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201. Reconstructing DNA copy number by joint segmentation of multiple sequences

Author

Zhang, Zhongyang, Zhang, Zhongyang, Lange, Kenneth, Sabatti, Chiara, Zhang, Zhongyang, Zhang, Zhongyang, Lange, Kenneth, and Sabatti, Chiara

Abstract

Background Variations in DNA copy number carry information on the modalities of genome evolution and mis-regulation of DNA replication in cancer cells. Their study can help localize tumor suppressor genes, distinguish different populations of cancerous cells, and identify genomic variations responsible for disease phenotypes. A number of different high throughput technologies can be used to identify copy number variable sites, and the literature documents multiple effective algorithms. We focus here on the specific problem of detecting regions where variation in copy number is relatively common in the sample at hand. This problem encompasses the cases of copy number polymorphisms, related samples, technical replicates, and cancerous sub-populations from the same individual. Results We present a segmentation method named generalized fused lasso (GFL) to reconstruct copy number variant regions. GFL is based on penalized estimation and is capable of processing multiple signals jointly. Our approach is computationally very attractive and leads to sensitivity and specificity levels comparable to those of state-of-the-art specialized methodologies. We illustrate its applicability with simulated and real data sets. Conclusions The flexibility of our framework makes it applicable to data obtained with a wide range of technology. Its versatility and speed make GFL particularly useful in the initial screening stages of large data sets.

Published
2012

202. Biological, clinical and population relevance of 95 loci for blood lipids

Author

Teslovich, Tanya M., Musunuru, Kiran, Smith, Albert V., Edmondson, Andrew C., Stylianou, Ioannis M., Koseki, Masahiro, Pirruccello, James P., Ripatti, Samuli, Chasman, Daniel I., Willer, Cristen J., Johansen, Christopher T., Fouchier, Sigrid W., Isaacs, Aaron, Peloso, Gina M., Barbalic, Maja, Ricketts, Sally L., Bis, Joshua C., Aulchenko, Yurii S., Thorleifsson, Gudmar, Feitosa, Mary F., Chambers, John, Orho-Melander, Marju, Melander, Olle, Johnson, Toby, Li, Xiaohui, Guo, Xiuqing, Li, Mingyao, Cho, Yoon Shin, Go, Min Jin, Kim, Young Jin, Lee, Jong-Young, Park, Taesung, Kim, Kyunga, Sim, Xueling, Ong, Rick Twee-Hee, Croteau-Chonka, Damien C., Lange, Leslie A., Smith, Joshua D., Song, Kijoung, Zhao, Jing Hua, Yuan, Xin, Luan, Jian'an, Lamina, Claudia, Ziegler, Andreas, Zhang, Weihua, Zee, Robert Y. L., Wright, Alan F., Witteman, Jacqueline C. M., Wilson, James F., Willemsen, Gonneke, Wichmann, H. -Erich, Whitfield, John B., Waterworth, Dawn M., Wareham, Nicholas J., Waeber, Gerard, Vollenweider, Peter, Voight, Benjamin F., Vitart, Veronique, Uitterlinden, Andre G., Uda, Manuela, Tuomilehto, Jaakko, Thompson, John R., Tanaka, Toshiko, Surakka, Ida, Stringham, Heather M., Spector, Tim D., Soranzo, Nicole, Smit, Johannes H., Sinisalo, Juha, Silander, Kaisa, Sijbrands, Eric J. G., Scuteri, Angelo, Scott, James, Schlessinger, David, Sanna, Serena, Salomaa, Veikko, Saharinen, Juha, Sabatti, Chiara, Ruokonen, Aimo, Rudan, Igor, Rose, Lynda M., Roberts, Robert, Rieder, Mark, Psaty, Bruce M., Pramstaller, Peter P., Pichler, Irene, Perola, Markus, Penninx, Brenda W. J. H., Pedersen, Nancy L., Pattaro, Cristian, Parker, Alex N., Pare, Guillaume, Oostra, Ben A., O'Donnell, Christopher J., Nieminen, Markku S., Nickerson, Deborah A., Montgomery, Grant W., Meitinger, Thomas, McPherson, Ruth, McCarthy, Mark I., McArdle, Wendy, Masson, David, Martin, Nicholas G., Marroni, Fabio, Mangino, Massimo, Magnusson, Patrik K. E., Lucas, Gavin, Luben, Robert, Loos, Ruth J. F., Lokki, Marja-Liisa, Lettre, Guillaume, Langenberg, Claudia, Launer, Lenore J., Lakatta, Edward G., Laaksonen, Reijo, Kyvik, Kirsten O., Kronenberg, Florian, Koenig, Inke R., Khaw, Kay-Tee, Kaprio, Jaakko, Kaplan, Lee M., Johansson, Åsa, Jarvelin, Marjo-Riitta, Janssens, A. Cecile J. W., Ingelsson, Erik, Igi, Wilmar, Hovingh, G. Kees, Hottenga, Jouke-Jan, Hofman, Albert, Hicks, Andrew A., Hengstenberg, Christian, Heid, Iris M., Hayward, Caroline, Havulinna, Aki S., Hastie, Nicholas D., Harris, Tamara B., Haritunians, Talin, Hall, Alistair S., Gyllensten, Ulf, Guiducci, Candace, Groop, Leif C., Gonzalez, Elena, Gieger, Christian, Freimer, Nelson B., Ferrucci, Luigi, Erdmann, Jeanette, Elliott, Paul, Ejebe, Kenechi G., Doering, Angela, Dominiczak, Anna F., Demissie, Serkalem, Deloukas, Panagiotis, de Geus, Eco J. C., de Faire, Ulf, Crawford, Gabriel, Collins, Francis S., Chen, Yii-der I., Caulfield, Mark J., Campbell, Harry, Burtt, Noel P., Bonnycastle, Lori L., Boomsma, Dorret I., Boekholdt, S. Matthijs, Bergman, Richard N., Barroso, Ines, Bandinelli, Stefania, Ballantyne, Christie M., Assimes, Themistocles L., Quertermous, Thomas, Altshuler, David, Seielstad, Mark, Wong, Tien Y., Tai, E-Shyong, Feranil, Alan B., Kuzawa, Christopher W., Adair, Linda S., Taylor, Herman A., Jr., Borecki, Ingrid B., Gabriel, Stacey B., Wilson, James G., Holm, Hilma, Thorsteinsdottir, Unnur, Gudnason, Vilmundur, Krauss, Ronald M., Mohlke, Karen L., Ordovas, Jose M., Munroe, Patricia B., Kooner, Jaspal S., Tall, Alan R., Hegele, Robert A., Kastelein, John J. P., Schadt, Eric E., Rotter, Jerome I., Boerwinkle, Eric, Strachan, David P., Mooser, Vincent, Stefansson, Kari, Reilly, Muredach P., Samani, Nilesh J., Schunkert, Heribert, Cupples, L. Adrienne, Sandhu, Manjinder S., Ridker, Paul M., Rader, Daniel J., van Duijn, Cornelia M., Peltonen, Leena, Abecasis, Goncalo R., Boehnke, Michael, Kathiresan, Sekar, Teslovich, Tanya M., Musunuru, Kiran, Smith, Albert V., Edmondson, Andrew C., Stylianou, Ioannis M., Koseki, Masahiro, Pirruccello, James P., Ripatti, Samuli, Chasman, Daniel I., Willer, Cristen J., Johansen, Christopher T., Fouchier, Sigrid W., Isaacs, Aaron, Peloso, Gina M., Barbalic, Maja, Ricketts, Sally L., Bis, Joshua C., Aulchenko, Yurii S., Thorleifsson, Gudmar, Feitosa, Mary F., Chambers, John, Orho-Melander, Marju, Melander, Olle, Johnson, Toby, Li, Xiaohui, Guo, Xiuqing, Li, Mingyao, Cho, Yoon Shin, Go, Min Jin, Kim, Young Jin, Lee, Jong-Young, Park, Taesung, Kim, Kyunga, Sim, Xueling, Ong, Rick Twee-Hee, Croteau-Chonka, Damien C., Lange, Leslie A., Smith, Joshua D., Song, Kijoung, Zhao, Jing Hua, Yuan, Xin, Luan, Jian'an, Lamina, Claudia, Ziegler, Andreas, Zhang, Weihua, Zee, Robert Y. L., Wright, Alan F., Witteman, Jacqueline C. M., Wilson, James F., Willemsen, Gonneke, Wichmann, H. -Erich, Whitfield, John B., Waterworth, Dawn M., Wareham, Nicholas J., Waeber, Gerard, Vollenweider, Peter, Voight, Benjamin F., Vitart, Veronique, Uitterlinden, Andre G., Uda, Manuela, Tuomilehto, Jaakko, Thompson, John R., Tanaka, Toshiko, Surakka, Ida, Stringham, Heather M., Spector, Tim D., Soranzo, Nicole, Smit, Johannes H., Sinisalo, Juha, Silander, Kaisa, Sijbrands, Eric J. G., Scuteri, Angelo, Scott, James, Schlessinger, David, Sanna, Serena, Salomaa, Veikko, Saharinen, Juha, Sabatti, Chiara, Ruokonen, Aimo, Rudan, Igor, Rose, Lynda M., Roberts, Robert, Rieder, Mark, Psaty, Bruce M., Pramstaller, Peter P., Pichler, Irene, Perola, Markus, Penninx, Brenda W. J. H., Pedersen, Nancy L., Pattaro, Cristian, Parker, Alex N., Pare, Guillaume, Oostra, Ben A., O'Donnell, Christopher J., Nieminen, Markku S., Nickerson, Deborah A., Montgomery, Grant W., Meitinger, Thomas, McPherson, Ruth, McCarthy, Mark I., McArdle, Wendy, Masson, David, Martin, Nicholas G., Marroni, Fabio, Mangino, Massimo, Magnusson, Patrik K. E., Lucas, Gavin, Luben, Robert, Loos, Ruth J. F., Lokki, Marja-Liisa, Lettre, Guillaume, Langenberg, Claudia, Launer, Lenore J., Lakatta, Edward G., Laaksonen, Reijo, Kyvik, Kirsten O., Kronenberg, Florian, Koenig, Inke R., Khaw, Kay-Tee, Kaprio, Jaakko, Kaplan, Lee M., Johansson, Åsa, Jarvelin, Marjo-Riitta, Janssens, A. Cecile J. W., Ingelsson, Erik, Igi, Wilmar, Hovingh, G. Kees, Hottenga, Jouke-Jan, Hofman, Albert, Hicks, Andrew A., Hengstenberg, Christian, Heid, Iris M., Hayward, Caroline, Havulinna, Aki S., Hastie, Nicholas D., Harris, Tamara B., Haritunians, Talin, Hall, Alistair S., Gyllensten, Ulf, Guiducci, Candace, Groop, Leif C., Gonzalez, Elena, Gieger, Christian, Freimer, Nelson B., Ferrucci, Luigi, Erdmann, Jeanette, Elliott, Paul, Ejebe, Kenechi G., Doering, Angela, Dominiczak, Anna F., Demissie, Serkalem, Deloukas, Panagiotis, de Geus, Eco J. C., de Faire, Ulf, Crawford, Gabriel, Collins, Francis S., Chen, Yii-der I., Caulfield, Mark J., Campbell, Harry, Burtt, Noel P., Bonnycastle, Lori L., Boomsma, Dorret I., Boekholdt, S. Matthijs, Bergman, Richard N., Barroso, Ines, Bandinelli, Stefania, Ballantyne, Christie M., Assimes, Themistocles L., Quertermous, Thomas, Altshuler, David, Seielstad, Mark, Wong, Tien Y., Tai, E-Shyong, Feranil, Alan B., Kuzawa, Christopher W., Adair, Linda S., Taylor, Herman A., Jr., Borecki, Ingrid B., Gabriel, Stacey B., Wilson, James G., Holm, Hilma, Thorsteinsdottir, Unnur, Gudnason, Vilmundur, Krauss, Ronald M., Mohlke, Karen L., Ordovas, Jose M., Munroe, Patricia B., Kooner, Jaspal S., Tall, Alan R., Hegele, Robert A., Kastelein, John J. P., Schadt, Eric E., Rotter, Jerome I., Boerwinkle, Eric, Strachan, David P., Mooser, Vincent, Stefansson, Kari, Reilly, Muredach P., Samani, Nilesh J., Schunkert, Heribert, Cupples, L. Adrienne, Sandhu, Manjinder S., Ridker, Paul M., Rader, Daniel J., van Duijn, Cornelia M., Peltonen, Leena, Abecasis, Goncalo R., Boehnke, Michael, and Kathiresan, Sekar

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Published
2010
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203. Biological, clinical and population relevance of 95 loci for blood lipids.

Author

Teslovich, Tanya M, Teslovich, Tanya M, Musunuru, Kiran, Smith, Albert V, Edmondson, Andrew C, Stylianou, Ioannis M, Koseki, Masahiro, Pirruccello, James P, Ripatti, Samuli, Chasman, Daniel I, Willer, Cristen J, Johansen, Christopher T, Fouchier, Sigrid W, Isaacs, Aaron, Peloso, Gina M, Barbalic, Maja, Ricketts, Sally L, Bis, Joshua C, Aulchenko, Yurii S, Thorleifsson, Gudmar, Feitosa, Mary F, Chambers, John, Orho-Melander, Marju, Melander, Olle, Johnson, Toby, Li, Xiaohui, Guo, Xiuqing, Li, Mingyao, Shin Cho, Yoon, Jin Go, Min, Jin Kim, Young, Lee, Jong-Young, Park, Taesung, Kim, Kyunga, Sim, Xueling, Twee-Hee Ong, Rick, Croteau-Chonka, Damien C, Lange, Leslie A, Smith, Joshua D, Song, Kijoung, Hua Zhao, Jing, Yuan, Xin, Luan, Jian'an, Lamina, Claudia, Ziegler, Andreas, Zhang, Weihua, Zee, Robert YL, Wright, Alan F, Witteman, Jacqueline CM, Wilson, James F, Willemsen, Gonneke, Wichmann, H-Erich, Whitfield, John B, Waterworth, Dawn M, Wareham, Nicholas J, Waeber, Gérard, Vollenweider, Peter, Voight, Benjamin F, Vitart, Veronique, Uitterlinden, Andre G, Uda, Manuela, Tuomilehto, Jaakko, Thompson, John R, Tanaka, Toshiko, Surakka, Ida, Stringham, Heather M, Spector, Tim D, Soranzo, Nicole, Smit, Johannes H, Sinisalo, Juha, Silander, Kaisa, Sijbrands, Eric JG, Scuteri, Angelo, Scott, James, Schlessinger, David, Sanna, Serena, Salomaa, Veikko, Saharinen, Juha, Sabatti, Chiara, Ruokonen, Aimo, Rudan, Igor, Rose, Lynda M, Roberts, Robert, Rieder, Mark, Psaty, Bruce M, Pramstaller, Peter P, Pichler, Irene, Perola, Markus, Penninx, Brenda WJH, Pedersen, Nancy L, Pattaro, Cristian, Parker, Alex N, Pare, Guillaume, Oostra, Ben A, O'Donnell, Christopher J, Nieminen, Markku S, Nickerson, Deborah A, Montgomery, Grant W, Meitinger, Thomas, McPherson, Ruth, McCarthy, Mark I, Teslovich, Tanya M, Teslovich, Tanya M, Musunuru, Kiran, Smith, Albert V, Edmondson, Andrew C, Stylianou, Ioannis M, Koseki, Masahiro, Pirruccello, James P, Ripatti, Samuli, Chasman, Daniel I, Willer, Cristen J, Johansen, Christopher T, Fouchier, Sigrid W, Isaacs, Aaron, Peloso, Gina M, Barbalic, Maja, Ricketts, Sally L, Bis, Joshua C, Aulchenko, Yurii S, Thorleifsson, Gudmar, Feitosa, Mary F, Chambers, John, Orho-Melander, Marju, Melander, Olle, Johnson, Toby, Li, Xiaohui, Guo, Xiuqing, Li, Mingyao, Shin Cho, Yoon, Jin Go, Min, Jin Kim, Young, Lee, Jong-Young, Park, Taesung, Kim, Kyunga, Sim, Xueling, Twee-Hee Ong, Rick, Croteau-Chonka, Damien C, Lange, Leslie A, Smith, Joshua D, Song, Kijoung, Hua Zhao, Jing, Yuan, Xin, Luan, Jian'an, Lamina, Claudia, Ziegler, Andreas, Zhang, Weihua, Zee, Robert YL, Wright, Alan F, Witteman, Jacqueline CM, Wilson, James F, Willemsen, Gonneke, Wichmann, H-Erich, Whitfield, John B, Waterworth, Dawn M, Wareham, Nicholas J, Waeber, Gérard, Vollenweider, Peter, Voight, Benjamin F, Vitart, Veronique, Uitterlinden, Andre G, Uda, Manuela, Tuomilehto, Jaakko, Thompson, John R, Tanaka, Toshiko, Surakka, Ida, Stringham, Heather M, Spector, Tim D, Soranzo, Nicole, Smit, Johannes H, Sinisalo, Juha, Silander, Kaisa, Sijbrands, Eric JG, Scuteri, Angelo, Scott, James, Schlessinger, David, Sanna, Serena, Salomaa, Veikko, Saharinen, Juha, Sabatti, Chiara, Ruokonen, Aimo, Rudan, Igor, Rose, Lynda M, Roberts, Robert, Rieder, Mark, Psaty, Bruce M, Pramstaller, Peter P, Pichler, Irene, Perola, Markus, Penninx, Brenda WJH, Pedersen, Nancy L, Pattaro, Cristian, Parker, Alex N, Pare, Guillaume, Oostra, Ben A, O'Donnell, Christopher J, Nieminen, Markku S, Nickerson, Deborah A, Montgomery, Grant W, Meitinger, Thomas, McPherson, Ruth, and McCarthy, Mark I

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Published
2010

207. Abstract 2283: Nano-scale proteomic profiles of response to targeted therapy in patients with RCC.

Author

Fan, Alice C., primary, Leppert, John, additional, Liliental, Joanna E., additional, Xu, Liwen, additional, Metzner, Thomas J., additional, Shroff, Emelyn, additional, Yaghi, Alia, additional, Yost, Christine, additional, Brooks, James D., additional, Harshman, Lauren C., additional, Sabatti, Chiara, additional, Srinivas, Sandhya, additional, and Felsher, Dean W., additional

Published
2013
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208. 603 NANO-SCALE PROTEOMIC PROFILING TO DEFINE DIAGNOSTIC SIGNATURES AND BIOMARKERS OF THERAPEUTIC ACTIVITY IN RCC

Author

Leppert, John, primary, Fan, Alice, additional, Liliental, Joanna, additional, Xu, Liwen, additional, Thong, Alan, additional, Yost, Christine, additional, Yaghi, Alia, additional, Metzner, Thomas, additional, Brooks, James, additional, Harshman, Lauren, additional, Sabatti, Chiara, additional, Srinivas, Sandy, additional, and Felsher, Dean, additional

Published
2013
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209. Nanoscale proteomic profiling to define diagnostic signatures and biomarkers of therapeutic activity in patients with RCC.

Author

Fan, Alice C., primary, Leppert, John, additional, Liliental, Joanna E., additional, Xu, Liwen, additional, Thong, Alan E., additional, Yost, Christine, additional, Yaghi, Alia, additional, Brooks, James D., additional, Harshman, Lauren Christine, additional, Sabatti, Chiara, additional, Srinivas, Sandy, additional, and Felsher, Dean W., additional

Published
2013
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210. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics

Author

Barbeira, Alvaro N., Dickinson, Scott P., Bonazzola, Rodrigo, Zheng, Jiamao, Wheeler, Heather E., Torres, Jason M., Torstenson, Eric S., Shah, Kaanan P., Garcia, Tzintzuni, Edwards, Todd L., Stahl, Eli A., Huckins, Laura M., Aguet, François, Ardlie, Kristin G., Cummings, Beryl B., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Karczewski, Konrad J., Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Nedzel, Jared L., Nguyen, Duyen T., Noble, Michael S., Segrè, Ayellet V., Trowbridge, Casandra A., Tukiainen, Taru, Abell, Nathan S., Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K., Brown, Andrew, Brown, Christopher D., Castel, Stephane E., Chen, Lin S., Chiang, Colby, Conrad, Donald F., Damani, Farhan N., Davis, Joe R., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frésard, Laure, Gamazon, Eric R., Garrido-Martín, Diego, Gewirtz, Ariel D. H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Jo, Brian, Kang, Eun Yong, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I., McDowell, Ian C., Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B., Muñoz-Aguirre, Manuel, Ndungu, Anne W., Nobel, Andrew B., Oliva, Meritxell, Ongen, Halit, Palowitch, John J., Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J., Peterson, Christine B., Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J., Shabalin, Andrey A., Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E., Strober, Benjamin J., Sul, Jae Hoon, Tsang, Emily K., Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A., Xi, Hualin S., Yeger-Lotem, Esti, Zappala, Zachary, Zaugg, Judith B., Zhou, Yi-Hui, Akey, Joshua M., Bates, Daniel, Chan, Joanne, Claussnitzer, Melina, Demanelis, Kathryn, Diegel, Morgan, Doherty, Jennifer A., Feinberg, Andrew P., Fernando, Marian S., Halow, Jessica, Hansen, Kasper D., Haugen, Eric, Hickey, Peter F., Hou, Lei, Jasmine, Farzana, Jian, Ruiqi, Jiang, Lihua, Johnson, Audra, Kaul, Rajinder, Kellis, Manolis, Kibriya, Muhammad G., Lee, Kristen, Li, Jin Billy, Li, Qin, Lin, Jessica, Lin, Shin, Linder, Sandra, Linke, Caroline, Liu, Yaping, Maurano, Matthew T., Molinie, Benoit, Nelson, Jemma, Neri, Fidencio J., Park, Yongjin, Pierce, Brandon L., Rinaldi, Nicola J., Rizzardi, Lindsay F., Sandstrom, Richard, Skol, Andrew, Smith, Kevin S., Snyder, Michael P., Stamatoyannopoulos, John, Tang, Hua, Wang, Li, Wang, Meng, Van Wittenberghe, Nicholas, Wu, Fan, Zhang, Rui, Nierras, Concepcion R., Branton, Philip A., Carithers, Latarsha J., Guan, Ping, Moore, Helen M., Rao, Abhi, Vaught, Jimmie B., Gould, Sarah E., Lockart, Nicole C., Martin, Casey, Struewing, Jeffery P., Volpi, Simona, Addington, Anjene M., Koester, Susan E., Little, A. Roger, Brigham, Lori E., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F., Lonsdale, John T., McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Brian, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A., Gillard, Bryan M., Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T., Jewell, Scott D., Montroy, Robert G., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Undale, Anita H., Smith, Anna M., Tabor, David E., Roche, Nancy V., McLean, Jeffrey A., Vatanian, Negin, Robinson, Karna L., Sobin, Leslie, Barcus, Mary E., Valentino, Kimberly M., Qi, Liqun, Hunter, Steven, Hariharan, Pushpa, Singh, Shilpi, Um, Ki Sung, Matose, Takunda, Tomaszewski, Maria M., Barker, Laura K., Mosavel, Maghboeba, Siminoff, Laura A., Traino, Heather M., Flicek, Paul, Juettemann, Thomas, Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Craft, Brian, Goldman, Mary, Haeussler, Maximilian, Kent, W. James, Lee, Christopher M., Paten, Benedict, Rosenbloom, Kate R., Vivian, John, Zhu, Jingchun, Nicolae, Dan L., Cox, Nancy J., and Im, Hae Kyung

Abstract

Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.

Published
2018
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211. Characterization of Expression Quantitative Trait Loci in Pedigrees from Colombia and Costa Rica Ascertained for Bipolar Disorder.

Author

Peterson, Christine B., Service, Susan K., Jasinska, Anna J., Gao, Fuying, Zelaya, Ivette, Teshiba, Terri M., Bearden, Carrie E., Cantor, Rita M., Reus, Victor I., Macaya, Gabriel, López-Jaramillo, Carlos, Bogomolov, Marina, Benjamini, Yoav, Eskin, Eleazar, Coppola, Giovanni, Freimer, Nelson B., and Sabatti, Chiara

Subjects
GENETICS of bipolar disorder, LYMPHOBLASTOID cell lines, GENE expression, HERALDRY, BIPOLAR disorder in adolescence
Abstract

The observation that variants regulating gene expression (expression quantitative trait loci, eQTL) are at a high frequency among SNPs associated with complex traits has made the genome-wide characterization of gene expression an important tool in genetic mapping studies of such traits. As part of a study to identify genetic loci contributing to bipolar disorder and other quantitative traits in members of 26 pedigrees from Costa Rica and Colombia, we measured gene expression in lymphoblastoid cell lines derived from 786 pedigree members. The study design enabled us to comprehensively reconstruct the genetic regulatory network in these families, provide estimates of heritability, identify eQTL, evaluate missing heritability for the eQTL, and quantify the number of different alleles contributing to any given locus. In the eQTL analysis, we utilize a recently proposed hierarchical multiple testing strategy which controls error rates regarding the discovery of functional variants. Our results elucidate the heritability and regulation of gene expression in this unique Latin American study population and identify a set of regulatory SNPs which may be relevant in future investigations of complex disease in this population. Since our subjects belong to extended families, we are able to compare traditional kinship-based estimates with those from more recent methods that depend only on genotype information. [ABSTRACT FROM AUTHOR]

Published
2016
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212. Genetic Variant Selection: Learning Across Traits and Sites.

Author

Stell, Laurel and Sabatti, Chiara

Subjects
*GENETIC research, *BAYESIAN analysis, *REGRESSION analysis, *NUCLEOTIDE sequencing, *PHENOTYPES, *GENETIC mutation
Abstract

We consider resequencing studies of associated loci and the problem of prioritizing sequence variants for functional follow-up. Working within the multivariate linear regression framework helps us to account for the joint effects of multiple genes; and adopting a Bayesian approach leads to posterior probabilities that coherently incorporate all information about the variants' function. We describe two novel prior distributions that facilitate learning the role of each variable site by borrowing evidence across phenotypes and across mutations in the same gene. We illustrate their potential advantages with simulations and reanalyzing a data set of sequencing variants. [ABSTRACT FROM AUTHOR]

Published
2016
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214. Volume Measures for Linkage Disequilibrium

Author

Chen, Yuguo, Chen, Yuguo, Lin, Chia-Ho, Sabatti, Chiara, Chen, Yuguo, Chen, Yuguo, Lin, Chia-Ho, and Sabatti, Chiara

Abstract

We discuss the value of volume measures for linkage disequilibrium, showing how they are robust to small sample variation and easily generalized to multi-allelic markers. In particular we introduce Dvol, a volume analogue to D' and show that it performs substantially better when the sample size is small to moderate. Mvol is proposed as a generalization of this measure to multi-allelic markers. Finally a measure based on homozygosity Hvol is suggested as a generalization of R^2. To evaluate these measures, we introduce a sequential importance sampling algorithm. We illustrate their performance on simulated and real data.

Published
2006

215. Inferring genomic loss and location of tumor suppressor genes from high density genotypes

Author

Wang, Hui, Wang, Hui, Lee, Yohan, Nelson, Stanley, Sabatti, Chiara, Wang, Hui, Wang, Hui, Lee, Yohan, Nelson, Stanley, and Sabatti, Chiara

Abstract

Novel technologies, such as the 10k Affymetrix genotyping array, allow scoring of genetic polymorphisms at a very high density across the genome. This allows researchers to conduct traditional inquiries at an unprecedented resolution, while simutaneously motivates novel types of analysis, aimed at exploiting the increased information contained in these datasets. We consider how genotypes of cancer cell lines can be used to reconstruct genomic loss events and map putative tumor suppressor genes (TSG). Using a hidden Markov model framework, we adapt a previously described model for genomic instability in cancers to the current data structure. Simulations indicate that our procedure can be powerful and accurate and initial application to real data leads to encouraging results.

Published
2005

216. Reconstructing Ancestral Haplotypes with a Dictionary Model

Author

Ayers, Kristen L, Ayers, Kristen L, Sabatti, Chiara, Lange, Kenneth, Ayers, Kristen L, Ayers, Kristen L, Sabatti, Chiara, and Lange, Kenneth

Abstract

We propose a dictionary model for haplotypes. According to the model, a haplotype is con- structed by randomly concatenating haplotype segments from a given dictionary of segments. A haplotype block is defined as a set of haplotype segments that begin and end with the same pair of markers. In this framework, haplotype blocks can overlap, and the model provides a setting for testing the accuracy of simpler models invoking only nonoverlapping blocks. Each haplotype segment in a dictionary has an assigned probability and alternate spellings that ac- count for genotyping errors and mutation. The model also allows for missing data, unphased genotypes, and prior distribution of parameters. Likelihood evaluations rely on forward and backward recurrences similar to the ones encountered in hidden Markov models. Parameter estimation is carried out with an EM algorithm. The search for the optimal dictionary is a particularly difficult because of the variable dimension of the model space. We define a mini- mum description length criteria to evaluate each dictionary and use a combination of greedy search and careful initialization to select a best dictionary for a given data set. Application of the model to simulated data gives encouraging results. In a real data set, we are able to reconstruct a parsimonious dictionary that captures patterns of linkage disequilibrium well.

Published
2005

217. Empirical Bayes estimation of a sparse vector of gene expression changes

Author

Erickson, Stephen W, Erickson, Stephen W, Sabatti, Chiara, Erickson, Stephen W, Erickson, Stephen W, and Sabatti, Chiara

Abstract

Gene microarray technology is often used to compare the expression of thousand of genes in two different cell lines. Typically, one does not expect measurable changes in transcription amounts for a large number of genes; furthermore, the noise level of array experiments is rather high in relation to the available number of replicates. For the purpose of statistical analysis, inference on the “population” difference in expression for genes across the two cell lines is often cast in the framework of hypothesis testing, with the null hypothesis being no change in expression. Given that thousands of genes are investigated at the same time, this requires some multiple comparison correction procedure to be in place. We argue that hypothesis testing, with its emphasis on type I error and family analogues, may not address the exploratory nature of most microarray experiments. We instead propose viewing the problem as one of estimation of a vector known to have a large number of zero components. In a Bayesian framework, we describe the prior knowledge on expression changes using mixture priors that incorporate a mass at zero and we choose a loss function that favors the selection of sparse solutions. We consider two different models applicable to the microarray problem, depending on the nature of replicates available, and show how to explore the posterior distributions of the parameters using MCMC. Simulations show an interesting connection between this Bayesian estimation framework and both false discovery rate (FDR) control, and misclassification minimizing pro- cedures. Finally, two empirical examples illustrate the practical advantages of this Bayesian estimation paradigm

Published
2005

221. A Molecular Screening Approach to Identify and Characterize Inhibitors of Glioblastoma Stem Cells

Author

Visnyei, Koppany, primary, Onodera, Hideyuki, additional, Damoiseaux, Robert, additional, Saigusa, Kuniyasu, additional, Petrosyan, Syuzanna, additional, De Vries, David, additional, Ferrari, Denise, additional, Saxe, Jonathan, additional, Panosyan, Eduard H., additional, Masterman-Smith, Michael, additional, Mottahedeh, Jack, additional, Bradley, Kenneth A., additional, Huang, Jing, additional, Sabatti, Chiara, additional, Nakano, Ichiro, additional, and Kornblum, Harley I., additional

Published
2011
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223. Biological, clinical and population relevance of 95 loci for blood lipids

Author

Teslovich, Tanya M., primary, Musunuru, Kiran, additional, Smith, Albert V., additional, Edmondson, Andrew C., additional, Stylianou, Ioannis M., additional, Koseki, Masahiro, additional, Pirruccello, James P., additional, Ripatti, Samuli, additional, Chasman, Daniel I., additional, Willer, Cristen J., additional, Johansen, Christopher T., additional, Fouchier, Sigrid W., additional, Isaacs, Aaron, additional, Peloso, Gina M., additional, Barbalic, Maja, additional, Ricketts, Sally L., additional, Bis, Joshua C., additional, Aulchenko, Yurii S., additional, Thorleifsson, Gudmar, additional, Feitosa, Mary F., additional, Chambers, John, additional, Orho-Melander, Marju, additional, Melander, Olle, additional, Johnson, Toby, additional, Li, Xiaohui, additional, Guo, Xiuqing, additional, Li, Mingyao, additional, Shin Cho, Yoon, additional, Jin Go, Min, additional, Jin Kim, Young, additional, Lee, Jong-Young, additional, Park, Taesung, additional, Kim, Kyunga, additional, Sim, Xueling, additional, Twee-Hee Ong, Rick, additional, Croteau-Chonka, Damien C., additional, Lange, Leslie A., additional, Smith, Joshua D., additional, Song, Kijoung, additional, Hua Zhao, Jing, additional, Yuan, Xin, additional, Luan, Jian’an, additional, Lamina, Claudia, additional, Ziegler, Andreas, additional, Zhang, Weihua, additional, Zee, Robert Y. L., additional, Wright, Alan F., additional, Witteman, Jacqueline C. M., additional, Wilson, James F., additional, Willemsen, Gonneke, additional, Wichmann, H.-Erich, additional, Whitfield, John B., additional, Waterworth, Dawn M., additional, Wareham, Nicholas J., additional, Waeber, Gérard, additional, Vollenweider, Peter, additional, Voight, Benjamin F., additional, Vitart, Veronique, additional, Uitterlinden, Andre G., additional, Uda, Manuela, additional, Tuomilehto, Jaakko, additional, Thompson, John R., additional, Tanaka, Toshiko, additional, Surakka, Ida, additional, Stringham, Heather M., additional, Spector, Tim D., additional, Soranzo, Nicole, additional, Smit, Johannes H., additional, Sinisalo, Juha, additional, Silander, Kaisa, additional, Sijbrands, Eric J. G., additional, Scuteri, Angelo, additional, Scott, James, additional, Schlessinger, David, additional, Sanna, Serena, additional, Salomaa, Veikko, additional, Saharinen, Juha, additional, Sabatti, Chiara, additional, Ruokonen, Aimo, additional, Rudan, Igor, additional, Rose, Lynda M., additional, Roberts, Robert, additional, Rieder, Mark, additional, Psaty, Bruce M., additional, Pramstaller, Peter P., additional, Pichler, Irene, additional, Perola, Markus, additional, Penninx, Brenda W. J. H., additional, Pedersen, Nancy L., additional, Pattaro, Cristian, additional, Parker, Alex N., additional, Pare, Guillaume, additional, Oostra, Ben A., additional, O’Donnell, Christopher J., additional, Nieminen, Markku S., additional, Nickerson, Deborah A., additional, Montgomery, Grant W., additional, Meitinger, Thomas, additional, McPherson, Ruth, additional, McCarthy, Mark I., additional, McArdle, Wendy, additional, Masson, David, additional, Martin, Nicholas G., additional, Marroni, Fabio, additional, Mangino, Massimo, additional, Magnusson, Patrik K. E., additional, Lucas, Gavin, additional, Luben, Robert, additional, Loos, Ruth J. F., additional, Lokki, Marja-Liisa, additional, Lettre, Guillaume, additional, Langenberg, Claudia, additional, Launer, Lenore J., additional, Lakatta, Edward G., additional, Laaksonen, Reijo, additional, Kyvik, Kirsten O., additional, Kronenberg, Florian, additional, König, Inke R., additional, Khaw, Kay-Tee, additional, Kaprio, Jaakko, additional, Kaplan, Lee M., additional, Johansson, Åsa, additional, Jarvelin, Marjo-Riitta, additional, Cecile J. W. Janssens, A., additional, Ingelsson, Erik, additional, Igl, Wilmar, additional, Kees Hovingh, G., additional, Hottenga, Jouke-Jan, additional, Hofman, Albert, additional, Hicks, Andrew A., additional, Hengstenberg, Christian, additional, Heid, Iris M., additional, Hayward, Caroline, additional, Havulinna, Aki S., additional, Hastie, Nicholas D., additional, Harris, Tamara B., additional, Haritunians, Talin, additional, Hall, Alistair S., additional, Gyllensten, Ulf, additional, Guiducci, Candace, additional, Groop, Leif C., additional, Gonzalez, Elena, additional, Gieger, Christian, additional, Freimer, Nelson B., additional, Ferrucci, Luigi, additional, Erdmann, Jeanette, additional, Elliott, Paul, additional, Ejebe, Kenechi G., additional, Döring, Angela, additional, Dominiczak, Anna F., additional, Demissie, Serkalem, additional, Deloukas, Panagiotis, additional, de Geus, Eco J. C., additional, de Faire, Ulf, additional, Crawford, Gabriel, additional, Collins, Francis S., additional, Chen, Yii-der I., additional, Caulfield, Mark J., additional, Campbell, Harry, additional, Burtt, Noel P., additional, Bonnycastle, Lori L., additional, Boomsma, Dorret I., additional, Boekholdt, S. Matthijs, additional, Bergman, Richard N., additional, Barroso, Inês, additional, Bandinelli, Stefania, additional, Ballantyne, Christie M., additional, Assimes, Themistocles L., additional, Quertermous, Thomas, additional, Altshuler, David, additional, Seielstad, Mark, additional, Wong, Tien Y., additional, Tai, E-Shyong, additional, Feranil, Alan B., additional, Kuzawa, Christopher W., additional, Adair, Linda S., additional, Taylor Jr, Herman A., additional, Borecki, Ingrid B., additional, Gabriel, Stacey B., additional, Wilson, James G., additional, Holm, Hilma, additional, Thorsteinsdottir, Unnur, additional, Gudnason, Vilmundur, additional, Krauss, Ronald M., additional, Mohlke, Karen L., additional, Ordovas, Jose M., additional, Munroe, Patricia B., additional, Kooner, Jaspal S., additional, Tall, Alan R., additional, Hegele, Robert A., additional, Kastelein, John J.P., additional, Schadt, Eric E., additional, Rotter, Jerome I., additional, Boerwinkle, Eric, additional, Strachan, David P., additional, Mooser, Vincent, additional, Stefansson, Kari, additional, Reilly, Muredach P., additional, Samani, Nilesh J, additional, Schunkert, Heribert, additional, Cupples, L. Adrienne, additional, Sandhu, Manjinder S., additional, Ridker, Paul M, additional, Rader, Daniel J., additional, van Duijn, Cornelia M., additional, Peltonen, Leena, additional, Abecasis, Gonçalo R., additional, Boehnke, Michael, additional, and Kathiresan, Sekar, additional

Published
2010
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227. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population

Author

Sabatti, Chiara, primary, Service, Susan K, additional, Hartikainen, Anna-Liisa, additional, Pouta, Anneli, additional, Ripatti, Samuli, additional, Brodsky, Jae, additional, Jones, Chris G, additional, Zaitlen, Noah A, additional, Varilo, Teppo, additional, Kaakinen, Marika, additional, Sovio, Ulla, additional, Ruokonen, Aimo, additional, Laitinen, Jaana, additional, Jakkula, Eveliina, additional, Coin, Lachlan, additional, Hoggart, Clive, additional, Collins, Andrew, additional, Turunen, Hannu, additional, Gabriel, Stacey, additional, Elliot, Paul, additional, McCarthy, Mark I, additional, Daly, Mark J, additional, Järvelin, Marjo-Riitta, additional, Freimer, Nelson B, additional, and Peltonen, Leena, additional

Published
2008
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228. Results of a SNP genome screen in a large Costa Rican Pedigree segregating for severe bipolar disorder

Author

Service, Susan, primary, Molina, Julio, additional, DeYoung, Joseph, additional, Jawaheer, Damini, additional, Aldana, Ileana, additional, Vu, Thuy, additional, Araya, Carmen, additional, Araya, Xinia, additional, Bejarano, Julio, additional, Fournier, Eduardo, additional, Ramirez, Magui, additional, Mathews, Carol A., additional, Davanzo, Pablo, additional, Macaya, Gabriel, additional, Sandkuijl, Lodewijk, additional, Sabatti, Chiara, additional, Reus, Victor, additional, and Freimer, Nelson, additional

Published
2008
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233. Results of a SNP genome screen in a large Costa Rican pedigree segregating for severe bipolar disorder

Author

Service, Susan, primary, Molina, Julio, additional, DeYoung, Joseph, additional, Jawaheer, Damini, additional, Aldana, Ileana, additional, Vu, Thuy, additional, Bejarano, Julio, additional, Fournier, Eduardo, additional, Ramirez, Magui, additional, Mathews, Carol A., additional, Davanzo, Pablo, additional, Macaya, Gabriel, additional, Sandkuijl, Lodewijk, additional, Sabatti, Chiara, additional, Reus, Victor, additional, and Freimer, Nelson, additional

Published
2006
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234. Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies

Author

Service, Susan, primary, DeYoung, Joseph, additional, Karayiorgou, Maria, additional, Roos, J Louw, additional, Pretorious, Herman, additional, Bedoya, Gabriel, additional, Ospina, Jorge, additional, Ruiz-Linares, Andres, additional, Macedo, António, additional, Palha, Joana Almeida, additional, Heutink, Peter, additional, Aulchenko, Yurii, additional, Oostra, Ben, additional, van Duijn, Cornelia, additional, Jarvelin, Marjo-Riitta, additional, Varilo, Teppo, additional, Peddle, Lynette, additional, Rahman, Proton, additional, Piras, Giovanna, additional, Monne, Maria, additional, Murray, Sarah, additional, Galver, Luana, additional, Peltonen, Leena, additional, Sabatti, Chiara, additional, Collins, Andrew, additional, and Freimer, Nelson, additional

Published
2006
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249. Inferring protein domain interactions from databases of interacting proteins

Author

Riley, Robert, Lee, Christopher, Sabatti, Chiara, and Eisenberg, David

Subjects
Models, Molecular, Proto-Oncogene Proteins p21(ras), Protein Interaction Mapping, Method, Animals, Humans, Proteins, Databases, Protein, Heterotrimeric GTP-Binding Proteins, Protein Binding, Protein Structure, Tertiary
Abstract

A new method for inferring domain interactions from databases of interacting proteins was used to deduce 3,005 high-confidence domain interactions from over 177,000 potential interactions., We describe domain pair exclusion analysis (DPEA), a method for inferring domain interactions from databases of interacting proteins. DPEA features a log odds score, Eij, reflecting confidence that domains i and j interact. We analyzed 177,233 potential domain interactions underlying 26,032 protein interactions. In total, 3,005 high-confidence domain interactions were inferred, and were evaluated using known domain interactions in the Protein Data Bank. DPEA may prove useful in guiding experiment-based discovery of previously unrecognized domain interactions.

Published
2005

250. Avoiding False Discoveries in Association Studies.

Author

Walker, John M., Collins, Andrew R., and Sabatti, Chiara

Abstract

We consider the problem of controlling false discoveries in association studies. We assume that the design of the study is adequate so that the "false discoveries" are potentially only because of random chance, not to confounding or other flaws. Under this premise, we review the statistical framework for hypothesis testing and correction for multiple comparisons. We consider in detail the currently accepted strategies in linkage analysis. We then examine the underlying similarities and differences between linkage and association studies and document some of the most recent methodological developments for association mapping. [ABSTRACT FROM AUTHOR]

Published
2007
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