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202. Reference-based phasing using the Haplotype Reference Consortium panel

Author

Loh, Po-Ru, primary, Danecek, Petr, additional, Palamara, Pier Francesco, additional, Fuchsberger, Christian, additional, A Reshef, Yakir, additional, K Finucane, Hilary, additional, Schoenherr, Sebastian, additional, Forer, Lukas, additional, McCarthy, Shane, additional, Abecasis, Goncalo R, additional, Durbin, Richard, additional, and L Price, Alkes, additional

Published
2016
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211. Integrative approaches for large-scale transcriptome-wide association studies

Author

Gusev, Alexander, primary, Ko, Arthur, additional, Shi, Huwenbo, additional, Bhatia, Gaurav, additional, Chung, Wonil, additional, Penninx, Brenda W J H, additional, Jansen, Rick, additional, de Geus, Eco J C, additional, Boomsma, Dorret I, additional, Wright, Fred A, additional, Sullivan, Patrick F, additional, Nikkola, Elina, additional, Alvarez, Marcus, additional, Civelek, Mete, additional, Lusis, Aldons J, additional, Lehtimäki, Terho, additional, Raitoharju, Emma, additional, Kähönen, Mika, additional, Seppälä, Ilkka, additional, Raitakari, Olli T, additional, Kuusisto, Johanna, additional, Laakso, Markku, additional, Price, Alkes L, additional, Pajukanta, Päivi, additional, and Pasaniuc, Bogdan, additional

Published
2016
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212. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.

Author

Bulik-Sullivan, Brendan K, Bulik-Sullivan, Brendan K, Loh, Po-Ru, Finucane, Hilary K, Ripke, Stephan, Yang, Jian, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Patterson, Nick, Daly, Mark J, Price, Alkes L, Neale, Benjamin M, Bulik-Sullivan, Brendan K, Bulik-Sullivan, Brendan K, Loh, Po-Ru, Finucane, Hilary K, Ripke, Stephan, Yang, Jian, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Patterson, Nick, Daly, Mark J, Price, Alkes L, and Neale, Benjamin M

Abstract

Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

Published
2015

213. Efficient Bayesian mixed-model analysis increases association power in large cohorts.

Author

Loh, Po-Ru, Loh, Po-Ru, Tucker, George, Bulik-Sullivan, Brendan K, Vilhjálmsson, Bjarni J, Finucane, Hilary K, Salem, Rany M, Chasman, Daniel I, Ridker, Paul M, Neale, Benjamin M, Berger, Bonnie, Patterson, Nick, Price, Alkes L, Loh, Po-Ru, Loh, Po-Ru, Tucker, George, Bulik-Sullivan, Brendan K, Vilhjálmsson, Bjarni J, Finucane, Hilary K, Salem, Rany M, Chasman, Daniel I, Ridker, Paul M, Neale, Benjamin M, Berger, Bonnie, Patterson, Nick, and Price, Alkes L

Abstract

Linear mixed models are a powerful statistical tool for identifying genetic associations and avoiding confounding. However, existing methods are computationally intractable in large cohorts and may not optimize power. All existing methods require time cost O(MN(2)) (where N is the number of samples and M is the number of SNPs) and implicitly assume an infinitesimal genetic architecture in which effect sizes are normally distributed, which can limit power. Here we present a far more efficient mixed-model association method, BOLT-LMM, which requires only a small number of O(MN) time iterations and increases power by modeling more realistic, non-infinitesimal genetic architectures via a Bayesian mixture prior on marker effect sizes. We applied BOLT-LMM to 9 quantitative traits in 23,294 samples from the Women's Genome Health Study (WGHS) and observed significant increases in power, consistent with simulations. Theory and simulations show that the boost in power increases with cohort size, making BOLT-LMM appealing for genome-wide association studies in large cohorts.

Published
2015

214. Leveraging Distant Relatedness to Quantify Human Mutation and Gene-Conversion Rates

Author

Palamara, Pier Francesco, Francioli, Laurent C, Wilton, Peter R, Genovese, Giulio, Gusev, Alexander, Finucane, Hilary K, Sankararaman, Sriram, Sunyaev, Shamil R, de Bakker, Paul I W, Wakeley, John, Pe'er, Itsik, Price, Alkes L, Genome of the Netherlands Consortium, Palamara, Pier Francesco, Francioli, Laurent C, Wilton, Peter R, Genovese, Giulio, Gusev, Alexander, Finucane, Hilary K, Sankararaman, Sriram, Sunyaev, Shamil R, de Bakker, Paul I W, Wakeley, John, Pe'er, Itsik, Price, Alkes L, and Genome of the Netherlands Consortium

Published
2015

215. New data and an old puzzle : the negative association between schizophrenia and rheumatoid arthritis

Author

Lee, S Hong, Byrne, Enda M, Hultman, Christina M, Kähler, Anna, Vinkhuyzen, Anna Ae, Ripke, Stephan, Andreassen, Ole A, Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X, McGrath, John J, Mehta, Divya, Stahl, Eli A, Zhao, Qiongyi, Kendler, Kenneth S, Sullivan, Patrick F, Price, Alkes L, O'Donovan, Michael, Okada, Yukinori, Mowry, Bryan J, Raychaudhuri, Soumya, Wray, Naomi R, Byerley, William, Cahn, Wiepke, Cantor, Rita M, Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V, Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F, Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W, Nöthen, Markus M, O'Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N, Kahn, René S, Ophoff, Roel A, Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International, Lee, S Hong, Byrne, Enda M, Hultman, Christina M, Kähler, Anna, Vinkhuyzen, Anna Ae, Ripke, Stephan, Andreassen, Ole A, Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X, McGrath, John J, Mehta, Divya, Stahl, Eli A, Zhao, Qiongyi, Kendler, Kenneth S, Sullivan, Patrick F, Price, Alkes L, O'Donovan, Michael, Okada, Yukinori, Mowry, Bryan J, Raychaudhuri, Soumya, Wray, Naomi R, Byerley, William, Cahn, Wiepke, Cantor, Rita M, Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V, Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F, Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W, Nöthen, Markus M, O'Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N, Kahn, René S, Ophoff, Roel A, and Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International

Published
2015

216. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Author

Day, Felix R., Ruth, Katherine S., Thompson, Deborah J., Lunetta, Kathryn L., Pervjakova, Natalia, Chasman, Daniel I., Stolk, Lisette, Finucane, Hilary K., Sulem, Patrick, Bulik-Sullivan, Brendan, Esko, Tonu, Johnson, Andrew D., Elks, Cathy E., Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A., Franke, Lude L., Huffman, Jennifer E., Keller, Margaux F., McArdle, Patrick F., Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Smith, Jennifer A., Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke-Jan, Mangino, Massimo, Smith, Albert V., Tanaka, Toshiko, Abecasis, Goncalo R., Andrulis, Irene L., Anton-Culver, Hoda, Antoniou, Antonis C., Arndt, Volker, Arnold, Alice M., Barbieri, Caterina, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J., Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Borresen-Dale, Anne-Lise, Boutin, Thibaud S., Brauch, Hiltrud, Brenner, Hermann, Bruening, Thomas, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J., Chapman, J. Ross, Chen, Yii-Der Ida, Chenevix-Trench, Georgia, Couch, Fergus J., Coviello, Andrea D., Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Devilee, Peter, Doerk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Eicher, John D., Fasching, Peter A., Faul, Jessica D., Figueroa, Jonine, Flesch-Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E., Garcia-Closas, Montserrat, Giles, Graham G., Girotto, Giorgia G., Goldberg, Mark S., Gonzalez-Neira, Anna, Goodarzi, Mark O., Grove, Megan L., Gudbjartsson, Daniel F., Guenel, Pascal, Guo, Xiuqing, Haiman, Christopher A., Hall, Per, Hamann, Ute, Henderson, Brian E., Hocking, Lynne J., Hofman, Albert, Homuth, Georg, Hooning, Maartje J., Hopper, John L., Hu, Frank B., Huang, Jinyan, Humphreys, Keith, Hunter, David J., Jakubowska, Anna, Jones, Samuel E., Kabisch, Maria, Karasik, David, Knight, Julia A., Kolcic, Ivana, Kooperberg, Charles, Kosma, Veli-Matti, Kriebel, Jennifer, Kristensen, Vessela, Lambrechts, Diether, Langenberg, Claudia, Li, Jingmei, Li, Xin, Lindstroem, Sara, Liu, Yongmei, Luan, Jian'an, Lubinski, Jan, Maegi, Reedik, Mannermaa, Arto, Manz, Judith, Margolin, Sara, Marten, Jonathan, Martin, Nicholas G., Masciullo, Corrado, Meindl, Alfons, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L., Mueller-Nurasyid, Martina, Nalls, Michael, Neale, Benjamin M., Nevanlinna, Heli, Neven, Patrick, Newman, Anne B., Nordestgaard, Borge G., Olson, Janet E., Padmanabhan, Sandosh, Peterlongo, Paolo, Peters, Ulrike, Petersmann, Astrid, Peto, Julian, Pharoah, Paul D. P., Pirastu, Nicola N., Pirie, Ailith, Pistis, Giorgio, Polasek, Ozren, Porteous, David, Psaty, Bruce M., Pylkas, Katri, Radice, Paolo, Raffel, Leslie J., Rivadeneira, Fernando, Rudan, Igor, Rudolph, Anja, Ruggiero, Daniela, Sala, Cinzia F., Sanna, Serena, Sawyer, Elinor J., Schlessinger, David, Schmidt, Marjanka K., Schmidt, Frank, Schmutzler, Rita K., Schoemaker, Minouk J., Scott, Robert A., Seynaeve, Caroline M., Simard, Jacques, Sorice, Rossella, Southey, Melissa C., Stoeckl, Doris, Strauch, Konstantin, Swerdlow, Anthony, Taylor, Kent D., Thorsteinsdottir, Unnur, Toland, Amanda E., Tomlinson, Ian, Truong, Therese, Tryggvadottir, Laufey, Turner, Stephen T., Vozzi, Diego, Wang, Qin, Wellons, Melissa, Willemsen, Gonneke, Wilson, James F., Winqvist, Robert, Wolffenbuttel, Bruce B. H. R., Wright, Alan F., Yannoukakos, Drakoulis, Zemunik, Tatijana, Zheng, Wei, Zygmunt, Marek, Bergmann, Sven, Boomsma, Dorret I., Buring, Julie E., Ferrucci, Luigi, Montgomery, Grant W., Gudnason, Vilmundur, Spector, Tim D., van Duijn, Cornelia M., Alizadeh, Behrooz Z., Ciullo, Marina, Crisponi, Laura, Easton, Douglas F., Gasparini, Paolo P., Gieger, Christian, Harris, Tamara B., Hayward, Caroline, Kardia, Sharon L. R., Kraft, Peter, McKnight, Barbara, Metspalu, Andres, Morrison, Alanna C., Reiner, Alex P., Ridker, Paul M., Rotter, Jerome I., Toniolo, Daniela, Uitterlinden, Andre G., Ulivi, Sheila, Voelzke, Henry, Wareham, Nicholas J., Weir, David R., Yerges-Armstrong, Laura M., Price, Alkes L., Stefansson, Kari, Visser, Jenny A., Ong, Ken K., Chang-Claude, Jenny, Murabito, Joanne M., Perry, John R. B., Murray, Anna, Day, Felix R., Ruth, Katherine S., Thompson, Deborah J., Lunetta, Kathryn L., Pervjakova, Natalia, Chasman, Daniel I., Stolk, Lisette, Finucane, Hilary K., Sulem, Patrick, Bulik-Sullivan, Brendan, Esko, Tonu, Johnson, Andrew D., Elks, Cathy E., Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A., Franke, Lude L., Huffman, Jennifer E., Keller, Margaux F., McArdle, Patrick F., Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Smith, Jennifer A., Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke-Jan, Mangino, Massimo, Smith, Albert V., Tanaka, Toshiko, Abecasis, Goncalo R., Andrulis, Irene L., Anton-Culver, Hoda, Antoniou, Antonis C., Arndt, Volker, Arnold, Alice M., Barbieri, Caterina, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J., Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Borresen-Dale, Anne-Lise, Boutin, Thibaud S., Brauch, Hiltrud, Brenner, Hermann, Bruening, Thomas, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J., Chapman, J. Ross, Chen, Yii-Der Ida, Chenevix-Trench, Georgia, Couch, Fergus J., Coviello, Andrea D., Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Devilee, Peter, Doerk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Eicher, John D., Fasching, Peter A., Faul, Jessica D., Figueroa, Jonine, Flesch-Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E., Garcia-Closas, Montserrat, Giles, Graham G., Girotto, Giorgia G., Goldberg, Mark S., Gonzalez-Neira, Anna, Goodarzi, Mark O., Grove, Megan L., Gudbjartsson, Daniel F., Guenel, Pascal, Guo, Xiuqing, Haiman, Christopher A., Hall, Per, Hamann, Ute, Henderson, Brian E., Hocking, Lynne J., Hofman, Albert, Homuth, Georg, Hooning, Maartje J., Hopper, John L., Hu, Frank B., Huang, Jinyan, Humphreys, Keith, Hunter, David J., Jakubowska, Anna, Jones, Samuel E., Kabisch, Maria, Karasik, David, Knight, Julia A., Kolcic, Ivana, Kooperberg, Charles, Kosma, Veli-Matti, Kriebel, Jennifer, Kristensen, Vessela, Lambrechts, Diether, Langenberg, Claudia, Li, Jingmei, Li, Xin, Lindstroem, Sara, Liu, Yongmei, Luan, Jian'an, Lubinski, Jan, Maegi, Reedik, Mannermaa, Arto, Manz, Judith, Margolin, Sara, Marten, Jonathan, Martin, Nicholas G., Masciullo, Corrado, Meindl, Alfons, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L., Mueller-Nurasyid, Martina, Nalls, Michael, Neale, Benjamin M., Nevanlinna, Heli, Neven, Patrick, Newman, Anne B., Nordestgaard, Borge G., Olson, Janet E., Padmanabhan, Sandosh, Peterlongo, Paolo, Peters, Ulrike, Petersmann, Astrid, Peto, Julian, Pharoah, Paul D. P., Pirastu, Nicola N., Pirie, Ailith, Pistis, Giorgio, Polasek, Ozren, Porteous, David, Psaty, Bruce M., Pylkas, Katri, Radice, Paolo, Raffel, Leslie J., Rivadeneira, Fernando, Rudan, Igor, Rudolph, Anja, Ruggiero, Daniela, Sala, Cinzia F., Sanna, Serena, Sawyer, Elinor J., Schlessinger, David, Schmidt, Marjanka K., Schmidt, Frank, Schmutzler, Rita K., Schoemaker, Minouk J., Scott, Robert A., Seynaeve, Caroline M., Simard, Jacques, Sorice, Rossella, Southey, Melissa C., Stoeckl, Doris, Strauch, Konstantin, Swerdlow, Anthony, Taylor, Kent D., Thorsteinsdottir, Unnur, Toland, Amanda E., Tomlinson, Ian, Truong, Therese, Tryggvadottir, Laufey, Turner, Stephen T., Vozzi, Diego, Wang, Qin, Wellons, Melissa, Willemsen, Gonneke, Wilson, James F., Winqvist, Robert, Wolffenbuttel, Bruce B. H. R., Wright, Alan F., Yannoukakos, Drakoulis, Zemunik, Tatijana, Zheng, Wei, Zygmunt, Marek, Bergmann, Sven, Boomsma, Dorret I., Buring, Julie E., Ferrucci, Luigi, Montgomery, Grant W., Gudnason, Vilmundur, Spector, Tim D., van Duijn, Cornelia M., Alizadeh, Behrooz Z., Ciullo, Marina, Crisponi, Laura, Easton, Douglas F., Gasparini, Paolo P., Gieger, Christian, Harris, Tamara B., Hayward, Caroline, Kardia, Sharon L. R., Kraft, Peter, McKnight, Barbara, Metspalu, Andres, Morrison, Alanna C., Reiner, Alex P., Ridker, Paul M., Rotter, Jerome I., Toniolo, Daniela, Uitterlinden, Andre G., Ulivi, Sheila, Voelzke, Henry, Wareham, Nicholas J., Weir, David R., Yerges-Armstrong, Laura M., Price, Alkes L., Stefansson, Kari, Visser, Jenny A., Ong, Ken K., Chang-Claude, Jenny, Murabito, Joanne M., Perry, John R. B., and Murray, Anna

Abstract

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in similar to 70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (similar to 6% increase in risk per year; P = 3 x 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Published
2015

217. New data and an old puzzle : The negative association between schizophrenia and rheumatoid arthritis

Author

Hong Lee, S., Byrne, Enda M., Hultman, Christina M., Kähler, Anna, Vinkhuyzen, Anna A.E., Ripke, Stephan, Andreassen, Ole A., Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X., McGrath, John J., Mehta, Divya, Stahl, Eli A., Zhao, Qiongyi, Kendler, Kenneth S., Sullivan, Patrick F., Price, Alkes L., O'Donovan, Michael, Okada, Yukinori, Mowry, Bryan J., Raychaudhuri, Soumya, Wray, Naomi R., Agartz, Ingrid, Amin, Farooq, Azevedo, Maria H., Bass, Nicholas, Black, Donald W., Blackwood, Douglas H.R., Bruggeman, Richard, Buccola, Nancy G., Choudhury, Khalid, Cloninger, C. Robert, Corvin, Aiden, Craddock, Nicholas, Daly, Mark J., Datta, Susmita, Donohoe, Gary J., Duan, Jubao, Dudbridge, Frank, Fanous, Ayman, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Gill, Michael, Gurling, Hugh, Haan, Lieuwe De, Hamshere, Marian L., Hartmann, Annette M., Holmans, Peter A., Kahn, Rene S., Keller, Matthew C., Kenny, Elaine, Kirov, George K., Krabbendam, Lydia, Krasucki, Robert, Lawrence, Jacob, Lencz, Todd, Levinson, Douglas F., Lieberman, Jeffrey A., Lin, Dan Yu, Linszen, Don H., Magnusson, Patrik K.E., Maier, Wolfgang, Malhotra, Anil K., Mattheisen, Manuel, Mattingsdal, Morten, McCarroll, Steven A., Medeiros, Helena, Melle, Ingrid, Milanova, Vihra, Myin-Germeys, Inez, Neale, Benjamin M., Ophoff, Roel A., Owen, Michael J., Pimm, Jonathan, Purcell, Shaun M., Puri, Vinay, Quested, Digby J., Rossin, Lizzy, Ruderfer, Douglas, Sanders, Alan R., Shi, Jianxin, Sklar, Pamela, St Clair, David, Scott Stroup, T., Van Os, Jim, Visscher, Peter M., Wiersma, Durk, Zammit, Stanley, Byerley, William, Cahn, Wiepke, Cantor, Rita M., Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V., Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F., Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H., McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W., Nöthen, Markus M., O'Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N., Pato, Michele T., Pickard, Benjamin S., Posthuma, Danielle, Rasmussen, Henrik B., Rietschel, Marcella, Rujescu, Dan, Schulze, Thomas G., Silverman, Jeremy M., Thirumalai, Srinivasa, Werge, Thomas, Louis Bridges, S., Choi, Hyon K., Coenen, Marieke J.H., De Vries, Niek, Dieud, Philippe, Greenberg, Jeffrey D., Huizinga, Tom W.J., Padyukov, Leonid, Siminovitch, Katherine A., Tak, Paul P., Worthington, Jane, De Jager, Philip L., Denny, Joshua C., Gregersen, Peter K., Klareskog, Lars, Mariette, Xavier, Plenge, Robert M., Van Laar, Mart, Van Riel, Piet, Hong Lee, S., Byrne, Enda M., Hultman, Christina M., Kähler, Anna, Vinkhuyzen, Anna A.E., Ripke, Stephan, Andreassen, Ole A., Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X., McGrath, John J., Mehta, Divya, Stahl, Eli A., Zhao, Qiongyi, Kendler, Kenneth S., Sullivan, Patrick F., Price, Alkes L., O'Donovan, Michael, Okada, Yukinori, Mowry, Bryan J., Raychaudhuri, Soumya, Wray, Naomi R., Agartz, Ingrid, Amin, Farooq, Azevedo, Maria H., Bass, Nicholas, Black, Donald W., Blackwood, Douglas H.R., Bruggeman, Richard, Buccola, Nancy G., Choudhury, Khalid, Cloninger, C. Robert, Corvin, Aiden, Craddock, Nicholas, Daly, Mark J., Datta, Susmita, Donohoe, Gary J., Duan, Jubao, Dudbridge, Frank, Fanous, Ayman, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Gill, Michael, Gurling, Hugh, Haan, Lieuwe De, Hamshere, Marian L., Hartmann, Annette M., Holmans, Peter A., Kahn, Rene S., Keller, Matthew C., Kenny, Elaine, Kirov, George K., Krabbendam, Lydia, Krasucki, Robert, Lawrence, Jacob, Lencz, Todd, Levinson, Douglas F., Lieberman, Jeffrey A., Lin, Dan Yu, Linszen, Don H., Magnusson, Patrik K.E., Maier, Wolfgang, Malhotra, Anil K., Mattheisen, Manuel, Mattingsdal, Morten, McCarroll, Steven A., Medeiros, Helena, Melle, Ingrid, Milanova, Vihra, Myin-Germeys, Inez, Neale, Benjamin M., Ophoff, Roel A., Owen, Michael J., Pimm, Jonathan, Purcell, Shaun M., Puri, Vinay, Quested, Digby J., Rossin, Lizzy, Ruderfer, Douglas, Sanders, Alan R., Shi, Jianxin, Sklar, Pamela, St Clair, David, Scott Stroup, T., Van Os, Jim, Visscher, Peter M., Wiersma, Durk, Zammit, Stanley, Byerley, William, Cahn, Wiepke, Cantor, Rita M., Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V., Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F., Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H., McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W., Nöthen, Markus M., O'Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N., Pato, Michele T., Pickard, Benjamin S., Posthuma, Danielle, Rasmussen, Henrik B., Rietschel, Marcella, Rujescu, Dan, Schulze, Thomas G., Silverman, Jeremy M., Thirumalai, Srinivasa, Werge, Thomas, Louis Bridges, S., Choi, Hyon K., Coenen, Marieke J.H., De Vries, Niek, Dieud, Philippe, Greenberg, Jeffrey D., Huizinga, Tom W.J., Padyukov, Leonid, Siminovitch, Katherine A., Tak, Paul P., Worthington, Jane, De Jager, Philip L., Denny, Joshua C., Gregersen, Peter K., Klareskog, Lars, Mariette, Xavier, Plenge, Robert M., Van Laar, Mart, and Van Riel, Piet

Abstract

Background: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. Methods: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. Results: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090).Conclusions: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.

Published
2015

218. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores.

Author

Vilhjálmsson, Bjarni J, Vilhjálmsson, Bjarni J, Yang, Jian, Finucane, Hilary K, Gusev, Alexander, Lindström, Sara, Ripke, Stephan, Genovese, Giulio, Loh, Po-Ru, Bhatia, Gaurav, Do, Ron, Hayeck, Tristan, Won, Hong-Hee, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Kathiresan, Sekar, Pato, Michele, Pato, Carlos, Tamimi, Rulla, Stahl, Eli, Zaitlen, Noah, Pasaniuc, Bogdan, Belbin, Gillian, Kenny, Eimear E, Schierup, Mikkel H, De Jager, Philip, Patsopoulos, Nikolaos A, McCarroll, Steve, Daly, Mark, Purcell, Shaun, Chasman, Daniel, Neale, Benjamin, Goddard, Michael, Visscher, Peter M, Kraft, Peter, Patterson, Nick, Price, Alkes L, Vilhjálmsson, Bjarni J, Vilhjálmsson, Bjarni J, Yang, Jian, Finucane, Hilary K, Gusev, Alexander, Lindström, Sara, Ripke, Stephan, Genovese, Giulio, Loh, Po-Ru, Bhatia, Gaurav, Do, Ron, Hayeck, Tristan, Won, Hong-Hee, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Kathiresan, Sekar, Pato, Michele, Pato, Carlos, Tamimi, Rulla, Stahl, Eli, Zaitlen, Noah, Pasaniuc, Bogdan, Belbin, Gillian, Kenny, Eimear E, Schierup, Mikkel H, De Jager, Philip, Patsopoulos, Nikolaos A, McCarroll, Steve, Daly, Mark, Purcell, Shaun, Chasman, Daniel, Neale, Benjamin, Goddard, Michael, Visscher, Peter M, Kraft, Peter, Patterson, Nick, and Price, Alkes L

Abstract

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

Published
2015

219. Leveraging Distant Relatedness to Quantify Human Mutation and Gene-Conversion Rates

Author

CMM Groep Kaaij, JC onderzoeksprogramma Methodologie, Cancer, Palamara, Pier Francesco, Francioli, Laurent C, Wilton, Peter R, Genovese, Giulio, Gusev, Alexander, Finucane, Hilary K, Sankararaman, Sriram, Sunyaev, Shamil R, de Bakker, Paul I W, Wakeley, John, Pe'er, Itsik, Price, Alkes L, Genome of the Netherlands Consortium, CMM Groep Kaaij, JC onderzoeksprogramma Methodologie, Cancer, Palamara, Pier Francesco, Francioli, Laurent C, Wilton, Peter R, Genovese, Giulio, Gusev, Alexander, Finucane, Hilary K, Sankararaman, Sriram, Sunyaev, Shamil R, de Bakker, Paul I W, Wakeley, John, Pe'er, Itsik, Price, Alkes L, and Genome of the Netherlands Consortium

Published
2015

220. New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis

Author

Affectieve & Psychotische Med., Onderzoek, Brain, Lee, S Hong, Byrne, Enda M, Hultman, Christina M, Kähler, Anna, Vinkhuyzen, Anna Ae, Ripke, Stephan, Andreassen, Ole A, Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X, McGrath, John J, Mehta, Divya, Stahl, Eli A, Zhao, Qiongyi, Kendler, Kenneth S, Sullivan, Patrick F, Price, Alkes L, O'Donovan, Michael, Okada, Yukinori, Mowry, Bryan J, Raychaudhuri, Soumya, Wray, Naomi R, Byerley, William, Cahn, Wiepke, Cantor, Rita M, Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V, Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F, Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W, Nöthen, Markus M, O'Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N, Kahn, René S, Ophoff, Roel A, Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International, Affectieve & Psychotische Med., Onderzoek, Brain, Lee, S Hong, Byrne, Enda M, Hultman, Christina M, Kähler, Anna, Vinkhuyzen, Anna Ae, Ripke, Stephan, Andreassen, Ole A, Frisell, Thomas, Gusev, Alexander, Hu, Xinli, Karlsson, Robert, Mantzioris, Vasilis X, McGrath, John J, Mehta, Divya, Stahl, Eli A, Zhao, Qiongyi, Kendler, Kenneth S, Sullivan, Patrick F, Price, Alkes L, O'Donovan, Michael, Okada, Yukinori, Mowry, Bryan J, Raychaudhuri, Soumya, Wray, Naomi R, Byerley, William, Cahn, Wiepke, Cantor, Rita M, Cichon, Sven, Cormican, Paul, Curtis, David, Djurovic, Srdjan, Escott-Price, Valentina, Gejman, Pablo V, Georgieva, Lyudmila, Giegling, Ina, Hansen, Thomas F, Ingason, Andrés, Kim, Yunjung, Konte, Bettina, Lee, Phil H, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek W, Nöthen, Markus M, O'Dushlaine, Colm, Olincy, Ann, Olsen, Line, Pato, Carlos N, Kahn, René S, Ophoff, Roel A, and Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium International

Published
2015

224. Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair

Author

Day, Felix R., primary, Ruth, Katherine S., additional, Thompson, Deborah J., additional, Lunetta, Kathryn L., additional, Pervjakova, Natalia, additional, Chasman, Daniel I., additional, Stolk, Lisette, additional, Finucane, Hilary K., additional, Sulem, Patrick, additional, Bulik-Sullivan, Brendan, additional, Esko, Tõnu, additional, Johnson, Andrew D., additional, Elks, Cathy E., additional, Franceschini, Nora, additional, He, Chunyan, additional, Altmaier, Elisabeth, additional, Brody, Jennifer A., additional, Franke, Lude L., additional, Huffman, Jennifer E., additional, Keller, Margaux F., additional, McArdle, Patrick F., additional, Nutile, Teresa, additional, Porcu, Eleonora, additional, Robino, Antonietta, additional, Rose, Lynda M., additional, Schick, Ursula M., additional, Smith, Jennifer A., additional, Teumer, Alexander, additional, Traglia, Michela, additional, Vuckovic, Dragana, additional, Yao, Jie, additional, Zhao, Wei, additional, Albrecht, Eva, additional, Amin, Najaf, additional, Corre, Tanguy, additional, Hottenga, Jouke-Jan, additional, Mangino, Massimo, additional, Smith, Albert V., additional, Tanaka, Toshiko, additional, Abecasis, Gonçalo R., additional, Andrulis, Irene L., additional, Anton-Culver, Hoda, additional, Antoniou, Antonis C., additional, Arndt, Volker, additional, Arnold, Alice M., additional, Barbieri, Caterina, additional, Beckmann, Matthias W., additional, Beeghly-Fadiel, Alicia, additional, Benitez, Javier, additional, Bernstein, Leslie, additional, Bielinski, Suzette J., additional, Blomqvist, Carl, additional, Boerwinkle, Eric, additional, Bogdanova, Natalia V., additional, Bojesen, Stig E., additional, Bolla, Manjeet K., additional, Borresen-Dale, Anne-Lise, additional, Boutin, Thibaud S., additional, Brauch, Hiltrud, additional, Brenner, Hermann, additional, Brüning, Thomas, additional, Burwinkel, Barbara, additional, Campbell, Archie, additional, Campbell, Harry, additional, Chanock, Stephen J., additional, Chapman, J. Ross, additional, Ida Chen, Yii-Der, additional, Chenevix-Trench, Georgia, additional, Couch, Fergus J., additional, Coviello, Andrea D., additional, Cox, Angela, additional, Czene, Kamila, additional, Darabi, Hatef, additional, De Vivo, Immaculata, additional, Demerath, Ellen W., additional, Dennis, Joe, additional, Devilee, Peter, additional, Dörk, Thilo, additional, dos-Santos-Silva, Isabel, additional, Dunning, Alison M., additional, Eicher, John D., additional, Fasching, Peter A., additional, Faul, Jessica D., additional, Figueroa, Jonine, additional, Flesch-Janys, Dieter, additional, Gandin, Ilaria, additional, Garcia, Melissa E., additional, García-Closas, Montserrat, additional, Giles, Graham G., additional, Girotto, Giorgia G., additional, Goldberg, Mark S., additional, González-Neira, Anna, additional, Goodarzi, Mark O., additional, Grove, Megan L., additional, Gudbjartsson, Daniel F., additional, Guénel, Pascal, additional, Guo, Xiuqing, additional, Haiman, Christopher A., additional, Hall, Per, additional, Hamann, Ute, additional, Henderson, Brian E., additional, Hocking, Lynne J., additional, Hofman, Albert, additional, Homuth, Georg, additional, Hooning, Maartje J., additional, Hopper, John L., additional, Hu, Frank B., additional, Huang, Jinyan, additional, Humphreys, Keith, additional, Hunter, David J., additional, Jakubowska, Anna, additional, Jones, Samuel E., additional, Kabisch, Maria, additional, Karasik, David, additional, Knight, Julia A., additional, Kolcic, Ivana, additional, Kooperberg, Charles, additional, Kosma, Veli-Matti, additional, Kriebel, Jennifer, additional, Kristensen, Vessela, additional, Lambrechts, Diether, additional, Langenberg, Claudia, additional, Li, Jingmei, additional, Li, Xin, additional, Lindström, Sara, additional, Liu, Yongmei, additional, Luan, Jian’an, additional, Lubinski, Jan, additional, Mägi, Reedik, additional, Mannermaa, Arto, additional, Manz, Judith, additional, Margolin, Sara, additional, Marten, Jonathan, additional, Martin, Nicholas G., additional, Masciullo, Corrado, additional, Meindl, Alfons, additional, Michailidou, Kyriaki, additional, Mihailov, Evelin, additional, Milani, Lili, additional, Milne, Roger L., additional, Müller-Nurasyid, Martina, additional, Nalls, Michael, additional, Neale, Benjamin M., additional, Nevanlinna, Heli, additional, Neven, Patrick, additional, Newman, Anne B., additional, Nordestgaard, Børge G., additional, Olson, Janet E., additional, Padmanabhan, Sandosh, additional, Peterlongo, Paolo, additional, Peters, Ulrike, additional, Petersmann, Astrid, additional, Peto, Julian, additional, Pharoah, Paul D. P., additional, Pirastu, Nicola N., additional, Pirie, Ailith, additional, Pistis, Giorgio, additional, Polasek, Ozren, additional, Porteous, David, additional, Psaty, Bruce M., additional, Pylkäs, Katri, additional, Radice, Paolo, additional, Raffel, Leslie J., additional, Rivadeneira, Fernando, additional, Rudan, Igor, additional, Rudolph, Anja, additional, Ruggiero, Daniela, additional, Sala, Cinzia F., additional, Sanna, Serena, additional, Sawyer, Elinor J., additional, Schlessinger, David, additional, Schmidt, Marjanka K., additional, Schmidt, Frank, additional, Schmutzler, Rita K., additional, Schoemaker, Minouk J., additional, Scott, Robert A., additional, Seynaeve, Caroline M., additional, Simard, Jacques, additional, Sorice, Rossella, additional, Southey, Melissa C., additional, Stöckl, Doris, additional, Strauch, Konstantin, additional, Swerdlow, Anthony, additional, Taylor, Kent D., additional, Thorsteinsdottir, Unnur, additional, Toland, Amanda E., additional, Tomlinson, Ian, additional, Truong, Thérèse, additional, Tryggvadottir, Laufey, additional, Turner, Stephen T., additional, Vozzi, Diego, additional, Wang, Qin, additional, Wellons, Melissa, additional, Willemsen, Gonneke, additional, Wilson, James F., additional, Winqvist, Robert, additional, Wolffenbuttel, Bruce B. H. R., additional, Wright, Alan F., additional, Yannoukakos, Drakoulis, additional, Zemunik, Tatijana, additional, Zheng, Wei, additional, Zygmunt, Marek, additional, Bergmann, Sven, additional, Boomsma, Dorret I., additional, Buring, Julie E., additional, Ferrucci, Luigi, additional, Montgomery, Grant W., additional, Gudnason, Vilmundur, additional, Spector, Tim D., additional, van Duijn, Cornelia M., additional, Alizadeh, Behrooz Z., additional, Ciullo, Marina, additional, Crisponi, Laura, additional, Easton, Douglas F., additional, Gasparini, Paolo P., additional, Gieger, Christian, additional, Harris, Tamara B., additional, Hayward, Caroline, additional, Kardia, Sharon L. R., additional, Kraft, Peter, additional, McKnight, Barbara, additional, Metspalu, Andres, additional, Morrison, Alanna C., additional, Reiner, Alex P., additional, Ridker, Paul M., additional, Rotter, Jerome I., additional, Toniolo, Daniela, additional, Uitterlinden, André G., additional, Ulivi, Sheila, additional, Völzke, Henry, additional, Wareham, Nicholas J., additional, Weir, David R., additional, Yerges-Armstrong, Laura M., additional, Price, Alkes L., additional, Stefansson, Kari, additional, Visser, Jenny A., additional, Ong, Ken K., additional, Chang-Claude, Jenny, additional, Murabito, Joanne M., additional, Perry, John R. B., additional, and Murray, Anna, additional

Published
2015
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225. Leveraging Distant Relatedness to Quantify Human Mutation and Gene-Conversion Rates

Author

Palamara, Pier Francesco, primary, Francioli, Laurent C., additional, Wilton, Peter R., additional, Genovese, Giulio, additional, Gusev, Alexander, additional, Finucane, Hilary K., additional, Sankararaman, Sriram, additional, Sunyaev, Shamil R., additional, de Bakker, Paul I.W., additional, Wakeley, John, additional, Pe’er, Itsik, additional, and Price, Alkes L., additional

Published
2015
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226. Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

Author

Gusev, Alexander, primary, Lee, S. Hong, additional, Trynka, Gosia, additional, Finucane, Hilary, additional, Vilhjálmsson, Bjarni J., additional, Xu, Han, additional, Zang, Chongzhi, additional, Ripke, Stephan, additional, Bulik-Sullivan, Brendan, additional, Stahl, Eli, additional, Kähler, Anna K., additional, Hultman, Christina M., additional, Purcell, Shaun M., additional, McCarroll, Steven A., additional, Daly, Mark, additional, Pasaniuc, Bogdan, additional, Sullivan, Patrick F., additional, Neale, Benjamin M., additional, Wray, Naomi R., additional, Raychaudhuri, Soumya, additional, Price, Alkes L., additional, Neale, Benjamin M., additional, Corvin, Aiden, additional, Walters, James T.R., additional, Farh, Kai-How, additional, Holmans, Peter A., additional, Lee, Phil, additional, Collier, David A., additional, Huang, Hailiang, additional, Pers, Tune H., additional, Agartz, Ingrid, additional, Agerbo, Esben, additional, Albus, Margot, additional, Alexander, Madeline, additional, Amin, Farooq, additional, Bacanu, Silviu A., additional, Begemann, Martin, additional, Belliveau, Richard A., additional, Bene, Judit, additional, Bergen, Sarah E., additional, Bevilacqua, Elizabeth, additional, Bigdeli, Tim B., additional, Black, Donald W., additional, Børglum, Anders D., additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buckner, Randy L., additional, Byerley, William, additional, Cahn, Wiepke, additional, Cai, Guiqing, additional, Campion, Dominique, additional, Cantor, Rita M., additional, Carr, Vaughan J., additional, Carrera, Noa, additional, Catts, Stanley V., additional, Chambert, Kimberly D., additional, Chan, Raymond C.K., additional, Chen, Ronald Y.L., additional, Chen, Eric Y.H., additional, Cheng, Wei, additional, Cheung, Eric F.C., additional, Chong, Siow Ann, additional, Cloninger, C. Robert, additional, Cohen, David, additional, Cohen, Nadine, additional, Cormican, Paul, additional, Craddock, Nick, additional, Crowley, James J., additional, Curtis, David, additional, Davidson, Michael, additional, Davis, Kenneth L., additional, Degenhardt, Franziska, additional, Del Favero, Jurgen, additional, DeLisi, Lynn E., additional, Demontis, Ditte, additional, Dikeos, Dimitris, additional, Dinan, Timothy, additional, Djurovic, Srdjan, additional, Donohoe, Gary, additional, Drapeau, Elodie, additional, Duan, Jubao, additional, Dudbridge, Frank, additional, Durmishi, Naser, additional, Eichhammer, Peter, additional, Eriksson, Johan, additional, Escott-Price, Valentina, additional, Essioux, Laurent, additional, Fanous, Ayman H., additional, Farrell, Martilias S., additional, Frank, Josef, additional, Franke, Lude, additional, Freedman, Robert, additional, Freimer, Nelson B., additional, Friedl, Marion, additional, Friedman, Joseph I., additional, Fromer, Menachem, additional, Genovese, Giulio, additional, Georgieva, Lyudmila, additional, Gershon, Elliot S., additional, Giegling, Ina, additional, Giusti-Rodrguez, Paola, additional, Godard, Stephanie, additional, Goldstein, Jacqueline I., additional, Golimbet, Vera, additional, Gopal, Srihari, additional, Gratten, Jacob, additional, Grove, Jakob, additional, de Haan, Lieuwe, additional, Hammer, Christian, additional, Hamshere, Marian L., additional, Hansen, Mark, additional, Hansen, Thomas, additional, Haroutunian, Vahram, additional, Hartmann, Annette M., additional, Henskens, Frans A., additional, Herms, Stefan, additional, Hirschhorn, Joel N., additional, Hoffmann, Per, additional, Hofman, Andrea, additional, Hollegaard, Mads V., additional, Hougaard, David M., additional, Ikeda, Masashi, additional, Joa, Inge, additional, Julià, Antonio, additional, Kahn, René S., additional, Kalaydjieva, Luba, additional, Karachanak-Yankova, Sena, additional, Karjalainen, Juha, additional, Kavanagh, David, additional, Keller, Matthew C., additional, Kelly, Brian J., additional, Kennedy, James L., additional, Khrunin, Andrey, additional, Kim, Yunjung, additional, Klovins, Janis, additional, Knowles, James A., additional, Konte, Bettina, additional, Kucinskas, Vaidutis, additional, Kucinskiene, Zita Ausrele, additional, Kuzelova-Ptackova, Hana, additional, Kähler, Anna K., additional, Laurent, Claudine, additional, Keong, Jimmy Lee Chee, additional, Legge, Sophie E., additional, Lerer, Bernard, additional, Li, Miaoxin, additional, Li, Tao, additional, Liang, Kung-Yee, additional, Lieberman, Jeffrey, additional, Limborska, Svetlana, additional, Loughland, Carmel M., additional, Lubinski, Jan, additional, Lnnqvist, Jouko, additional, Macek, Milan, additional, Magnusson, Patrik K.E., additional, Maher, Brion S., additional, Maier, Wolfgang, additional, Mallet, Jacques, additional, Marsal, Sara, additional, Mattheisen, Manuel, additional, Mattingsdal, Morten, additional, McCarley, Robert W., additional, McDonald, Colm, additional, McIntosh, Andrew M., additional, Meier, Sandra, additional, Meijer, Carin J., additional, Melegh, Bela, additional, Melle, Ingrid, additional, Mesholam-Gately, Raquelle I., additional, Metspalu, Andres, additional, Michie, Patricia T., additional, Milani, Lili, additional, Milanova, Vihra, additional, Mokrab, Younes, additional, Morris, Derek W., additional, Mors, Ole, additional, Mortensen, Preben B., additional, Murphy, Kieran C., additional, Murray, Robin M., additional, Myin-Germeys, Inez, additional, Mller-Myhsok, Bertram, additional, Nelis, Mari, additional, Nenadic, Igor, additional, Nertney, Deborah A., additional, Nestadt, Gerald, additional, Nicodemus, Kristin K., additional, Nikitina-Zake, Liene, additional, Nisenbaum, Laura, additional, Nordin, Annelie, additional, O’Callaghan, Eadbhard, additional, O’Dushlaine, Colm, additional, O’Neill, F. Anthony, additional, Oh, Sang-Yun, additional, Olincy, Ann, additional, Olsen, Line, additional, Van Os, Jim, additional, Pantelis, Christos, additional, Papadimitriou, George N., additional, Papiol, Sergi, additional, Parkhomenko, Elena, additional, Pato, Michele T., additional, Paunio, Tiina, additional, Pejovic-Milovancevic, Milica, additional, Perkins, Diana O., additional, Pietilinen, Olli, additional, Pimm, Jonathan, additional, Pocklington, Andrew J., additional, Powell, John, additional, Price, Alkes, additional, Pulver, Ann E., additional, Purcell, Shaun M., additional, Quested, Digby, additional, Rasmussen, Henrik B., additional, Reichenberg, Abraham, additional, Reimers, Mark A., additional, Richards, Alexander L., additional, Roffman, Joshua L., additional, Roussos, Panos, additional, Ruderfer, Douglas M., additional, Salomaa, Veikko, additional, Sanders, Alan R., additional, Schall, Ulrich, additional, Schubert, Christian R., additional, Schulze, Thomas G., additional, Schwab, Sibylle G., additional, Scolnick, Edward M., additional, Scott, Rodney J., additional, Seidman, Larry J., additional, Shi, Jianxin, additional, Sigurdsson, Engilbert, additional, Silagadze, Teimuraz, additional, Silverman, Jeremy M., additional, Sim, Kang, additional, Slominsky, Petr, additional, Smoller, Jordan W., additional, So, Hon-Cheong, additional, Spencer, Chris C.A., additional, Stahl, Eli A., additional, Stefansson, Hreinn, additional, Steinberg, Stacy, additional, Stogmann, Elisabeth, additional, Straub, Richard E., additional, Strengman, Eric, additional, Strohmaier, Jana, additional, Stroup, T. Scott, additional, Subramaniam, Mythily, additional, Suvisaari, Jaana, additional, Svrakic, Dragan M., additional, Szatkiewicz, Jin P., additional, Sderman, Erik, additional, Thirumalai, Srinivas, additional, Toncheva, Draga, additional, Tooney, Paul A., additional, Tosato, Sarah, additional, Veijola, Juha, additional, Waddington, John, additional, Walsh, Dermot, additional, Wang, Dai, additional, Wang, Qiang, additional, Webb, Bradley T., additional, Weiser, Mark, additional, Wildenauer, Dieter B., additional, Williams, Nigel M., additional, Williams, Stephanie, additional, Witt, Stephanie H., additional, Wolen, Aaron R., additional, Wong, Emily H.M., additional, Wormley, Brandon K., additional, Wu, Jing Qin, additional, Xi, Hualin Simon, additional, Zai, Clement C., additional, Zheng, Xuebin, additional, Zimprich, Fritz, additional, Wray, Naomi R., additional, Stefansson, Kari, additional, Visscher, Peter M., additional, Adolfsson, Rolf, additional, Andreassen, Ole A., additional, Blackwood, Douglas H.R., additional, Bramon, Elvira, additional, Buxbaum, Joseph D., additional, Brglum, Anders D., additional, Cichon, Sven, additional, Darvasi, Ariel, additional, Domenici, Enrico, additional, Ehrenreich, Hannelore, additional, Esko, Tõnu, additional, Gejman, Pablo V., additional, Gill, Michael, additional, Gurling, Hugh, additional, Hultman, Christina M., additional, Iwata, Nakao, additional, Jablensky, Assen V., additional, Jönsson, Erik G., additional, Kendler, Kenneth S., additional, Kirov, George, additional, Knight, Jo, additional, Lencz, Todd, additional, Levinson, Douglas F., additional, Li, Qingqin S., additional, Liu, Jianjun, additional, Malhotra, Anil K., additional, McCarroll, Steven A., additional, McQuillin, Andrew, additional, Moran, Jennifer L., additional, Mowry, Bryan J., additional, Nthen, Markus M., additional, Ophoff, Roel A., additional, Owen, Michael J., additional, Palotie, Aarno, additional, Pato, Carlos N., additional, Petryshen, Tracey L., additional, Posthuma, Danielle, additional, Rietschel, Marcella, additional, Riley, Brien P., additional, Rujescu, Dan, additional, Sham, Pak C., additional, Sklar, Pamela, additional, St. Clair, David, additional, Weinberger, Daniel R., additional, Wendland, Jens R., additional, Werge, Thomas, additional, Daly, Mark J., additional, Sullivan, Patrick F., additional, O’Donovan, Michael C., additional, Chambert, Kimberly, additional, Moran, Jennifer L., additional, Akterin, Susanne, additional, Bergen, Sarah, additional, Magnusson, Patrik K.E., additional, Ruderfer, Douglas, additional, Scolnick, Edward, additional, Purcell, Shaun, additional, and McCarroll, Steve, additional

Published
2014
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227. Orthologous repeats and mammalian phylogenetic inference

Author

Bashir, Ali, Chun Ye, Price, Alkes L., and Bafna, Vineet

Subjects
Phylogeny -- Research, Mammals -- Research, Sequential analysis, Health
Abstract

A novel computational method for inferring phylogenetic relationships from partial sequence data using orthologous repeats is presented. Methods of reconstructing the phylogeny of 28 mammals is applied, using more than 1000 orthologous repeats obtained from sequence data available from the NISC Comparative Sequencing Program.

Published
2005

228. Whole-genome analysis of Alu repeat elements reveals complex evolutionary history

Author

Price, Alkes L., Eskin, Eleazar, and Pevzner, Pavel A.

Subjects
Genetic markers -- Research, Human genetics -- Research, Genetic research, Health
Abstract

Alu repeats are used to study the history of substitution patterns in the human genome and polymorphic Alu insertions are used as markers to determine genetic distances between human subpopulations. In genome-wide analysis, investigators have identified and statistically validated 213 Alu subfamilies, built an evolutionary tree of these subfamilies.

Published
2004

229. Estimating and interpreting F[subscript ST]: The impact of rare variants

Author

Bhatia, Gaurav, Patterson, Nick, Sankararaman, Sriram, Price, Alkes L., Whitaker College of Health Sciences and Technology, Harvard University--MIT Division of Health Sciences and Technology, and Bhatia, Gaurav

Abstract

In a pair of seminal papers, Sewall Wright and Gustave Malécot introduced F[subscript ST] as a measure of structure in natural populations. In the decades that followed, a number of papers provided differing definitions, estimation methods, and interpretations beyond Wright's. While this diversity in methods has enabled many studies in genetics, it has also introduced confusion regarding how to estimate F[subscript ST] from available data. Considering this confusion, wide variation in published estimates ofF[subscript ST] for pairs of HapMap populations is a cause for concern. These estimates changed—in some cases more than twofold—when comparing estimates from genotyping arrays to those from sequence data. Indeed, changes in F[subscript ST] from sequencing data might be expected due to population genetic factors affecting rare variants. While rare variants do influence the result, we show that this is largely through differences in estimation methods. Correcting for this yields estimates of F[subscript ST] that are much more concordant between sequence and genotype data. These differences relate to three specific issues: (1) estimating F[subscript ST] for a single SNP, (2) combining estimates of F[subscript ST] across multiple SNPs, and (3) selecting the set of SNPs used in the computation. Changes in each of these aspects of estimation may result in F[subscript ST] estimates that are highly divergent from one another. Here, we clarify these issues and propose solutions., National Institutes of Health (U.S.) (Grant T32 HG002295), National Institutes of Health (U.S.) (Grant R03 HG006170)

Published
2013

230. Using population admixture to help complete maps of the human genome

Author

Genovese, Giulio, Handsaker, Robert E, Li, Heng, Altemose, Nicolas, Lindgren, Amelia M, Chambert, Kimberly, Pasaniuc, Bogdan, Price, Alkes L, Reich, David, Morton, Cynthia C, Pollak, Martin R, Wilson, James G, and McCarroll, Steven A

Subjects
Genome, Evolution, Population, Human Genome, Chromosome Mapping, Computational Biology, Molecular, Genetic Variation, Biological Sciences, Medical and Health Sciences, Fluorescence, Euchromatin, Heterochromatin, Gene Duplication, Genetics, Humans, In Situ Hybridization, Human, Developmental Biology
Abstract

Tens of millions of base pairs of euchromatic human genome sequence, including many protein-coding genes, have no known location in the human genome. We describe an approach for localizing the human genome's missing pieces using the patterns of genome sequence variation created by population admixture. We mapped the locations of 70 scaffolds spanning 4 million base pairs of the human genome's unplaced euchromatic sequence, including more than a dozen protein-coding genes, and identified 8 new large interchromosomal segmental duplications. We find that most of these sequences are hidden in the genome's heterochromatin, particularly its pericentromeric regions. Many cryptic, pericentromeric genes are expressed at the RNA level and have been maintained intact for millions of years while their expression patterns diverged from those of paralogous genes elsewhere in the genome. We describe how knowledge of the locations of these sequences can inform disease association and genome biology studies.

Published
2013

231. Response to Sul & Eskin

Author

Price, Alkes L., Zaitlen, Noah A., Reich, David, and Patterson, Nick

Subjects
Models, Genetic, Humans, Article, Genome-Wide Association Study
Published
2013

232. Genome-wide scan of 29,141 African Americans finds no evidence of selection since admixture

Author

Bhatia, Gaurav, Tandon, Arti, Aldrich, Melinda C., Ambrosone, Christine B., Amos, Christopher, Bandera, Elisa V., Berndt, Sonja I., Bernstein, Leslie, Blot, William J., Bock, Cathryn H., Caporaso, Neil, Casey, Graham, Deming, Sandra L., Diver, W. Ryan, Gapstur, Susan M., Gillanders, Elizabeth M., Harris, Curtis C., Henderson, Brian E., Ingles, Sue A., Isaacs, William, John, Esther M., Kittles, Rick A., Larkin, Emma, McNeill, Lorna H., Millikan, Robert C., Murphy, Adam, Neslund-Dudas, Christine, Nyante, Sarah, Press, Michael F., Rodriguez-Gil, Jorge L., Rybicki, Benjamin A., Schwartz, Ann G., Signorello, Lisa B., Spitz, Margaret, Strom, Sara S., Tucker, Margaret A., Wiencke, John K., Witte, John S., Wu, Xifeng, Yamamura, Yuko, Zanetti, Krista A., Zheng, Wei, Ziegler, Regina G., Chanock, Stephen J., Haiman, Christopher A., Reich, David, and Price, Alkes L.

Subjects
FOS: Biological sciences, Populations and Evolution (q-bio.PE), Quantitative Biology - Populations and Evolution
Abstract

We scanned through the genomes of 29,141 African Americans, searching for loci where the average proportion of African ancestry deviates significantly from the genome-wide average. We failed to find any genome-wide significant deviations, and conclude that any selection in African Americans since admixture is sufficiently weak that it falls below the threshold of our power to detect it using a large sample size. These results stand in contrast to the findings of a recent study of selection in African Americans. That study, which had 15 times fewer samples, reported six loci with significant deviations. We show that the discrepancy is likely due to insufficient correction for multiple hypothesis testing in the previous study. The same study reported 14 loci that showed greater population differentiation between African Americans and Nigerian Yoruba than would be expected in the absence of natural selection. Four such loci were previously shown to be genome-wide significant and likely to be affected by selection, but we show that most of the 10 additional loci are likely to be false positives. Additionally, the most parsimonious explanation for the loci that have significant evidence of unusual differentiation in frequency between Nigerians and Africans Americans is selection in Africa prior to their forced migration to the Americas.

Published
2013
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233. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations.

Author

Loh, Po-Ru, Genovese, Giulio, Handsaker, Robert E., Finucane, Hilary K., Reshef, Yakir A., Palamara, Pier Francesco, Birmann, Brenda M., Talkowski, Michael E., Bakhoum, Samuel F., McCarroll, Steven A., and Price, Alkes L.

Abstract

The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6-9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3-TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5-50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health. Analysis of genotyping data for more than 150,000 individuals from the UK Biobank using long-range phase information sheds light on mechanisms of clonal haematopoiesis. [ABSTRACT FROM AUTHOR]

Published
2018
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236. Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Author

Sobrin, Lucia, Yong He Chong, Qiao Fan, Gan, Alfred, Stanwyck, Lynn K., Kaidonis, Georgia, Craig, Jamie E., Jihye Kim, Wen-Ling Liao, Yu-Chuen Huang, Wen-Jane Lee, Yi-Jen Hung, Xiuqing Guo, Yang Hai, Ipp, Eli, Pollack, Samuela, Hancock, Heather, Price, Alkes, Penman, Alan, and Mitchell, Paul

Subjects
DIABETIC retinopathy, DYSLIPIDEMIA, BLOOD lipids, GENETIC pleiotropy, SINGLE nucleotide polymorphisms, RETINAL diseases, DISEASE risk factors, GENETIC polymorphisms, LIPIDS, META-analysis, RELATIVE medical risk, SEQUENCE analysis
Abstract

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist. [ABSTRACT FROM AUTHOR]

Published
2017
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237. Population‐based identity‐by‐descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Author

Harold, Denise, Connolly, Siobhan, Riley, Brien P., Kendler, Kenneth S., McCarthy, Shane E., McCombie, William R., Richards, Alex, Owen, Michael J., O'Donovan, Michael C., Walters, James, Donnelly, Peter, Bates, Lesley, Barroso, Ines, Blackwell, Jenefer M., Bramon, Elvira, Brown, Matthew A., Casas, Juan P., Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S., Mathew, Christopher G., Palmer, Colin N. A., Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J., Trembath, Richard C., Viswanathan, Ananth C., Wood, Nicholas W., Spencer, Chris C. A., Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Hopkins, Lucinda, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E., Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J., Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T., Liddle, Jennifer, Potter, Simon C., Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T. R., Farh, Kai‐How, Holmans, Peter A., Lee, Phil, Bulik‐Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberley D., Chan, Raymond C. K., Chan, Ronald Y. L., Chen, Eric Y. H., Cheng, Wei, Cheung, Eric F. C., Chong, Siow Ann, Cloninger, C. Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott‐Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti‐Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kalaydjieva, Luba, Karachanak‐Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova‐Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Lee, Jimmy, Lee, S. Hong, Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung‐Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam‐Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin‐Germeys, Inez, Müller‐Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina‐Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F. Anthony, Oh, Sang‐Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic‐Milovancevic, Milica, Perkins, Diana O., Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon‐Cheong, Spencer, Chris C. A., Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Strohmaier, Jana, Stroup, T. Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wong, Emily H. M., Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H. R., Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jönsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Riley, Brien P., Rujescu, Dan, Sham, Pak C., Sklar, Pamela, Clair, David St, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., Sullivan, Patrick F., O'Donovan, Michael C., Donohoe, Gary, Gill, Michael, Corvin, Aiden, and Morris, Derek W.

Abstract

Genome‐wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re‐analyze an Irish schizophrenia GWAS dataset (n= 3,473) by performing identity‐by‐descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNTbut did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow‐up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

Published
2019
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238. Distinguishing genetic correlation from causation across 52 diseases and complex traits

Author

O’Connor, Luke J. and Price, Alkes L.

Abstract

Mendelian randomization, a method to infer causal relationships, is confounded by genetic correlations reflecting shared etiology. We developed a model in which a latent causal variable mediates the genetic correlation; trait 1 is partially genetically causal for trait 2 if it is strongly genetically correlated with the latent causal variable, quantified using the genetic causality proportion. We fit this model using mixed fourth moments E(a12a1a2)and Ea22a1a2of marginal effect sizes for each trait; if trait 1 is causal for trait 2, then SNPs affecting trait 1 (large a12) will have correlated effects on trait 2 (large a1a2), but not vice versa. In simulations, our method avoided false positives due to genetic correlations, unlike Mendelian randomization. Across 52 traits (average n?=?331,000), we identified 30 causal relationships with high genetic causality proportion estimates. Novel findings included a causal effect of low-density lipoprotein on bone mineral density, consistent with clinical trials of statins in osteoporosis.

Published
2018
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239. Reconstructing Native American population history

Author

Reich, David, Patterson, Nick, Campbell, Desmond, Tandon, Arti, Mazieres, Stéphane, Ray, Nicolas, Parra, Maria V, Rojas, Winston, Duque, Constanza, Mesa, Natalia, García, Luis F, Triana, Omar, Blair, Silvia, Maestre, Amanda, Dib, Juan C, Bravi, Claudio M, Bailliet, Graciela, Corach, Daniel, Hünemeier, Tábita, Bortolini, Maria Cátira, Salzano, Francisco M, Petzl-Erler, María Luiza, Acuña-Alonzo, Victor, Aguilar-Salinas, Carlos, Canizales-Quinteros, Samuel, Tusié-Luna, Teresa, Riba, Laura, Rodríguez-Cruz, Maricela, Lopez-Alarcón, Mardia, Coral-Vazquez, Ramón, Canto-Cetina, Thelma, Silva-Zolezzi, Irma, Fernandez-Lopez, Juan Carlos, Contreras, Alejandra V, Jimenez-Sanchez, Gerardo, Gómez-Vázquez, Maria José, Molina, Julio, Carracedo, Angel, Salas, Antonio, Gallo, Carla, Poletti, Giovanni, Witonsky, David B, Alkorta-Aranburu, Gorka, Sukernik, Rem I, Osipova, Ludmila, Fedorova, Sardana A, Vasquez, René, Villena, Mercedes, Moreau, Claudia, Barrantes, Ramiro, Pauls, David, Excoffier, Laurent, Bedoya, Gabriel, Rothhammer, Francisco, Dugoujon, Jean-Michel, Larrouy, Georges, Klitz, William, Labuda, Damian, Kidd, Judith, Kidd, Kenneth, Di Rienzo, Anna, Freimer, Nelson B, Price, Alkes L, and Ruiz-Linares, Andrés

Subjects
Gene Flow, History, Asia, General Science & Technology, Population, Single Nucleotide, Emigration and Immigration, Ancient, Siberia, Genetic, Indians, Models, Genetics, Humans, Cluster Analysis, Polymorphism, Americas, Phylogeny, North American, American Indian or Alaska Native
Abstract

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.

Published
2012

240. Exome sequencing and the genetic basis of complex traits

Author

Do, Ron, Garimella, Kiran, Neale, Benjamin M, Kiezun, Adam, Purcell, Shaun M, Stitziel, Nathan O, Sklar, Pamela, Lichtenstein, Paul, Price, Alkes L, Sunyaev, Shamil R, Magnusson, Patrik, Lehner, Thomas, Moran, Jennifer L, Shugart, Yin Yao, Hultman, Christina M, de Bakker, Paul I W, McLaren, Paul J, Gupta, Namrata, and Sullivan, Patrick F

Abstract

Exome sequencing is emerging as a popular approach to study the effect of rare coding variants on complex phenotypes. The promise of exome sequencing is grounded in theoretical population genetics and in empirical successes of candidate gene sequencing studies. Many projects aimed at common diseases are underway, and their results are eagerly anticipated. In this Perspective, using exome sequencing data from 438 individuals, we discuss several aspects of exome sequencing studies that we view as particularly important. We review processing and quality control of raw sequence data, evaluate the statistical properties of exome sequencing studies, discuss rare variant burden tests to detect association to phenotypes, and demonstrate the importance of accounting for population stratification in the analysis of rare variants. We conclude that enthusiasm for exome sequencing studies of complex traits should be combined with the caution that thousands of samples may be required to reach sufficient statistical power.

Published
2012
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243. Integrative approaches for large-scale transcriptome-wide association studies

Author

Gusev, Alexander, primary, Ko, Arthur, additional, Shi, Huwenbo, additional, Bhatia, Gaurav, additional, Chung, Wonil, additional, Penninx, Brenda WJ, additional, Jansen, Rick, additional, de Geus, Eco JC, additional, Boomsma, Dorret I, additional, Wright, Fred A, additional, Sullivan, Patrick F, additional, Nikkola, Elina, additional, Alvarez, Marcus, additional, Civelek, Mete, additional, Lusis, Aldons J, additional, Lehtimaki, Terho, additional, Raitoharju, Emma, additional, Kahonen, Mika, additional, Seppala, Ilkka, additional, Raitakari, Olli, additional, Kuusisto, Johanna, additional, Laakso, Markku, additional, Price, Alkes L, additional, Pajukanta, Paivi, additional, and Pasaniuc, Bogdan, additional

Published
2015
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245. Mixed Model with Correction for Case-Control Ascertainment Increases Association Power

Author

Hayeck, Tristan J., primary, Zaitlen, Noah A., additional, Loh, Po-Ru, additional, Vilhjalmsson, Bjarni, additional, Pollack, Samuela, additional, Gusev, Alexander, additional, Yang, Jian, additional, Chen, Guo-Bo, additional, Goddard, Michael E., additional, Visscher, Peter M., additional, Patterson, Nick, additional, and Price, Alkes L., additional

Published
2015
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248. Contrasting regional architectures of schizophrenia and other complex diseases using fast variance components analysis

Author

Loh, Po-Ru, primary, Bhatia, Gaurav, additional, Gusev, Alexander, additional, Finucane, Hilary K, additional, Bulik-Sullivan, Brendan K, additional, Pollack, Samuela J, additional, Psychiatric Genomics Consortium, Schizophrenia Working Group, additional, de Candia, Teresa R, additional, Lee, Sang Hong, additional, Wray, Naomi R, additional, Kendler, Kenneth S, additional, O'Donovan, Michael C, additional, Neale, Benjamin M, additional, Patterson, Nick, additional, and Price, Alkes L, additional

Published
2015
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249. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Author

Vilhjalmsson, Bjarni, primary, Yang, Jian, additional, Finucane, Hilary Kiyo, additional, Gusev, Alexander, additional, Lindstrom, Sara, additional, Ripke, Stephan, additional, Genovese, Giulio, additional, Loh, Po-Ru, additional, Bhatia, Gaurav, additional, Do, Ron, additional, Hayeck, Tristian, additional, Won, Hong-Hee, additional, Genomics Consortium, Schizophrenia Working Group of the, additional, Variants in Breast Cancer (DRIVE) study, the Discovery, Biology, and Risk of, additional, Kathiresan, Sekar, additional, Pato, Michele, additional, Pato, Carlos, additional, Tamimi, Rulla, additional, Stahl, Eli, additional, Zaitlen, Noah, additional, Pasaniuc, Bogdan, additional, Schierup, Mikkel, additional, De Jager, Phillip, additional, Patsopoulos, Nikolaos, additional, McCarroll, Steven A, additional, Daly, Mark, additional, Purcell, Shaun, additional, Chasman, Daniel, additional, Neale, Benjamin, additional, Goddard, Mike, additional, Visscher, Peter M, additional, Kraft, Peter, additional, Patterson, Nick J, additional, and Price, Alkes L, additional

Published
2015
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250. Efficient Bayesian mixed-model analysis increases association power in large cohorts

Author

Loh, Po-Ru, primary, Tucker, George, additional, Bulik-Sullivan, Brendan K, additional, Vilhjálmsson, Bjarni J, additional, Finucane, Hilary K, additional, Salem, Rany M, additional, Chasman, Daniel I, additional, Ridker, Paul M, additional, Neale, Benjamin M, additional, Berger, Bonnie, additional, Patterson, Nick, additional, and Price, Alkes L, additional

Published
2015
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