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The genetic architecture of the human cerebral cortex
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Science | March 19, 2020 | Volume: 367 | Issue: 6484 | Pages: No page available
INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci ( P < 5 × 10 −8 ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P < 8.3 × 10 −10 ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS
Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk
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Human Molecular Genetics | November 6, 2014 | Volume: 24 | Issue: 5 | Pages: 1478-1492
GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment
Rietveld, Cornelius A. , Medland, Sarah E. , Derringer, Jaime , Esko, Tõnu , Martín, Nicolás W., Westra, Harm-Jan , Shakhbazov, Konstantin, Abdellaoui, Abdel , Albrecht, Eva, Alizadeh, Behrooz Z. , Amin, Najaf , Baumeister, Sebastian E. , Benke, Kelly S. , Bielak, Lawrence F. , Boatman, Jeffrey A. , Boyle, Patricia A. , Davies, Gail , Leeuw, Christiaan de , Eklund, Niina, Evans, Daniel S. , Ferhmann, Rudolf, Fischer, Krista , Gieger, Christian , Gjessing, Håkon K. , Hägg, Sara , Harris, Jennifer R. , Hayward, Caroline , Jacobsson, Bo , Joshi, Peter K. , Jugessur, Astanand , Kaakinen, Marika , Kanoni, Stavroula , Karjalainen, Juha, Kolčić, Ivana , Kristiansson, Kati , Kutalik, Zoltán , Lahti, Jari , Lee, Sang , Lin, Peng, Lind, Penelope A. , Lohman, Kurt, Loitfelder, Marisa, McMahon, George, Marques‐Vidal, Pedro , Meirelles, Osorio , Milani, Lili , Myhre, Ronny , Nuotio, Marja-Liisa , Oldmeadow, Christopher , Petrovic, Katja, Peyrot, Wouter J. , Polašek, Ozren , Quaye, Lydia, Reinmaa, Eva, Rice, John P. , Rizzi, Thais S., Schmidt, Helena , Schmidt, Reinhold, Smith, Albert V. , Smith, Jennifer A. , Terracciano, Antonio , Loos, Matthijs J. H. M. van der, Vitart, Véronique , Völzke, Henry , Wellmann, Jürgen , Yu, Lei , Zhao, Wei , Allïk, Jüri , Bandinelli, Stefania , Bastardot, François , Beauchamp, Jonathan , Bennett, David A. , Berger, Klaus, Bültmann, Ute , Campbell, Harry, Chabris, Christopher F., Cherkas, Lynn, Chung, Mina K. , Cucca, Francesco , Jager, Philip L. De , Neve, Jan-Emmanuel De, Deary, Ian J. , Dedoussis, George , Deloukas, Panos , Dimitriou, Maria , Eiríksdóttir, Guðný , Elderson, Martin F., Eriksson, Johan G. , Evans, David M. , Faul, Jessica D. , Ferrucci, Luigi , Garcia, Melissa E., Grönberg, Henrik , Guðnason, Vilmundur , Harris, Tamara B., Hastie, Nicholas D. , Hernández, Dena , Hoffmann, Wolfgang , Hofman, Adriaan, Holle, Rolf , Holliday, Elizabeth G., Hottenga, Jouke‐Jan , Illig, Thomas, Järvelin, Marjo‐Riitta , Kähönen, Mika , Kaprio, Jaakko , Kirkpatrick, Robert M. , Kowgier, Matthew , Latvala, Antti , Lawlor, Debbie A. , Lehtimäki, Terho , Li, Jingmei , Lichtenstein, Paul , Lichtner, Peter , Liewald, David C. , Madden, Pamela A. F., Magnusson, Patrik K. E. , Mäkinen, Tomi E., Masala, Marco , McGue, Matt , Mielck, Andreas, Miller, Michael B., Montgomery, Grant W. , Mukherjee, Sutapa , Nyholt, Dale R. , Oostra, Ben A., Palmer, Lyle J. , Palotie, Aarno , Perola, Markus, Peyser, Patricia A. , Preisig, Martin , Räikkönen, Katri , Rivadeneira, Fernando , Rudan, Igor , Rustichini, Aldo , Sarin, Antti-Pekka, Schlessinger, David, Scott, Rodney J. , Snieder, Harold , Pourcain, Beaté St , Starr, John M. , Sul, Jae Hoon , Surakka, Ida , Svento, Rauli , Teumer, Alexander , Study, The LifeLines Cohort, Tiemeier, Henning , Rooij, Frank J.A. van , Wagoner, David R. Van , Vartiainen, Erkki , Viikari, Jorma , Vollenweider, Péter , Vonk, Judith M. , Waeber, Gérard , Weir, David R. , Wichmann, H.‐Erich , Widén, Elisabeth , Willemsen, Gonneke , Wright, Alan F., Davey-Smith, George, Franke, Lude , Groenen, Patrick J. F. , Hofman, Albert , Johannesson, Magnus , Kardia, Sharon L. R., Krueger, Robert F., Laibson, David, Martin, Nicholas G. , Meyer, Michelle N., Posthuma, Daniëlle , Thurik, Roy , Timpson, Nicholas J. , Uitterlinden, André G. , Duijn, Cornelia M. van , Visscher, Peter M. , Benjamin, Daniel J. , Cesarini, David , Koellinger, Philipp , Bennett, David A. , Smith, George Davey , Meyer, Michelle N. , Westra, Harm-Jan , Yang, Jian , Agrawal, Arpana , Barnard, John , Holzapfel, Christina M. , Ibrahim‐Verbaas, Carla A. , Ingelsson, Erik , Lin, Peng, Liu, Ching‐Ti , Tanaka, Toshiko , Attia, John , Berger, Klaus, Bierut, Laura Jean , Boomsma, Dorret I , Andrade, Mariza de , Hall, Per N , Harris, Juliette , Heath, Andrew C. , Hofman, Adriaan, Holliday, Elizabeth G., Iacono, William G. , Launer, Lenore J. , Mäkinen, Tomi E., Metspalu, Andres , Palotie, Aarno V. , Penninx, Brenda W.J.H. , Raitakari, Olli Tuomas , Realo, Anu , Ring, Susan M. , Ripatti, Samuli , Salomaa, Veikko , Study, The LifeLines Cohort, Wilson, James Fox , Conley, Dalton , Davey-Smith, George, Smith, Jennifer A , Hottenga, Jouke-Jan , Martin, Nicholas G , Posthuma, Danielle , St Pourcain, Beate , Medland, Sarah E , Li, Jingmei , Teumer, Alexander , van Duijn, Cornelia M , Smith, Albert V , Ferrucci, Luigi , Davey Smith, George , Vonk, Judith M , Kanoni, Stavroula , Surakka, Ida
Science | May 31, 2013 | Volume: 340 | Issue: 6139 | Pages: 1467-1471
Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.
Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity
Jahanshad, Neda , Rajagopalan, Priya , Hua, Xue , Hibar, Derrek P., Nir, Talia M. , Toga, Arthur W. , Jack, Clifford R., Saykin, Andrew J. , Weiner, Michael W. , Medland, Sarah E. , Montgomery, Grant W. , Hansell, Narelle K. , McMahon, Katie L. , Zubicaray, Greig I. de , Martin, Nicholas G. , Wright, Margaret J. , Thompson, Paul M. , Initiative, the Alzheimer’s Disease Neuroimaging, Aisen, Paul, Petersen, Ronald, Jagust, William J. , Trojanowski, John Q. , Toga, Arthur W., Green, Robert C., Liu, Enchi , Green, Robert C., Montine, Tom, Gamst, Anthony, Thomas, Ronald G. , Donohue, Michael, Walter, Sarah , Gessert, Devon, Sather, Tamie, Harvey, Danielle, Donohue, Michael, Kornak, John , Jack, Clifford R., Felmlee, Joel P. , Schuff, Norbert, Alexander, Gene, DeCarli, Charles , Bandy, Dan, Foster, Norm, Reiman, Eric M. , Mathis, Chet, Cairns, Nigel J. , Taylor‐Reinwald, Lisa, Trojanowki, John Q., Shaw, Les, Korecka, Magdalena , Toga, Arthur W., Crawford, Karen , Neu, Scott, Khachaturian, Zaven S., Frank, R.T., Molchan, Susan, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S. , Pawluczyk, Sonia, Spann, Bryan M., Brewer, James, Vanderswag, Helen, Heidebrink, Judith L. , Johnson, Kris , Doody, Rachelle S., Chowdhury, Munir , Bell, Karen L. , Carroll, Maria , Leon, Sue, Mintun, Mark A., Schneider, Stacy, Marson, Daniel , Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo‐Morrell, Leyla, Duara, Ranjan , Varon, Daniel, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie , Glodzik, Lidia , Santi, Susan De , Doraiswamy, P. Murali , Petrella, Jeffrey R. , Coleman, Robert E. , Arnold, Steven E. , Karlawish, Jason H., Smith, Charles D., Jicha, Gregory A. , Hardy, Peter , Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Goldstein, Bonnie S., Martin, Kim, Makino, Kelly M., Ismail, M. Saleem , Brand, Connie, Mulnard, Ruth A., Thai, Gaby , Mc-Adams-Ortiz, Catherine, Mathews, Dana, Quiceno, Mary , King, Richard, Martin-Cook, Kristen, Devous, Michael D. , Cellar, Janet S., Anderson, Heather S., Swerdlow, Russell H. , Apostolova, Liana , Lu, Po H. , Bartzokis, George, Graff‐Radford, Neill R. , Parfitt, Francine, Farlow, Martin R. , Hake, Ann Marie , Matthews, Brandy R., Herring, Scott, Dyck, Christopher H. van , Carson, Richard E. , MacAvoy, Martha G., Chertkow, Howard , Bergman, Howard , Hosein, Chris, Caldwell, Curtis, Hsiung, Ging‐Yuek Robin , Feldman, Howard J., Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles , Munic, Donna, Mesulam, Marek-Marsel, Lipowski, Kristina, Wu, Chuang‐Kuo, Johnson, Nancy E., Sadowsky, Carl, Villena, Teresa, Johnson, Kathleen, Reynolds, Brigid, Marshall, Gad A. , Frey, Meghan , Yesavage, Jerome A. , Taylor, Joy L. , Lane, Barton , Rosen, Allyson , Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine M. , Jacobson, Sandra A. , Kowall, Neil W. , Budson, Andrew E. , Johnson, Patricia Lynn, Wolday, Saba, Bwayo, Salome K., Lerner, Alan J. , Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Olichney, John , Kittur, Smita, Borrie, Michael, Lee, T.-Y., Bartha, Robert , Asthana, Sanjay , Carlsson, Cynthia M., Preda, Adrian , Tariot, Pierre N. , Fleisher, Adam , Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Kataki, Maria , Zimmerman, Earl A. , Celmins, Dzintra, Brown, Alice D., Blank, Karen, Anderson, Karen, Santulli, Robert B. , Schwartz, Eben S., Williamson, Jeff D. , Garg, Pradeep , Watkins, Franklin, Ott, Brian R. , Querfurth, Henry, Tremont, Geoffrey , Salloway, Stephen , Malloy, Paul, Correia, Stephen , Rosen, Howard J., Mintzer, Jacobo , Longmire, Crystal Flynn, Spicer, Kenneth, Rachinsky, Irina, Kertesz, Andrew, Drost, Dick, Lee, Ting‐Yim , Jack, Clifford R., Green, Robert C. , Initiative, the Alzheimer’s Disease Neuroimaging, Jack, Clifford R. , Toga, Arthur W., Beckett, Laurel , Green, Robert C., Morris, John C. , Green, Robert C., Donohue, Michael, Sather, Tamie, Donohue, Michael, Jack, Clifford R., Dale, Anders M. , Bernstein, Matt A. , Fox, Nick C. , Koeppe, Robert A. , Chen, Kewei , Mathis, Chet, Lee, Virginia M.‐Y. , Toga, Arthur W., Foroud, Tatiana , Potkin, Steven G. , Shen, Li , Snyder, Peter J. , Kaye, Jeffrey , Lord, Joanne L. , Villanueva-Meyer, Javier E. , Stern, Yaakov , Honig, Lawrence S. , Ances, Beau M. , Grossman, Hillel, Shah, Raj C. , Duara, Ranjan , Varón, Daniel , Rusinek, Henry , Leon, Mony J. de , Karlawish, Jason , Wolk, David A. , Porsteinsson, Anton P. , Womack, Kyle , Diaz‐Arrastia, Ramon , Weiner, Myron , Levey, Allan I. , Lah, James J. , Burns, Jeffrey M. , Silverman, Daniel H.S. , Johnson, Heather M. , Black, Sandra E. , Stefanovic, Bojana , Kertesz, Andrew, Kerwin, Diana , Martínez, Walter Fabián , Turner, Raymond Scott , Sperling, Reisa Anne , Johnson, Keith A. , Killiany, Ronald , Norbash, Alexander , Obisesan, Thomas O. , Carmichael, Owen , Johnson, Sterling C. , Nguyen, Dana R. , Reeder, Stephanie, Scharre, Douglas W. , Pearlson, Godfrey D. , Sink, Kaycee M. , Miller, Bruce L. , Finger, Elizabeth C. , Kertesz, Andrew, de Zubicaray, Greig I , Hansell, Narelle K , Saykin, Andrew J , Preda, Adrian , Martin, Nicholas G , Toga, Arthur W , Wright, Margaret J , Thompson, Paul M , Medland, Sarah E , Hsiung, Gink-Yuek , Jicha, Gregory A
Proceedings of the National Academy of Sciences | March 5, 2013 | Volume: 110 | Issue: 12 | Pages: 4768-4773
Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.
A commonly carried genetic variant in the delta opioid receptor gene, OPRD1, is associated with smaller regional brain volumes: Replication in elderly and young populations
Roussotte, Florence F. , Jahanshad, Neda , Hibar, Derrek P., Sowell, Elizabeth R. , Kohannim, Omid , Barysheva, Marina, Hansell, Narelle K. , McMahon, Katie L. , Zubicaray, Greig I. de , Montgomery, Grant W. , Martin, Nicholas G. , Wright, Margaret J. , Weiner, Michael W. , Thompson, Paul M. , ADNI, the, Toga, Arthur W. , Jack, Clifford R. , ADNI, the, de Zubicaray, Greig I , Hansell, Narelle K , Martin, Nicholas G , Wright, Margaret J , Thompson, Paul M
Human Brain Mapping | February 21, 2013 | Volume: 35 | Issue: 4 | Pages: 1226-1236
Delta opioid receptors are implicated in a variety of psychiatric and neurological disorders. These receptors play a key role in the reinforcing properties of drugs of abuse, and polymorphisms in OPRD1 (the gene encoding delta opioid receptors) are associated with drug addiction. Delta opioid receptors are also involved in protecting neurons against hypoxic and ischemic stress. Here, we first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative. We hypothesized that common variants in OPRD1 would be associated with differences in brain structure, particularly in regions relevant to addictive and neurodegenerative disorders. One very common variant (rs678849) predicted differences in regional brain volumes. We replicated the association of this single‐nucleotide polymorphism with regional tissue volumes in a large sample of young participants in the Queensland Twin Imaging study. Although the same allele was associated with reduced volumes in both cohorts, the brain regions affected differed between the two samples. In healthy elderly, exploratory analyses suggested that the genotype associated with reduced brain volumes in both cohorts may also predict cerebrospinal fluid levels of neurodegenerative biomarkers, but this requires confirmation. If opiate receptor genetic variants are related to individual differences in brain structure, genotyping of these variants may be helpful when designing clinical trials targeting delta opioid receptors to treat neurological disorders. Hum Brain Mapp 35:1226–1236, 2014 . © 2013 Wiley Periodicals, Inc.
A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11
Siddiq, Afshan , Chen, Gary K., Lindström, Sara, Eccles, Diana , Millikan, Robert C., Michailidou, Kyriaki , Beckmann, Lars , Aittomäki, Kristiina , Apicella, Carmel, Investigators, Australian Breast Cancer Tissue Bank, Baglietto, Laura , Bandera, Elisa V. , Beckmann, Matthias W. , Berg, Christine D. , Blomqvist, Carl , Brauch, Hiltrud , Brinton, Louise A. , Bui, Minh , Buring, Julie E. , Campa, Daniele , Carpenter, Jane, Chang‐Claude, Jenny, Chen, Constance, Clavel-Chapelon, Françoise, Cox, Angela , Cross, Simon S. , Czene, Kamila , Deming, Sandra L., Diasio, Robert B. , Diver, W. Ryan , Dunning, Alison M. , Durcan, Lorraine , Ekici, Arif B. , Fasching, Peter A. , Study, Familial Breast Cancer, Fejerman, Laura , Figueroa, Jonine D. , Flesch‐Janys, Dieter, Gaudet, Mia M., Gerty, Susan M. , Rodriguez‐Gil, Jorge L. , Giles, Graham G. , Gils, Carla H. van , Graham, Nikki , Greco, Dario , Hankinson, Susan E. , Hartmann, Arndt, Hein, Rebecca, Heinz, Judith , Hoover, Robert N. , Hu, Jennifer J. , Huntsman, Scott , Irwanto, Astrid , Jacobs, Kevin B. , John, Esther M. , Justenhoven, Christina , Kolonel, Laurence N. , Coetzee, Gerhard A. , Lathrop, Mark, Lee, I‐Min , Lesnick, Timothy G. , Lichtner, Peter , Liu, Jianjun , Lund, Eiliv , Makalic, Enes , Martin, Nicholas G. , McLean, Catriona , Meijers‐Heijboer, Hanne , Meindl, Alfons , Miron, Penelope , Montgomery, Grant W. , Müller‐Myhsok, Bertram , Nickels, Stefan , Nyante, Sarah J. , Olswold, Curtis, Overvad, Kim , Palli, Domenico , Park, Daniel J. , Palmer, Julie R. , Peto, Julian , Rahman, Nazneen , Rivadeneira, Fernando , Schmutzler, Rita K. , Slager, Susan, Southey, Melissa C. , Stevens, Kristen N., Sinn, Hans‐Peter , Ross, Eric A. , Ríboli, Elio , Schumacher, Fredrick R. , Severi, Gianluca , Stone, Jennifer , Sund, Malin , Tapper, William , Thun, Michael J., Travis, Ruth C. , Turnbull, Clare , Uitterlinden, André G. , Waisfisz, Quinten , Wang, Zhaoming , Weaver, JoEllen , Schulz-Wendtland, Rüdiger, Nevanlinna, Heli , Easton, Douglas F., Hunter, David J. , Henderson, Brian E., García‐Closas, Montserrat , Kraft, Peter , Haiman, Christopher A. , Vachon, Celine M. , Zheng, Wei , Purrington, Kristen S. , Couch, Fergus J. , Stram, Daniel O. , Rhie, Suhn K. , Ambrosone, Christine B. , Amiano, Pilar , Investigators, Australian Breast Cancer Tissue Bank, Bernstein, Leslie , Bui, Minh , Buys, Saundra S. , Chasman, Daniel I. , Study, Familial Breast Cancer, Feigelson, Heather Spencer , Fletcher, Olivia , Godwin, Andrew K. , Hall, Per N , Hankinson, Susan E. , Hopper, John L. , Ingles, Sue A. , Isaacs, Claudine , Kaaks, Rudolf , Marchand, Loı̈c Le , Lee, Adam M. , Meindl, Alfons , Monroe, Kristine R. , Pathak, Harsh B. , Pharoah, Paul D.P. , Schmidt, Daniel F. , Press, Michael F. , Ridker, Paul M. , dos‐Santos‐Silva, Isabel , Wang, Xianshu , Wilkens, Lynne R. , Berg, David Van Den , Zheng, Wei , Ziegler, Regina G. , Ziv, Elad , Chanock, Stephen Jacob , Vachon, Celine M. , Nevanlinna, H , Giles, Graham G , Eccles, Diana , John, Esther M , Palli, Domenico , Southey, Melissa C , Martin, Nicholas G , Sinn, Peter , Travis, Ruth C , Wang, Zhaoming , Dunning, Alison M , Cox, Angela , García-Closas, Montserrat , Severi, Gianluca , Makalic, Enes , Ekici, Arif B , Michailidou, Kyriaki , Palmer, Julie R , Kraft, Peter , Zheng, Wei , Figueroa, Jonine D , Nyante, Sarah , Czene, Kamila , Stone, Jennifer , Riboli, Elio , Sund, Malin , Baglietto, Laura , Purrington, Kristen S , Mclean, Catriona , Brauch, Hiltrud , Liu, Jing , Bandera, Elisa V.
Human Molecular Genetics | September 14, 2012 | Volume: 21 | Issue: 24 | Pages: 5373-5384
Common Breast Cancer Susceptibility Loci Are Associated with Triple-Negative Breast Cancer
Stevens, Kristen N., Vachon, Celine M. , Slager, Susan, Lesnick, Timothy G. , Olswold, Curtis, Fasching, Peter A. , Miron, Penelope , Eccles, Diana , Carpenter, Jane, Winqvist, Robert , Brauch, Hiltrud , Schmidt, Marjanka K. , Cox, Angela , Cross, Simon S. , Sawyer, Elinor J. , Hartmann, Arndt, Beckmann, Matthias W. , Schulz-Wendtland, Rüdiger, Ekici, Arif B. , Tapper, William , Gerty, Susan M. , Durcan, Lorraine , Graham, Nikki , Hein, Rebecca, Nickels, Stephan, Flesch‐Janys, Dieter, Heinz, Judith , Sinn, Hans‐Peter , Konstantopoulou, Irene , Pectasides, Dimitrios , Dimopoulos, Athanasios M., Clarke, Christine L. , Balleine, Rosemary L. , Fredericksen, Zachary, Diasio, Robert B. , Ross, Eric A. , Weaver, JoEllen , Rüdiger, Thomas , Dünnebier, Thomas, Ademuyiwa, Foluso O. , Kulkarni, Swati , Pylkäs, Katri , Jukkola‐Vuorinen, Arja , Ko, Yon‐Dschun, Limbergen, Erik Van, Janssen, Hilde, Peto, Julian , Fletcher, Olivia , Giles, Graham G. , Baglietto, Laura , Verhoef, Senno, Tomlinson, Ian , Kosma, Veli‐Matti , Greco, Dario , Blomqvist, Carl , Irwanto, Astrid , Liu, Jianjun , Blows, Fiona M., Dawson, Sarah‐Jane , Margolin, Sara , Mannermaa, Arto, Martin, Nicholas G. , Montgomery, Grant W. , Lambrechts, Diether , dos‐Santos‐Silva, Isabel , Severi, Gianluca , Hamann, Ute, Easton, Douglas F., Chang‐Claude, Jenny , Yannoukakos, Drakoulis , Nevanlinna, Heli , Dimopoulos, Meletios Α. , Purrington, Kristen S. , Lambrechts, Diether , Vachon, Celine M. , Lee, Adam M. , Godwin, Andrew K. , Ambrosone, Christine B. , Fostira, Florentia , Dimopoulos, Athanasios M., Fountzilas, George , Olson, Janet E. , Pathak, Harsh B. , Försti, Asta , Beesley, Jonathan , Mannermaa, Arto, Pharoah, Paul D.P. , Wang, Xianshu , Couch, Fergus J. , Nevanlinna, H , Lambrechts, Diether , Giles, Graham G , Eccles, Diana , Dimopoulos, Meletios A , Konstantopoulou, Irene , Martin, Nicholas G , Sinn, Peter , Lambrechts, Diether , Cox, Angela , Schmidt, Marjanka K , Severi, Gianluca , Ekici, Arif B , Ademuyiwa, Foluso O , Pylkäs, Katri , Yannoukakos, Drakoulis , Baglietto, Laura , Fletcher, Olivia , Purrington, Kristen S , Brauch, Hiltrud , Sawyer, Elinor J , Liu, Jing
Cancer Research | August 15, 2011 | Volume: 71 | Issue: 19 | Pages: 6240-6249
Abstract Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer. Cancer Res; 71(19); 6240–9. ©2011 AACR.