Morris A. | Swift, Amy J. | Syvänen, Ann-Christine | Tan, Sian-Tsung | Tayo, Bamidele O. | Thorand, Barbara | Thorleifsson, Gudmar | Tyrer, Jonathan P. | Uh, Hae-Won | Vandenput, Liesbeth | Verhulst, Frank C. | Vermeulen, Sita H. | Verweij, Niek | Vonk, Judith M. | Waite, Lindsay L. | Warren, Helen R. | Waterworth, Dawn | Weedon, Michael N. | Wilkens, Lynne R. | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K. | Wong, Andrew | Wright, Alan F. | Zhang, Qunyuan | Brennan, Eoin P. | Choi, Murim | Dastani, Zari | Drong, Alexander W. | Eriksson, Per | Franco-Cereceda, Anders | Gådin, Jesper R. | Gharavi, Ali G. | Goddard, Michael E. | Handsaker, Robert E. | Huang, Jinyan | Karpe, Fredrik | Kathiresan, Sekar | Keildson, Sarah | Kiryluk, Krzysztof | Kubo, Michiaki | Lee, Jong-Young | Liang, Liming | Lifton, Richard P. | Ma, Baoshan | McCarroll, Steven A. | McKnight, Amy J. | Min, Josine L. | Moffatt, Miriam F. | Montgomery, Grant W. | Murabito, Joanne M. | Nicholson, George | Nyholt, Dale R. | Okada, Yukinori | Perry, John R. B. | Dorajoo, Rajkumar | Reinmaa, Eva | Salem, Rany M. | Sandholm, Niina | Scott, Robert A. | Stolk, Lisette | Takahashi, Atsushi | Tanaka, Toshihiro | van ’t Hooft, Ferdinand M. | Vinkhuyzen, Anna A. E. | Westra, Harm-Jan | Zheng, Wei | Zondervan, Krina T. | Heath, Andrew C. | Arveiler, Dominique | Bakker, Stephan J. L. | Beilby, John | Bergman, Richard N. | Blangero, John | Bovet, Pascal | Campbell, Harry | Caulfield, Mark J. | Cesana, Giancarlo | Chakravarti, Aravinda | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Crawford, Dana C. | Cupples, L. Adrienne | Cusi, Daniele | Danesh, John | de Faire, Ulf | den Ruijter, Hester M. | Dominiczak, Anna F. | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G. | Farrall, Martin | Felix, Stephan B. | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G. | Forrester, Terrence | Franco, Oscar H. | Gansevoort, Ron T. | Gejman, Pablo V. | Gieger, Christian | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Hall, Alistair S. | Harris, Tamara B. | Hattersley, Andrew T. | Hicks, Andrew A. | Hindorff, Lucia A. | Hingorani, Aroon D. | Hofman, Albert | Homuth, Georg | Hovingh, G. Kees | Humphries, Steve E. | Hunt, Steven C. | Hyppönen, Elina | Illig, Thomas | Jacobs, Kevin B. | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Johansen, Berit | Jousilahti, Pekka | Jukema, J. Wouter | Jula, Antti M. | Kaprio, Jaakko | Kastelein, John J. P. | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Knekt, Paul | Kooner, Jaspal S. | Kooperberg, Charles | Kovacs, Peter | Kraja, Aldi T. | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A. | Langenberg, Claudia | Marchand, Loic Le | Lehtimäki, Terho | Lyssenko, Valeriya | Männistö, Satu | Marette, André | Matise, Tara C. | McKenzie, Colin A. | McKnight, Barbara | Moll, Frans L. | Morris, Andrew D. | Morris, Andrew P. | Murray, Jeffrey C. | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J. | Ong, Ken K. | Madden, Pamela A. F. | Pasterkamp, Gerard | Peden, John F. | Peters, Annette | Postma, Dirkje S. | Pramstaller, Peter P. | Price, Jackie F. | Qi, Lu | Raitakari, Olli T. | Rankinen, Tuomo | Rao, D. C. | Rice, Treva K. | Ridker, Paul M. | Rioux, John D. | Ritchie, Marylyn D. | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J. | Saramies, Jouko | Sarzynski, Mark A. | Schunkert, Heribert | Schwarz, Peter E. H. | Sever, Peter | Shuldiner, Alan R. | Sinisalo, Juha | Stolk, Ronald P. | Strauch, Konstantin | Tönjes, Anke | Trégouët, David-Alexandre | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Völker, Uwe | Waeber, Gérard | Willemsen, Gonneke | Witteman, Jacqueline C. | Zillikens, M. Carola | Adair, Linda S. | Amouyel, Philippe | Asselbergs, Folkert W. | Assimes, Themistocles L. | Bochud, Murielle | Boehm, Bernhard O. | Boerwinkle, Eric | Bornstein, Stefan R. | Bottinger, Erwin P. | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C. | Chanock, Stephen J. | Cooper, Richard S. | de Bakker, Paul I. W. | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W. | Froguel, Philippe | Groop, Leif C. | Haiman, Christopher A. | Hamsten, Anders | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Kaplan, Robert C. | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G. | März, Winfried | Melbye, Mads | Metspalu, Andres | Moebus, Susanne | Munroe, Patricia B. | Njølstad, Inger | Oostra, Ben A. | Palmer, Colin N. A. | Pedersen, Nancy L. | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Rivadeneira, Fernando | Saaristo, Timo E. | Saleheen, Danish | Sattar, Naveed | Schadt, Eric E. | Schlessinger, David | Slagboom, P. Eline | Snieder, Harold | Spector, Tim D. | Thorsteinsdottir, Unnur | Stumvoll, Michael | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Walker, Mark | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Weir, David R. | Wichmann, H-Erich | Wilson, James F. | Zanen, Pieter | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Heid, Iris M. | O’Connell, Jeffrey R. | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Abecasis, Gonçalo R. | Franke, Lude | Frayling, Timothy M. | McCarthy, Mark I. | Visscher, Peter M. | Scherag, André | Willer, Cristen J. | Boehnke, Michael | Mohlke, Karen L. | Lindgren, Cecilia M. | Beckmann, Jacques S. | Barroso, Inês | North, Kari E. | Ingelsson, Erik | Hirschhorn, Joel N. | Loos, Ruth J. F. | Speliotes, Elizabeth K.
Nature  2015;518(7538):197-206.
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
doi:10.1038/nature14177
PMCID: PMC4382211  PMID: 25673413
15.  Proteomics profiling identify CAPS as a potential predictive marker of tamoxifen resistance in estrogen receptor positive breast cancer 
Clinical Proteomics  2015;12(1):8.
Background
Despite the success of tamoxifen since its introduction, about one-third of patients with estrogen (ER) and/or progesterone receptor (PgR) - positive breast cancer (BC) do not benefit from therapy. Here, we aim to identify molecular mechanisms and protein biomarkers involved in tamoxifen resistance.
Results
Using iTRAQ and Immobilized pH gradient-isoelectric focusing (IPG-IEF) mass spectrometry based proteomics we compared tumors from 12 patients with early relapses (<2 years) and 12 responsive to therapy (relapse-free > 7 years). A panel of 13 proteins (TCEAL4, AZGP1, S100A10, ALDH6A1, AHNAK, FBP1, S100A4, HSP90AB1, PDXK, GFPT1, RAB21, MX1, CAPS) from the 3101 identified proteins, potentially separate relapse from non-relapse BC patients. The proteins in the panel are involved in processes such as calcium (Ca2+) signaling, metabolism, epithelial mesenchymal transition (EMT), metastasis and invasion. Validation of the highest expressed proteins in the relapse group identify high tumor levels of CAPS as predictive of tamoxifen response in a patient cohort receiving tamoxifen as only adjuvant therapy.
Conclusions
This data implicate CAPS in tamoxifen resistance and as a potential predictive marker.
Electronic supplementary material
The online version of this article (doi:10.1186/s12014-015-9080-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12014-015-9080-y
PMCID: PMC4389343  PMID: 25878567
Estrogen receptor; Endocrine resistance; Receptor-positive breast cancer; Proteomics; Calcyphosine; CAPS; MX1
16.  The Genetic Basis of Quality of Life in Healthy Swedish Women: A Candidate Gene Approach 
PLoS ONE  2015;10(2):e0118292.
Background
Quality of life (QoL) is an increasingly important parameter in clinical practice as it predicts mortality and poor health outcomes. It is hypothesized that one may have a genetic predisposition for QoL. We therefore related 139 candidate genes, selected through a literature search, to QoL in healthy females.
Methods
In 5,142 healthy females, background characteristics (i.e. demographic, clinical, lifestyle, and psychological factors) were assessed. QoL was measured by the EORTC QLQ-C30, which consists of 15 domains. For all women genotype information was available. For each candidate gene, single nucleotide polymorphisms (SNPs) were identified based on their functional (n = 2,663) and physical annotation (n = 10,649). SNPs were related to each QoL-domain, while controlling for background characteristics and population stratification. Finally, gene-based analyses were performed relating the combined effect of 10,649 SNPs (selected based on physical annotation) for each gene, to QoL using the statistical software package VEGAS.
Results
Overall, we found no relation between genetic variations (SNPs and genes) and 14 out of 15 QoL-domains. The strongest association was found between cognitive functioning and the top SNP rs1468951 (p = 1.21E-05) in the GSTZ1 gene. Furthermore, results of the gene-based test showed that the combined effect of 11 SNPs within the GSTZ1 gene is significantly associated with cognitive functioning (p = 2.60E-05).
Conclusion
If validated, the involvement of GSTZ1 in cognitive functioning underscores its heritability which is likely the result of differences in the dopamine pathway, as GSTZ1 contributes to the equilibrium between dopamine and its neurotoxic metabolites via the glutathione redox cycle.
doi:10.1371/journal.pone.0118292
PMCID: PMC4326277  PMID: 25675377
17.  Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy 
Lei, Jieping | Rudolph, Anja | Moysich, Kirsten B | Rafiq, Sajjad | Behrens, Sabine | Goode, Ellen L | Pharoah, Paul PD | Seibold, Petra | Fasching, Peter A | Andrulis, Irene L | Kristensen, Vessela N | Couch, Fergus J | Hamann, Ute | Hooning, Maartje J | Nevanlinna, Heli | Eilber, Ursula | Bolla, Manjeet K | Dennis, Joe | Wang, Qin | Lindblom, Annika | Mannermaa, Arto | Lambrechts, Diether | García-Closas, Montserrat | Hall, Per | Chenevix-Trench, Georgia | Shah, Mitul | Luben, Robert | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Knight, Julia A | Glendon, Gord | Tchatchou, Sandrine | Alnæs, Grethe I Grenaker | Borresen-Dale, Anne-Lise | Nord, Silje | Olson, Janet E | Hallberg, Emily | Vachon, Celine | Torres, Diana | Ulmer, Hans-Ulrich | Rüdiger, Thomas | Jager, Agnes | van Deurzen, Carolien HM | Tilanus-Linthorst, Madeleine MA | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Margolin, Sara | Kosma, Veli-Matti | Hartikainen, Jaana M | Kataja, Vesa | Hatse, Sigrid | Wildiers, Hans | Smeets, Ann | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Li, Jingmei | Humphreys, Keith | Phillips, Kelly-Anne | Linn, Sabine | Cornelissen, Sten | van den Broek, Sandra Alexandra J | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K | Yoo, Keun-Young | Hsiung, Chia-Ni | Wu, Pei-Ei | Hou, Ming-Feng | Shen, Chen-Yang | Teo, Soo Hwang | Taib, Nur Aishah Mohd | Yip, Cheng Har | Ho, Gwo Fuang | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Dunning, Alison M | Benitez, Javier | Czene, Kamila | Sucheston, Lara E | Maishman, Tom | Tapper, William J | Eccles, Diana | Easton, Douglas F | Schmidt, Marjanka K | Chang-Claude, Jenny
Introduction
Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).
Methods
We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.
Results
Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10−3) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10−4) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10−3). Two SNPs in IL12B (r2 = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10−4), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10−4). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10−5) without study heterogeneity.
Conclusions
TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0522-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0522-2
PMCID: PMC4374346  PMID: 25849327
18.  Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2 
Orr, Nick | Dudbridge, Frank | Dryden, Nicola | Maguire, Sarah | Novo, Daniela | Perrakis, Eleni | Johnson, Nichola | Ghoussaini, Maya | Hopper, John L. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Schmidt, Marjanka K. | Broeks, Annegien | Van't Veer, Laura J. | Hogervorst, Frans B. | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Gibson, Lorna | Aitken, Zoe | Warren, Helen | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Chistof | Guénel, Pascal | Truong, Thérèse | Cordina-Duverger, Emilie | Sanchez, Marie | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Maria Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan L. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Hamann, Ute | Brauch, Hiltrud | Justenhoven, Christina | Brüning, Thomas | Ko, Yon-Dschun | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Bogdanova, Natalia | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Chenevix-Trench, Georgia | Beesley, Jonathan | Lambrechts, Diether | Moisse, Matthieu | Floris, Guiseppe | Beuselinck, Benoit | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Peissel, Bernard | Pensotti, Valeria | Couch, Fergus J. | Olson, Janet E. | Slettedahl, Seth | Vachon, Celine | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Kristensen, Vessela | Alnæs, Grethe Grenaker | Nord, Silje | Borresen-Dale, Anne-Lise | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha | Long, Jirong | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Devilee, Peter | Tollenaar, Robertus A. E. M. | Seynaeve, Caroline M. | Van Asperen, Christi J. | Garcia-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J. | Lissowska, Jolanta | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Klevebring, Daniel | Hooning, Maartje J. | Hollestelle, Antoinette | van Deurzen, Carolien H. M. | Kriege, Mieke | Hall, Per | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Perkins, Barbara J. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Ashworth, Alan | Swerdlow, Anthony | Jones, Michael | Schoemaker, Minouk J. | Meindl, Alfons | Schmutzler, Rita K. | Olswold, Curtis | Slager, Susan | Toland, Amanda E. | Yannoukakos, Drakoulis | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Matsuo, Keitaro | Ito, Hidema | Iwata, Hiroji | Ishiguro, Junko | Wu, Anna H. | Tseng, Chiu-chen | Van Den Berg, David | Stram, Daniel O. | Teo, Soo Hwang | Yip, Cheng Har | Kang, Peter | Ikram, Mohammad Kamran | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K. | Noh, Dong-Young | Hartman, Mikael | Miao, Hui | Lim, Wei Yen | Lee, Soo Chin | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | Mckay, James | Wu, Pei-Ei | Hou, Ming-Feng | Yu, Jyh-Cherng | Shen, Chen-Yang | Blot, William | Cai, Qiuyin | Signorello, Lisa B. | Luccarini, Craig | Bayes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Hunter, David J. | Lindstrom, Sara | Dennis, Joe | Michailidou, Kyriaki | Bolla, Manjeet K. | Easton, Douglas F. | dos Santos Silva, Isabel | Fletcher, Olivia | Peto, Julian
Human Molecular Genetics  2015;24(10):2966-2984.
We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P-value = 1.58 × 10−25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P-value = 7.89 × 10−09) and rs13294895 (OR = 1.09 [1.06–1.12]; P-value = 2.97 × 10−11). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P-value = 2.77 × 10−05). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
doi:10.1093/hmg/ddv035
PMCID: PMC4406292  PMID: 25652398
19.  CYP2B6*6 is associated with increased breast cancer risk 
The cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of testosterone. Functional changes in this enzyme may influence endogenous hormone exposure, which has been associated with risk of breast cancer. To assess potential associations between two functional polymorphisms CYP2B6_516_G>T (rs3745274) and CYP2B6_785_A>G (rs2279343) and breast cancer risk we established a specific matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) assay. The GENICA breast cancer case-control study showed associations between the variant genotypes CYP2B6_516_TT and CYP2B6_785_GG and breast cancer risk with odds ratios (ORs) of 1.34 (p = 0.001) and 1.31 (p = 0.002), respectively. A similar effect was observed for carriers of the CYP2B6_516_T allele in a validation study including four independent studies from Germany, Sweden and USA. In a pooled analysis of all five studies involving 4,638 breast cancer cases and 3,594 controls of European ancestry, carriers of the CYP2B6_516_G and the CYP2B6_785_G variant had an increased breast cancer risk with ORs of 1.10 (p = 0.027) and 1.10 (p = 0.031), respectively. We conclude that the genetic variants CYP2B6_516_G and CYP2B6_785_G (designated CYP2B6*6), which are known to decrease activity of the CYP2B6 enzyme, contribute to an increased breast cancer risk.
doi:10.1002/ijc.28356
PMCID: PMC3883876  PMID: 23824676
CYP2B6; polymorphism; testosterone; breast cancer risk
20.  Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia 
Spurdle, Amanda B | Couch, Fergus J | Parsons, Michael T | McGuffog, Lesley | Barrowdale, Daniel | Bolla, Manjeet K | Wang, Qin | Healey, Sue | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Hahnen, Eric | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hansjoerg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Ellis, Steve | Frost, Debra | Platte, Radka | Perkins, Jo | Evans, D Gareth | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Scuvera, Giulietta | Manoukian, Siranoush | Bonanni, Bernardo | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Pasini, Barbara | Papi, Laura | Varesco, Liliana | Balleine, Rosemary | Nathanson, Katherine L | Domchek, Susan M | Offitt, Kenneth | Jakubowska, Anna | Lindor, Noralane | Thomassen, Mads | Jensen, Uffe Birk | Rantala, Johanna | Borg, Åke | Andrulis, Irene L | Miron, Alexander | Hansen, Thomas VO | Caldes, Trinidad | Neuhausen, Susan L | Toland, Amanda E | Nevanlinna, Heli | Montagna, Marco | Garber, Judy | Godwin, Andrew K | Osorio, Ana | Factor, Rachel E | Terry, Mary B | Rebbeck, Timothy R | Karlan, Beth Y | Southey, Melissa | Rashid, Muhammad Usman | Tung, Nadine | Pharoah, Paul DP | Blows, Fiona M | Dunning, Alison M | Provenzano, Elena | Hall, Per | Czene, Kamila | Schmidt, Marjanka K | Broeks, Annegien | Cornelissen, Sten | Verhoef, Senno | Fasching, Peter A | Beckmann, Matthias W | Ekici, Arif B | Slamon, Dennis J | Bojesen, Stig E | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Chang-Claude, Jenny | Flesch-Janys, Dieter | Rudolph, Anja | Seibold, Petra | Aittomäki, Kristiina | Muranen, Taru A | Heikkilä, Päivi | Blomqvist, Carl | Figueroa, Jonine | Chanock, Stephen J | Brinton, Louise | Lissowska, Jolanta | Olson, Janet E | Pankratz, Vernon S | John, Esther M | Whittemore, Alice S | West, Dee W | Hamann, Ute | Torres, Diana | Ulmer, Hans Ulrich | Rüdiger, Thomas | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Van Asperen, Christi J | Eccles, Diana M | Tapper, William J | Durcan, Lorraine | Jones, Louise | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Dwek, Miriam | Swann, Ruth | Bane, Anita L | Glendon, Gord | Mulligan, Anna M | Giles, Graham G | Milne, Roger L | Baglietto, Laura | McLean, Catriona | Carpenter, Jane | Clarke, Christine | Scott, Rodney | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Cox, Angela | Cross, Simon S | Reed, Malcolm WR | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Gronwald, Jacek | Dörk, Thilo | Bogdanova, Natalia | Park-Simon, Tjoung-Won | Hillemanns, Peter | Haiman, Christopher A | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Burwinkel, Barbara | Marme, Frederik | Surovy, Harald | Yang, Rongxi | Anton-Culver, Hoda | Ziogas, Argyrios | Hooning, Maartje J | Collée, J Margriet | Martens, John WM | Tilanus-Linthorst, Madeleine MA | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volke | Stegmaier, Christa | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Lindblom, Annika | Margolin, Sara | Joseph, Vijai | Robson, Mark | Rau-Murthy, Rohini | González-Neira, Anna | Arias, José Ignacio | Zamora, Pilar | Benítez, Javier | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Peterlongo, Paolo | Zaffaroni, Daniela | Barile, Monica | Capra, Fabio | Radice, Paolo | Teo, Soo H | Easton, Douglas F | Antoniou, Antonis C | Chenevix-Trench, Georgia | Goldgar, David E
Breast Cancer Research : BCR  2014;16(6):3419.
Introduction
The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.
Methods
Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.
Results
ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).
Conclusions
These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0474-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0474-y
PMCID: PMC4352262  PMID: 25857409
21.  Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: A genome-wide interaction study 
Endocrine-related cancer  2013;20(6):875-887.
Women using menopausal hormone therapy (MHT) are at increased risk to develop breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in eleven case-control studies. We used a case-only design to assess interactions between single nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2,920 cases (541 lobular) from four genome-wide association studies. The top 1,391 SNPs showing P-values for interaction (Pint) <3.0×10−03 were selected for replication using pooled case-control data from eleven studies of the Breast Cancer Association Consortium, including 7,689 cases (676 lobular) and 9,266 controls. Fixed effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint≤8.9×10−06), two SNPs in SLC25A21 (combined Pint≤4.8×10−05), and three SNPs in PLCG2 (combined Pint≤4.5×10−05). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint≤2.7×10−05), one SNP in CD80 (combined Pint≤8.2×10−06), three SNPs on chr17 near TMEM132E (combined Pint≤2.2×10−06), and two SNPs on chr18 near SLC25A52 (combined Pint≤4.6×10−05). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.
doi:10.1530/ERC-13-0349
PMCID: PMC3863710  PMID: 24080446
breast cancer; genetic variation; menopausal hormone therapy; genome-wide
22.  MicroRNA Related Polymorphisms and Breast Cancer Risk 
Khan, Sofia | Greco, Dario | Michailidou, Kyriaki | Milne, Roger L. | Muranen, Taru A. | Heikkinen, Tuomas | Aaltonen, Kirsimari | Dennis, Joe | Bolla, Manjeet K. | Liu, Jianjun | Hall, Per | Irwanto, Astrid | Humphreys, Keith | Li, Jingmei | Czene, Kamila | Chang-Claude, Jenny | Hein, Rebecca | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fletcher, Olivia | Peto, Julian | dos Santos Silva, Isabel | Johnson, Nichola | Gibson, Lorna | Aitken, Zoe | Hopper, John L. | Tsimiklis, Helen | Bui, Minh | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A. | van der Luijt, Rob B. | Meindl, Alfons | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Lichtner, Peter | Turnbull, Clare | Rahman, Nazneen | Chanock, Stephen J. | Hunter, David J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Schmidt, Marjanka K. | Broeks, Annegien | Veer, Laura J. V. a. n't. | Hogervorst, Frans B. | Fasching, Peter A. | Schrauder, Michael G. | Ekici, Arif B. | Beckmann, Matthias W. | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Pilar M. | Perez, Jose I. A. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Olson, Janet E. | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Mulot, Claire | Marme, Frederick | Burwinkel, Barbara | Schneeweiss, Andreas | Sohn, Christof | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Tchatchou, Sandrine | Mulligan, Anna Marie | Dörk, Thilo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Anton-Culver, Hoda | Darabi, Hatef | Eriksson, Mikael | Garcia-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Kristensen, Vessela N. | Slager, Susan | Toland, Amanda E. | Ambrosone, Christine B. | Yannoukakos, Drakoulis | Lindblom, Annika | Margolin, Sara | Radice, Paolo | Peterlongo, Paolo | Barile, Monica | Mariani, Paolo | Hooning, Maartje J. | Martens, John W. M. | Collée, J. Margriet | Jager, Agnes | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Giles, Graham G. | McLean, Catriona | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Mannermaa, Arto | Hamann, Ute | Chenevix-Trench, Georgia | Blomqvist, Carl | Aittomäki, Kristiina | Easton, Douglas F. | Nevanlinna, Heli
PLoS ONE  2014;9(11):e109973.
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
doi:10.1371/journal.pone.0109973
PMCID: PMC4229095  PMID: 25390939
23.  Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk 
Painter, Jodie N. | O'Mara, Tracy A. | Batra, Jyotsna | Cheng, Timothy | Lose, Felicity A. | Dennis, Joe | Michailidou, Kyriaki | Tyrer, Jonathan P. | Ahmed, Shahana | Ferguson, Kaltin | Healey, Catherine S. | Kaufmann, Susanne | Hillman, Kristine M. | Walpole, Carina | Moya, Leire | Pollock, Pamela | Jones, Angela | Howarth, Kimberley | Martin, Lynn | Gorman, Maggie | Hodgson, Shirley | De Polanco, Ma. Magdalena Echeverry | Sans, Monica | Carracedo, Angel | Castellvi-Bel, Sergi | Rojas-Martinez, Augusto | Santos, Erika | Teixeira, Manuel R. | Carvajal-Carmona, Luis | Shu, Xiao-Ou | Long, Jirong | Zheng, Wei | Xiang, Yong-Bing | Montgomery, Grant W. | Webb, Penelope M. | Scott, Rodney J. | McEvoy, Mark | Attia, John | Holliday, Elizabeth | Martin, Nicholas G. | Nyholt, Dale R. | Henders, Anjali K. | Fasching, Peter A. | Hein, Alexander | Beckmann, Matthias W. | Renner, Stefan P. | Dörk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo | Lambrechts, Diether | Coenegrachts, Lieve | Schrauwen, Stefanie | Amant, Frederic | Winterhoff, Boris | Dowdy, Sean C. | Goode, Ellen L. | Teoman, Attila | Salvesen, Helga B. | Trovik, Jone | Njolstad, Tormund S. | Werner, Henrica M.J. | Ashton, Katie | Proietto, Tony | Otton, Geoffrey | Tzortzatos, Gerasimos | Mints, Miriam | Tham, Emma | Hall, Per | Czene, Kamila | Liu, Jianjun | Li, Jingmei | Hopper, John L. | Southey, Melissa C. | Ekici, Arif B. | Ruebner, Matthias | Johnson, Nicola | Peto, Julian | Burwinkel, Barbara | Marme, Frederik | Brenner, Hermann | Dieffenbach, Aida K. | Meindl, Alfons | Brauch, Hiltrud | Lindblom, Annika | Depreeuw, Jeroen | Moisse, Matthieu | Chang-Claude, Jenny | Rudolph, Anja | Couch, Fergus J. | Olson, Janet E. | Giles, Graham G. | Bruinsma, Fiona | Cunningham, Julie M. | Fridley, Brooke L. | Børresen-Dale, Anne-Lise | Kristensen, Vessela N. | Cox, Angela | Swerdlow, Anthony J. | Orr, Nicholas | Bolla, Manjeet K. | Wang, Qin | Weber, Rachel Palmieri | Chen, Zhihua | Shah, Mitul | French, Juliet D. | Pharoah, Paul D.P. | Dunning, Alison M. | Tomlinson, Ian | Easton, Douglas F. | Edwards, Stacey L. | Thompson, Deborah J. | Spurdle, Amanda B.
Human Molecular Genetics  2014;24(5):1478-1492.
Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
doi:10.1093/hmg/ddu552
PMCID: PMC4321445  PMID: 25378557
24.  Area and Volumetric Density Estimation in Processed Full-Field Digital Mammograms for Risk Assessment of Breast Cancer 
PLoS ONE  2014;9(10):e110690.
Introduction
Mammographic density, the white radiolucent part of a mammogram, is a marker of breast cancer risk and mammographic sensitivity. There are several means of measuring mammographic density, among which are area-based and volumetric-based approaches. Current volumetric methods use only unprocessed, raw mammograms, which is a problematic restriction since such raw mammograms are normally not stored. We describe fully automated methods for measuring both area and volumetric mammographic density from processed images.
Methods
The data set used in this study comprises raw and processed images of the same view from 1462 women. We developed two algorithms for processed images, an automated area-based approach (CASAM-Area) and a volumetric-based approach (CASAM-Vol). The latter method was based on training a random forest prediction model with image statistical features as predictors, against a volumetric measure, Volpara, for corresponding raw images. We contrast the three methods, CASAM-Area, CASAM-Vol and Volpara directly and in terms of association with breast cancer risk and a known genetic variant for mammographic density and breast cancer, rs10995190 in the gene ZNF365. Associations with breast cancer risk were evaluated using images from 47 breast cancer cases and 1011 control subjects. The genetic association analysis was based on 1011 control subjects.
Results
All three measures of mammographic density were associated with breast cancer risk and rs10995190 (p<0.025 for breast cancer risk and p<1×10−6 for rs10995190). After adjusting for one of the measures there remained little or no evidence of residual association with the remaining density measures (p>0.10 for risk, p>0.03 for rs10995190).
Conclusions
Our results show that it is possible to obtain reliable automated measures of volumetric and area mammographic density from processed digital images. Area and volumetric measures of density on processed digital images performed similar in terms of risk and genetic association.
doi:10.1371/journal.pone.0110690
PMCID: PMC4203856  PMID: 25329322
25.  Large-scale genotyping identifies a new locus at 22q13.2 associated with female breast size 
Journal of medical genetics  2013;50(10):666-673.
Background
Individual differences in breast size are a conspicuous feature of variation in human females and have been associated with fecundity and advantage in selection of mates. To identify common variants that are associated with breast size, we conducted a large-scale genotyping association meta-analysis in 7,169 women of European descent across 3 independent sample collections with digital or screen film mammograms.
Methods
The samples consisted of the Swedish KARMA, LIBRO-1 and SASBAC studies genotyped on iCOGS, a custom illumina iSelect genotyping array comprising of 211,155 single nucleotide polymorphisms (SNPs) designed for replication and fine mapping of common and rare variants with relevance to breast, ovary and prostate cancer. Breast size of each subject was ascertained by measuring total breast area (mm2) on a mammogram.
Results
We confirm genome-wide significant associations at 8p11.23 (rs10086016, P = 1.3 × 10−14) and report a new locus at 22q13 (rs5995871, P = 3.2 × 10−8). The latter region contains the MKL1 gene, which has been shown to impact endogenous estrogen-receptor α transcriptional activity and is recruited on estradiol-sensitive genes. We also replicated previous GWAS findings for breast size at four other loci.
Conclusion
A new locus at 22q13 may be associated with female breast size.
doi:10.1136/jmedgenet-2013-101708
PMCID: PMC4159740  PMID: 23825393
Genome-wide association studies; population genetics; meta-analysis; breast size

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