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163 results on '"Mccarthy, Mark"'

1. Accounting Standards Codification 326: Three Years of Expected Credit Loss Reporting

Author: McCarthy, Mark and Schneider, Douglas K.
Subjects: JPMorgan Chase & Co. -- Forecasts and trends, Banking industry -- Forecasts and trends -- Standards, Financial statements -- Forecasts and trends, Accounting -- Standards, Market trend/market analysis, Banking industry, Banking, finance and accounting industries, Business
Abstract: IN BRIEF In the wake of the Great Recession, FASB spent years deliberating new guidance intended to provide users with more useful information on the expected credit losses on financial [...]
Published: 2024

2. Improving reporting standards for polygenic scores in risk prediction studies

Author: Wand, Hannah, Lambert, Samuel A., Tamburro, Cecelia, Iacocca, Michael A., O'Sullivan, Jack W., Sillari, Catherine, Kullo, Iftikhar J., Rowley, Robb, Dron, Jacqueline S., Brockma, Deanna, Venner, Eric, McCarthy, Mark I., Antoniou, Antonis C., Easton, Douglas F., Hegele, Robert A., Khera, Amit V., and Chatterjee, Nilanjan
Subjects: Health risk assessment -- Methods -- Genetic aspects, Genome-wide association studies, Multifactorial traits -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications. Items span detailed descriptions of study populations, statistical methods for the development and validation of PRSs and considerations for the potential limitations of these scores. In addition, we emphasize the need for data availability and transparency, and we encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice. An updated set of reporting standards for the development, interpretation and evaluation of polygenic risk scores is presented, which should aid the translation of these scores into clinical applications., Author(s): Hannah Wand [sup.1] [sup.2] , Samuel A. Lambert [sup.3] [sup.4] [sup.5] [sup.6] [sup.7] , Cecelia Tamburro [sup.8] , Michael A. Iacocca [sup.1] , Jack W. O'Sullivan [sup.1] [sup.2] , [...]
Published: 2021
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3. George Cruikshank's families

Author: McCarthy, Mark
Subjects: Literature/writing
Abstract: Norma Clarke's review of Uproar!, Alice Loxton's scintillating history of British satirical prints (April 14), retells the story that Eliza Cruikshank 'had known nothing' about her husband George's second family. [...]
Published: 2023

4. Britain and Europe

Author: McCarthy, Mark
Subjects: Literature/writing
Abstract: David Goodhart correctly comments that there was no plan for Brexit (March 31). But 'without any sort of consensus ... and without a cadre of officials and politicians who believed [...]
Published: 2023

5. The impact of rare variation on gene expression across tissues

Author: Li, Xin, Kim, Yungil, Tsang, Emily K., Davis, Joe R., Damani, Farhan N., Chiang, Colby, Hess, Gaelen T., Zappala, Zachary, Strober, Benjamin J., Scott, Alexandra J., Li, Amy, Ganna, Andrea, Bassik, Michael C., Merker, Jason D., Aguet, Franois, 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., Segr, 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., Conrad, Donald F., Cox, Nancy J., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frsard, Laure, Gamazon, Eric R., Garrido-Martn, Diego, Gewirtz, Ariel D.H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I., McDowell, Ian C., Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B., Muoz-Aguirre, Manuel, Ndungu, Anne W., Nicolae, Dan L., 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, Shabalin, Andrey A., Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E., Sul, Jae Hoon, Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A., Xi, Hualin S., Yeger-Lotem, Esti, 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, Billy Li, Jin, 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, and Zhu, Jingchun
Subjects: Disease susceptibility -- Genetic aspects, Genetic variation -- Observations, Gene expression -- Observations, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): Xin Li [1]; Yungil Kim [2]; Emily K. Tsang [1, 3]; Joe R. Davis [1, 4]; Farhan N. Damani [2]; Colby Chiang [5]; Gaelen T. Hess [4]; Zachary Zappala [...]
Published: 2017
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6. Dynamic landscape and regulation of RNA editing in mammals

Author: Tan, Meng How, Li, Qin, Shanmugam, Raghuvaran, Piskol, Robert, Kohler, Jennefer, Young, Amy N., Liu, Kaiwen Ivy, Zhang, Rui, Ramaswami, Gokul, Ariyoshi, Kentaro, Gupte, Ankita, Keegan, Liam P., George, Cyril X., Ramu, Avinash, Huang, Ni, Pollina, Elizabeth A., Leeman, Dena S., Rustighi, Alessandra, Goh, Y. P. Sharon, Aguet, Franois, 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., Segr, 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., Cox, Nancy J., Damani, Farhan N., Davis, Joe R., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frsard, Laure, Gamazon, Eric R., Garrido-Martn, Diego, Gewirtz, Ariel D. H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, 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., Muoz-Aguirre, Manuel, Ndungu, Anne W., Nicolae, Dan L., 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, 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, 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, Chawla, Ajay, Del Sal, Giannino, Peltz, Gary, Brunet, Anne, Samuel, Charles E., OConnell, Mary A., Walkley, Carl R., and Nishikura, Kazuko
Subjects: Genetic research, Mammals -- Genetic aspects, RNA processing -- Research, Genetic regulation, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): Meng How Tan (corresponding author) [1, 2, 3]; Qin Li [1]; Raghuvaran Shanmugam [2, 3]; Robert Piskol [1]; Jennefer Kohler [1]; Amy N. Young [1]; Kaiwen Ivy Liu [3]; [...]
Published: 2017
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7. Landscape of X chromosome inactivation across human tissues

Author: Tukiainen, Taru, Villani, Alexandra-Chlo, Yen, Angela, Rivas, Manuel A., Marshall, Jamie L., Satija, Rahul, Aguirre, Matt, Gauthier, Laura, Fleharty, Mark, Kirby, Andrew, Cummings, Beryl B., Castel, Stephane E., Karczewski, Konrad J., Aguet, Franois, Byrnes, Andrea, Ardlie, Kristin G., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Nedzel, Jared L., Nguyen, Duyen T., Noble, Michael S., Segr, Ayellet V., Trowbridge, Casandra A., Abell, Nathan S., Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K., Brown, Andrew, Brown, Christopher D., Chen, Lin S., Chiang, Colby, Conrad, Donald F., Cox, Nancy J., Damani, Farhan N., Davis, Joe R., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frsard, Laure, Gamazon, Eric R., Garrido-Martn, Diego, Gewirtz, Ariel D. H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, 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., Muoz-Aguirre, Manuel, Ndungu, Anne W., Nicolae, Dan L., 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, Regev, Aviv, and Hacohen, Nir
Subjects: Chromosomes -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): Taru Tukiainen (corresponding author) [1, 2]; Alexandra-Chlo Villani [2, 3]; Angela Yen [2, 4]; Manuel A. Rivas [1, 2, 5]; Jamie L. Marshall [1, 2]; Rahul Satija [2, 6, [...]
Published: 2017
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8. Analysis of protein-coding genetic variation in 60,706 humans

Author: Lek, Monkol, Karczewski, Konrad J., Minikel, Eric V., Samocha, Kaitlin E., Banks, Eric, Fennell, Timothy, ODonnell-Luria, Anne H., Ware, James S., Hill, Andrew J., Cummings, Beryl B., Tukiainen, Taru, Birnbaum, Daniel P., Kosmicki, Jack A., Duncan, Laramie E., Estrada, Karol, Zhao, Fengmei, Zou, James, Pierce-Hoffman, Emma, Berghout, Joanne, Cooper, David N., Deflaux, Nicole, DePristo, Mark, Do, Ron, Flannick, Jason, Fromer, Menachem, Gauthier, Laura, Goldstein, Jackie, Gupta, Namrata, Howrigan, Daniel, Kiezun, Adam, Kurki, Mitja I., Moonshine, Ami Levy, Natarajan, Pradeep, Orozco, Lorena, Peloso, Gina M., Poplin, Ryan, Rivas, Manuel A., Ruano-Rubio, Valentin, Rose, Samuel A., Ruderfer, Douglas M., Shakir, Khalid, Stenson, Peter D., Stevens, Christine, Thomas, Brett P., Tiao, Grace, Tusie-Luna, Maria T., Weisburd, Ben, Won, Hong-Hee, Yu, Dongmei, Altshuler, David M., Ardissino, Diego, Boehnke, Michael, Danesh, John, Donnelly, Stacey, Elosua, Roberto, Florez, Jose C., Gabriel, Stacey B., Getz, Gad, Glatt, Stephen J., Hultman, Christina M., Kathiresan, Sekar, Laakso, Markku, McCarroll, Steven, McCarthy, Mark I., McGovern, Dermot, McPherson, Ruth, Neale, Benjamin M., Palotie, Aarno, Purcell, Shaun M., Saleheen, Danish, Scharf, Jeremiah M., Sklar, Pamela, Sullivan, Patrick F., Tuomilehto, Jaakko, Tsuang, Ming T., Watkins, Hugh C., Wilson, James G., Daly, Mark J., and MacArthur, Daniel G.
Subjects: Humans -- Genetic aspects -- Research, Genetic variation -- Analysis, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human knockout variants in protein-coding genes., Author(s): Monkol Lek [1, 2, 3, 4]; Konrad J. Karczewski [1, 2]; Eric V. Minikel [1, 2, 5]; Kaitlin E. Samocha [1, 2, 5, 6]; Eric Banks [2]; Timothy Fennell [...]
Published: 2016
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9. Reporting of discontinued operations: past, present, and future

Author: Dickins, Denise, McCarthy, Mark, O'Reilly, Dennis, and Schneider, Douglas
Subjects: Financial statements -- Standards, Production management -- Standards, Financial disclosure -- Standards, Accounting standards -- Laws, regulations and rules, Government regulation, Banking, finance and accounting industries, Business, Financial Accounting Standards Board -- Powers and duties
Abstract: In April 2014, FASB issued Accounting Standards Update (ASU) 2014-08, Reporting Discontinued Operations and Disclosures of Disposals of Components of an Entity, which is effective for fiscal years beginning after [...]
Published: 2017

10. Association of vitamin D with risk of type 2 diabetes: A Mendelian randomisation study in European and Chinese adults

Author: Lu, Ling, Bennett, Derrick A., Millwood, Iona Y., Parish, Sarah, McCarthy, Mark I., Mahajan, Anubha, Lin, Xu, Bragg, Fiona, Guo, Yu, Holmes, Michael V., Afzal, Shoaib, Nordestgaard, Børge G., Bian, Zheng, Hill, Michael, Walters, Robin G., Li, Liming, Chen, Zhengming, and Clarke, Robert
Subjects: Genetic susceptibility -- Research, Type 2 diabetes -- Risk factors -- Genetic aspects, Medical research, Epidemiologic methods -- Research, Vitamin D -- Genetic aspects -- Health aspects, Biological sciences
Abstract: Background Observational studies have reported that higher plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal. The aim of this study was to test the relevance of 25(OH)D for type 2 diabetes using genetically instrumented differences in plasma 25(OH)D concentrations. Methods and findings Data were available on four 25(OH)D single nucleotide polymorphisms (SNPs; n = 82,464), plasma 25(OH)D concentrations (n = 13,565), and cases with diabetes (n = 5,565) in the China Kadoorie Biobank (CKB). The effects on risk of diabetes were assessed by a genetic score using two 25(OH)D synthesis SNPs (DHCR7-rs12785878 and CYP2R1-rs10741657), with and without the addition of SNPs affecting the transport (GC/DBP-rs2282679) and catabolism (CYP24A1-rs6013897) of 25(OH)D. The CKB results were combined in a meta-analysis of 10 studies for the 2 synthesis SNPs (n = 58,312 cases) and 7 studies for all 4 SNPs (n = 32,796 cases). Mean (SD) 25(OH)D concentration was 62 (20) nmol/l in CKB, and the per allele effects of genetic scores on 25(OH)D were 2.87 (SE 0.39) for the synthesis SNPs and 3.54 (SE 0.32) for all SNPs. A 25-nmol/l higher biochemically measured 25(OH)D was associated with a 9% (95% CI: 0%-18%) lower risk of diabetes in CKB. In a meta-analysis of all studies, a 25-nmol/l higher genetically instrumented 25(OH)D concentration was associated with a 14% (95% CI: 3%-23%) lower risk of diabetes (p = 0.01) using the 2 synthesis SNPs. An equivalent difference in 25(OH)D using a genetic score with 4 SNPs was not significantly associated with diabetes (odds ratio 8%, 95% CI: -1% to 16%, lower risk, p = 0.07), but had some evidence of pleiotropy. A limitation of the meta-analysis was the access only to study level rather than individual level data. Conclusions The concordant risks of diabetes for biochemically measured and genetically instrumented differences in 25(OH)D using synthesis SNPs provide evidence for a causal effect of higher 25(OH)D for prevention of diabetes., Author(s): Ling Lu 1,2, Derrick A. Bennett 1, Iona Y. Millwood 1,3, Sarah Parish 1,3, Mark I. McCarthy 4,5, Anubha Mahajan 5, Xu Lin 2, Fiona Bragg 1, Yu Guo [...]
Published: 2018
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11. Comment: an alternative interpretation of the relationship between TN:TP and microcystins in Canadian lakes

Author: Scott, J. Thad, McCarthy, Mark J., Otten, Timothy G., Steffen, Morgan M., Baker, Bryant C., Grantz, Erin M., Wilhelm, Steven W., and Paerl, Hans W.
Subjects: Lakes -- Chemical properties, Eutrophication -- Analysis -- Environmental aspects, Earth sciences
Abstract: Introduction Landscape-scale patterns of the cyanobacterial toxin, microcystin, in Canadian lakes were recently analyzed by Orihel et al. (2012). The analysis of this comprehensive dataset was important for linking accelerated [...]
Published: 2013
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12. Browning, John Edgar, and Caroline Joan Picart, eds.: Draculas, Vampires, and Other Undead Forms: Essays on Gender, Race, and Culture

Author: McCarthy, Mark R.
Subjects: Draculas, Vampires, and Other Undead Forms: Essays on Gender, Race, and Culture (Essay collection) -- Browning, John Edgar -- Picart, Caroline Joan -- Book reviews, Books -- Book reviews, Literature/writing
Abstract: Browning, John Edgar, and Caroline Joan Picart, eds. Draculas, Vampires, and Other Undead Forms: Essays on Gender, Race, and Culture. Lanham: Scarecrow Press, 2006. 338 pp. Hardback. ISBN 978-0810866966. $55.00. [...]
Published: 2012

13. Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes

Author: Rees, Matthew G., Ng, David, Ruppert, Sarah, Turner, Clesson, Beer, Nicola L., Swift, Amy J., Morken, Mario A., Below, Jennifer E., Blech, Ilana, Mullikin, James C., McCarthy, Mark I., Biesecker, Leslie G., Gloyn, Anna L., and Collins, Francis S.
Subjects: Glucokinase -- Health aspects -- Research, Genetic disorders -- Risk factors -- Diagnosis -- Care and treatment -- Research, Blood proteins -- Physiological aspects -- Research, Health care industry
Abstract: Defining the genetic contribution of rare variants to common diseases is a major basic and clinical science challenge that could offer new insights into disease etiology and provide potential for directed gene-and pathway-based prevention and treatment. Common and rare nonsynonymous variants in the GCKR gene are associated with alterations in metabolic traits, most notably serum triglyceride levels. GCKR encodes glucokinase regulatory protein (GKRP), a predominantly nuclear protein that inhibits hepatic glucokinase (GCK) and plays a critical role in glucose homeostasis. The mode of action of rare GCKR variants remains unexplored. We identified 19 nonsynonymous GCKR variants among 800 individuals from the ClinSeq medical sequencing project. Excluding the previously described common missense variant p.Pro446Leu, all variants were rare in the cohort. Accordingly, we functionally characterized all variants to evaluate their potential phenotypic effects. Defects were observed for the majority of the rare variants after assessment of cellular localization, ability to interact with GCK, and kinetic activity of the encoded proteins. Comparing the individuals with functional rare variants to those without such variants showed associations with lipid phenotypes. Our findings suggest that, while nonsynonymous GCKR variants, excluding p.Pro446Leu, are rare in individuals of mixed European descent, the majority do affect protein function. In sum, this study utilizes computational, cell biological, and biochemical methods to present a model for interpreting the clinical significance of rare genetic variants in common disease., Introduction Common human diseases result from the combined effects of genetic susceptibility and environmental factors. Understanding the genetic contribution to disease may offer new insights into disease etiology and provide [...]
Published: 2012
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14. Expression of phosphofructokinase in skeletal muscle is influenced by genetic variation and associated with insulin sensitivity

Author: Keildson, Sarah, Fadista, Joao, Ladenvall, Claes, Hedman, Asa K., Elgzyri, Targ, Small, Kerrin S., Grundberg, Elin, Nica, Alexandra C., Glass, Daniel, Richards, J. Brent, Barrett, Amy, Nisbet, James, Zheng, Hou-Feng, Ronn, Tina, Strom, Kristoffer, Eriksson, Karl-Fredrik, Prokopenko, Inga, Spector, Timothy D., Dermitzakis, Emmanouil T., Deloukas, Panos, McCarthy, Mark I., Rung, Johan, Groop, Leif, Franks, Paul W., Lindgren, Cecilia M., and Hansson, Ola
Subjects: Genetic research, Musculoskeletal system -- Physiological aspects, Genetic variation -- Research, Phosphotransferases -- Identification and classification, Health
Abstract: Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] DOI: 10.2337/db13-1301, Although genome-wide association studies (GWASs) have identified thousands of single nucleotide polymorphisms (SNPs) associated with traits and diseases, the molecular mechanisms underlying these associations remain largely unknown. Changes in gene [...]
Published: 2014
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15. Genomics, type 2 diabetes, and obesity

Author: McCarthy, Mark I.
Subjects: Type 2 diabetes -- Diagnosis, Type 2 diabetes -- Care and treatment, Type 2 diabetes -- Risk factors, Type 2 diabetes -- Genetic aspects, Obesity -- Risk factors, Obesity -- Diagnosis, Obesity -- Care and treatment, Obesity -- Genetic aspects
Abstract: Genomewide association studies of population-based samples were carried out to examine the full range of body-mass index (BMI) values and identify loci influencing BMI and the risk of obesity associated with prevalence of type 2 diabetes. An improved insight gained for pathophysiology achieved through genetic discovery would provide new opportunities for treatment, diagnosis and monitoring risk variants for type 2 diabetes in healthy populations.
Published: 2010

16. Anatomic posterolateral knee reconstructions require a popliteofibular ligament reconstruction through a tibial tunnel

Author: McCarthy, Mark, Camarda, Lawrence, Wijdicks, Coen A., Johansen, Steinar, Engebretsen, Lars, and LaPrade, Robert F.
Subjects: Popliteal fossa -- Physiological aspects, Popliteal fossa -- Research, Knee -- Injuries, Knee -- Care and treatment, Knee -- Patient outcomes, Knee -- Research, Health, Sports and fitness
Published: 2010

17. Distinct variants at LIN28B influence growth in height from birth to adulthood

Author: Widen, Elisabeth, Ripatti, Samuli, Cousminer, Diana L., Surakka, Ida, Lappalainen, Tuuli, Jarvelin, Marjo-Riitta, Eriksson, Johan G., Raitakari, Olli, Salomaa, Veikko, Sovio, Ulla, Hartikainen, Anna-Liisa, Pouta, Anneli, McCarthy, Mark I., Osmond, Clive, Kajantie, Eero, Lehtimaki, Terho, Viikari, Jorma, Kahonen, Mika, Tyler-Smith, Chris, Freimer, Nelson, Hirschhorn, Joel N., Peltonen, Leena, and Palotie, Aarno
Subjects: Human growth -- Research, Stature -- Genetic aspects, Genetic regulation -- Analysis, Human population genetics -- Research, Biological sciences
Abstract: A unique resource of longitudinal childhood height data available in Finnish population cohorts was used to study the largely unknown genetic underpinnings of height growth. The partially correlated variants at LIN28B which influence the entire period of postnatal growth implied a critical role for LIN28B in the regulation of human growth.
Published: 2010

18. Nitrogen fixation may not balance the nitrogen pool in lakes over timescales relevant to eutrophication management

Author: Scott, J. Thad and McCarthy, Mark J.
Subjects: Limnology -- Research, Eutrophication -- Control, Chlorophyll -- Properties, Nitrogen -- Fixation, Nitrogen -- Observations, Earth sciences
Abstract: We explored multiyear linear trends in nutrient concentrations, nitrogen (N) : phosphorus (P) ratio, and phytoplankton biomass within the 37-yr, whole-ecosystem nutrient enrichment experiment in Lake 227 of the Experimental Lakes Area, Canada. Based on experimental conditions, data were divided into subsets, which included (1) the period from 1969 to 1989 when the lake was fertilized with both N and P; (2) the period from 1990 to 2005 when the lake was fertilized with P alone; and (3) the period from 1997 to 2005 when the lake was fertilized with P alone and which also postdated a food web manipulation experiment, which left the lake without fish. After N fertilization was halted in 1990, total N concentrations decreased, which resulted in a decrease in the ratio of total N to total P and suggested increasing N deficiency. Chlorophyll a concentration decreased over this same period. Phytoplankton biomass (mg [m.sup.-3]) was highly variable during the food web manipulation experiment but exhibited a clear decrease from 1997 to 2005, which was the longest period of monotonic change in phytoplankton biomass over the entire 37-yr study. Collectively, these results suggest that Lake 227 has become increasingly N-limited since N fertilization was halted and indicate that N fixation by cyanobacteria was not sufficient to offset the decrease in external N inputs to Lake 227. Furthermore, phytoplankton biomass decreased in response to decreased N availability, suggesting that the degree of eutrophication can be controlled by managing N inputs concurrently with P. doi: 10.4319/lo.2010.55.3.1265
Published: 2010

19. Finding the missing heritability of complex diseases

Author: Manolio, Teri A., Collins, Francis S., Cox, Nancy J., Goldstein, David B., Hindorffs, Lucia A., Hunter, David J., McCarthy, Mark I., Ramos, Erin M., Cardon, Lon R., Chakravarti, Aravinda, Cho, Judy H., Guttmacher, Alan E., Kong, Augustine, Kruglyak, Leonid, Mardis, Elaine, Rotimi, Charles N., Slatkin, Montgomery, Valle, David, Whittemore, Alice S., Boehnke, Michael, Clark, Andrew G., Eichler, Evan E., Gibson, Greg, Haines, Jonathan L., Mackay, Trudy F.C., McCarroll, Steven A., and Visscher, Peter M.
Subjects: Diseases -- United States -- Genetic aspects -- Research, Genomes -- Health aspects -- Research -- Genetic aspects, Heritability -- Research -- Genetic aspects -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and search strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment., Many common human diseases and traits are known to cluster in families and are believed to be influenced by several genetic and environmental factors, but until recently the identification of [...]
Published: 2009

20. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease

Author: Elliott, Paul, Chambers, John C., Zhang, Weihua, Clarke, Robert, Hopewell, Jemma C., Peden, John F., Erdmann, Jeanette, Braund, Peter, Engert, James C., Bennett, Derrick, Coin, Lachlan, Ashby, Deborah, Tzoulaki, Ioanna, Brown, Ian J., Mt-Isa, Shahrul, McCarthy, Mark I., Peltonen, Leena, Freimer, Nelson B., Farrall, Martin, Ruokonen, Aima, Hamsten, Anders, Lim, Noha, Froguel, Philippe, Waterworth, Dawn M., Vollenweider, Peter, Waeber, Gerard, Jarvelin, Marjo-Riitta, Mooser,Vincent, Scott, James, Hall, Alistair S., Schunkert, Heribert, Anand, Sonia S., Collins, Rory, Samani, Nilesh J., Watkins, Hugh, and Kooner, Jaspal S.
Subjects: C-reactive protein -- Health aspects, Coronary heart disease -- Causes of, Coronary heart disease -- Risk factors
Abstract: A study was conducted to evaluate the association of loci with the C-reactive protein (CRP) levels and an increased risk of coronary heart disease. Results indicated that a causal relationship did exist between CRP and coronary heart disease.
Published: 2009

21. Optimization of human plasma [sup.1]H NMR spectroscopic data processing for high-throughput metabolic phenotyping studies and detection of insulin resistance related to type 2 diabetes

Author: Maher, Anthony D., Crockford, Derek, Toft, Henrik, Malmodin, Daniel, Faber, Johan H., McCarthy, Mark I., Barrett, Amy, Allen, Maxine, Walker, Mark, Holmes, Elaine, Lindon, John C., and Nicholson, Jeremy K.
Subjects: Type 2 diabetes -- Genetic aspects, Nuclear magnetic resonance spectroscopy -- Methods, Insulin resistance -- Genetic aspects, Blood plasma -- Properties, Blood plasma -- Genetic aspects, Phenotype -- Properties, Metabolism -- Genetic aspects, Electronic data processing -- Methods, Chemistry
Abstract: Optimizing NMR experimental parameters for high-through-put metabolic phenotyping requires careful examination of the total biochemical information obtainable from [sup.1]H NMR data, which includes concentration and molecular dynamics information. Here we have applied two different types of mathematical transformation (calculation of the first derivative of the NMR spectrum and Gaussian shaping of the free-induction decay) to attenuate broad spectral features from macromolecules and enhance the signals of small molecules. By application of chemometric methods such as principal component analysis (PCA), orthogonal projections to latent structures discriminant analysis (O-PLS-DA) and statistical spectroscopic tools such as statistical total correlation spectroscopy (STOCSY), we show that these methods successfully identify the same potential biomarkers as spin-echo [sup.1]H NMR spectra in which broad lines are suppressed via [T.sub.2] relaxation editing. Finally, we applied these methods for identification of the metabolic phenotype of patients with type 2 diabetes. This 'virtual' relaxation-edited spectroscopy (RESY) approach can be particularly useful for high-throughput screening of complex mixtures such as human plasma and may be useful for extraction of latent biochemical information from legacy or archived NMR data sets for which only standard 1D data sets exist.
Published: 2008

22. Regulation of Fto/Ftm gene expression in mice and humans

Author: Stratigopoulos, George, Padilla, Stephanie L., LeDuc, Charles A., Watson, Elizabeth, Hattersley, Andrew T., McCarthy, Mark I., Zeltser, Lori M., Chung, Wendy K., and Leibel, Rudolph L.
Subjects: Gene expression -- Analysis, Rodents as pets -- Genetic aspects, Rodents as pets -- Health aspects, Hypothalamus -- Research, Obesity -- Causes of, Obesity -- Research, Biological sciences
Abstract: Two recent, large whole-genome association studies (GWAS) in European populations have associated a ~47-kb region that contains part of the FTO gene with high body mass index (BMI). The functions of FTO and adjacent FTM in human biology are not clear. We examined expression of these genes in organs of mice segregating for monogenic obesity mutations, exposed to underfeeding/overfeeding, and to 4[degrees]C. Fto/Ftm expression was reduced in mesenteric adipose tissue of mice segregating for the [A.sup.y], [Lep.sup.ob], [Lepr.sup.db], [Cpe.sup.fat], or tub mutations, and there was a similar trend in other tissues. These effects were not due to adiposity per se. Hypothalamic Fto and Ftm expression were decreased by fasting in lean and obese animals and by cold exposure in lean mice. The fact that responses of Fto and Ftm expression to these manipulations were almost indistinguishable suggested that the genes might be coregulated. The putative overlapping regulatory region contains at least two canonical CUTL1 binding sites. One of these nominal CUTL1 sites includes rs8050136, a SNP associated with high body mass. The A allele of rs8050136 associated with lower body mass than the C allele preferentially bound CUTL1 in human fibroblast DNA. 70% knockdown of CUTL1 expression in human fibroblasts decreased FTO and FTM expression by 90 and 65%, respectively. Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed 'ciliopathy.' FTM has recently been shown to be a ciliary basal body protein. obesity; hypothalamus; adipose tissue; CUTL1
Published: 2008

23. Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable

Author: Lawlor, Debbie A., Timpson, Nicholas J., Harbord, Roger M., Leary, Sam, Ness, Andy, McCarthy, Mark I., Frayling, Timothy M., Hattersley, Andrew T., and Smith, George Davey
Subjects: Biological sciences
Abstract: Background The developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis. Methods and Findings We explored this hypothesis by comparing the associations of maternal and paternal prepregnancy body mass index (BMI) with offspring dual energy X-ray absorptiometry (DXA)-determined fat mass measured at 9 to 11 y (4,091 parent-offspring trios) and by using maternal FTO genotype, controlling for offspring FTO genotype, as an instrument for maternal adiposity. Both maternal and paternal BMI were positively associated with offspring fat mass, but the maternal association effect size was larger than that in the paternal association in all models: mean difference in offspring sex- and age-standardised fat mass z-score per 1 standard deviation BMI 0.24 (95% confidence interval [CI]: 0.22 to 0.26) for maternal BMI versus 0.13 (95% CI: 0.11, 0.15) for paternal BMI; p-value for difference in effect < 0.001. The stronger maternal association was robust to sensitivity analyses assuming levels of non-paternity up to 20%. When maternal FTO, controlling for offspring FTO, was used as an instrument for the effect of maternal adiposity, the mean difference in offspring fat mass z-score per 1 standard deviation maternal BMI was -0.08 (95% CI: -0.56 to 0.41), with no strong statistical evidence that this differed from the observational ordinary least squares analyses (p = 0.17). Conclusions Neither our parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9-11 y. Developmental overnutrition related to greater maternal BMI is unlikely to have driven the recent obesity epidemic. doi:10.1371/journal.pmed.0050033, Introduction According to the developmental overnutrition hypothesis, high maternal glucose and high free fatty acid and amino acid plasma concentrations result in permanent changes in appetite control, neuroendocrine functioning, or [...]
Published: 2008

24. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis

Author: Wheeler, Eleanor, Leong, Aaron, Liu, Ching-Ti, Hivert, Marie-France, Strawbridge, Rona J., Podmore, Clara, Li, Man, Yao, Jie, Sim, Xueling, Hong, Jaeyoung, Chu, Audrey Y., Zhang, Weihua, Wang, Xu, Chen, Peng, Maruthur, Nisa M., Porneala, Bianca C., Sharp, Stephen J., Jia, Yucheng, Kabagambe, Edmond K., Chang, Li-Ching, Chen, Wei-Min, Elks, Cathy E., Evans, Daniel S., Fan, Qiao, Giulianini, Franco, Go, Min Jin, Hottenga, Jouke-Jan, Hu, Yao, Jackson, Anne U., Kanoni, Stavroula, Kim, Young Jin, Kleber, Marcus E., Ladenvall, Claes, Lecoeur, Cecile, Lim, Sing-Hui, Lu, Yingchang, Mahajan, Anubha, Marzi, Carola, Nalls, Mike A., Navarro, Pau, Nolte, Ilja M., Rose, Lynda M., Rybin, Denis V., Sanna, Serena, Shi, Yuan, Stram, Daniel O., Takeuchi, Fumihiko, Tan, Shu Pei, van der Most, Peter J., Van Vliet-Ostaptchouk, Jana V., Wong, Andrew, Yengo, Loic, Zhao, Wanting, Goel, Anuj, Martinez Larrad, Maria Teresa, Radke, Dörte, Salo, Perttu, Tanaka, Toshiko, van Iperen, Erik P. A., Abecasis, Goncalo, Afaq, Saima, Alizadeh, Behrooz Z., Bertoni, Alain G., Bonnefond, Amelie, Böttcher, Yvonne, Bottinger, Erwin P., Campbell, Harry, Carlson, Olga D., Chen, Chien-Hsiun, Cho, Yoon Shin, Garvey, W. Timothy, Gieger, Christian, Goodarzi, Mark O., Grallert, Harald, Hamsten, Anders, Hartman, Catharina A., Herder, Christian, Hsiung, Chao Agnes, Huang, Jie, Igase, Michiya, Isono, Masato, Katsuya, Tomohiro, Khor, Chiea-Chuen, Kiess, Wieland, Kohara, Katsuhiko, Kovacs, Peter, Lee, Juyoung, Lee, Wen-Jane, Lehne, Benjamin, Li, Huaixing, Liu, Jianjun, Lobbens, Stephane, Luan, Jian'an, Lyssenko, Valeriya, Meitinger, Thomas, Miki, Tetsuro, Miljkovic, Iva, Moon, Sanghoon, Mulas, Antonella, Müller, Gabriele, Müller-Nurasyid, Martina, Nagaraja, Ramaiah, Nauck, Matthias, Pankow, James S., Polasek, Ozren, Prokopenko, Inga, Ramos, Paula S., Rasmussen-Torvik, Laura, Rathmann, Wolfgang, Rich, Stephen S., Robertson, Neil R., Roden, Michael, Roussel, Ronan, Rudan, Igor, Scott, Robert A., Scott, William R., Sennblad, Bengt, Siscovick, David S., Strauch, Konstantin, Sun, Liang, Swertz, Morris, Tajuddin, Salman M., Taylor, Kent D., Teo, Yik-Ying, Tham, Yih Chung, Tönjes, Anke, Wareham, Nicholas J., Willemsen, Gonneke, Wilsgaard, Tom, Hingorani, Aroon D., Egan, Josephine, Ferrucci, Luigi, Hovingh, G. Kees, Jula, Antti, Kivimaki, Mika, Kumari, Meena, Njølstad, Inger, Palmer, Colin N. A., Serrano Ríos, Manuel, Stumvoll, Michael, Watkins, Hugh, Aung, Tin, Blüher, Matthias, Boehnke, Michael, Boomsma, Dorret I., Bornstein, Stefan R., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chen, Yduan-Tsong, Cheng, Ching-Yu, Cucca, Francesco, de Geus, Eco J. C., Deloukas, Panos, Evans, Michele K., Fornage, Myriam, Friedlander, Yechiel, Froguel, Philippe, Groop, Leif, Gross, Myron D., Harris, Tamara B., Hayward, Caroline, Heng, Chew-Kiat, Ingelsson, Erik, Kato, Norihiro, Kim, Bong-Jo, Koh, Woon-Puay, Kooner, Jaspal S., Körner, Antje, Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lin, Xu, Liu, Yongmei, Loos, Ruth J. F., Magnusson, Patrik K. E., März, Winfried, McCarthy, Mark I., Oldehinkel, Albertine J., Ong, Ken K., Pedersen, Nancy L., Pereira, Mark A., Peters, Annette, Ridker, Paul M., Sabanayagam, Charumathi, Sale, Michele, Saleheen, Danish, Saltevo, Juha, Schwarz, Peter EH., Sheu, Wayne H. H., Snieder, Harold, Spector, Timothy D., Tabara, Yasuharu, Tuomilehto, Jaakko, van Dam, Rob M., Wilson, James G., Wilson, James F., Wolffenbuttel, Bruce H. R., Wong, Tien Yin, Wu, Jer-Yuarn, Yuan, Jian-Min, Zonderman, Alan B., Soranzo, Nicole, Guo, Xiuqing, Roberts, David J., Florez, Jose C., Sladek, Robert, Dupuis, Josée, Morris, Andrew P., Tai, E-Shyong, Selvin, Elizabeth, Rotter, Jerome I., Langenberg, Claudia, Barroso, Inês, and Meigs, James B.
Subjects: Genotypes -- Research, African Americans -- Analysis -- Health aspects, Type 2 diabetes -- Risk factors -- Diagnosis, Biological sciences
Abstract: Background Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. Methods & findings Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 x 10.sup.-29 ); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. Conclusions As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses., Author(s): Eleanor Wheeler 1, Aaron Leong 2,3, Ching-Ti Liu 4, Marie-France Hivert 5,6, Rona J. Strawbridge 7,8, Clara Podmore 9,10, Man Li 11,12,13, Jie Yao 14, Xueling Sim 15, Jaeyoung [...]
Published: 2017
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25. Rare and low-frequency coding variants alter human adult height

Author: Marouli, Eirini, Graff, Mariaelisa, Medina-Gomez, Carolina, Lo, Ken Sin, Wood, Andrew R., Kjaer, Troels R., Fine, Rebecca S., Lu, Yingchang, Schurmann, Claudia, Highland, Heather M., Reger, Sina, Thorleifsson, Gudmar, Justice, Anne E., Lamparter, David, Stirrups, Kathleen E., Turcot, Valrie, Young, Kristin L., Winkler, Thomas W., Esko, Tnu, Karaderi, Tugce, Locke, Adam E., Masca, Nicholas G. D., Ng, Maggie C. Y., Mudgal, Poorva, Rivas, Manuel A., Vedantam, Sailaja, Mahajan, Anubha, Guo, Xiuqing, Abecasis, Goncalo, Aben, Katja K., Adair, Linda S., Alam, Dewan S., Albrecht, Eva, Allin, Kristine H., Allison, Matthew, Amouyel, Philippe, Appel, Emil V., Arveiler, Dominique, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Banas, Bernhard, Bang, Lia E., Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blher, Matthias, Boeing, Heiner, Boerwinkle, Eric, Bger, Carsten A., Bonnycastle, Lori L., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Burt, Amber A., Butterworth, Adam S., Carey, David J., Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Galbany, Jordi Corominas, Cox, Amanda J., Cuellar-Partida, Gabriel, Danesh, John, Davies, Gail, de Bakker, Paul I. W., de Borst, Gert J., de Denus, Simon, de Groot, Mark C. H., de Mutsert, Rene, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., den Hollander, Anneke I., Dennis, Joe G., Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dunning, Alison M., Easton, Douglas F., Ebeling, Tapani, Edwards, Todd L., Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Faul, Jessica D., Feitosa, Mary F., Feng, Shuang, Ferrannini, Ele, Ferrario, Marco M., Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franks, Paul W., Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Giri, Ayush, Girotto, Giorgia, Gordon, Scott D., Gordon-Larsen, Penny, Gorski, Mathias, Grarup, Niels, Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Hayward, Caroline, He, Liang, Heid, Iris M., Heikkil, Kauko, Helgeland, yvind, Hernesniemi, Jussi, Hewitt, Alex W., Hocking, Lynne J., Hollensted, Mette, Holmen, Oddgeir L., Hovingh, G. Kees, Howson, Joanna M. M., Hoyng, Carel B., Huang, Paul L., Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Hkan, Jarvik, Gail P., Jensen, Gorm B., Jhun, Min A., Jia, Yucheng, Jiang, Xuejuan, Johansson, Stefan, Jrgensen, Marit E., Jrgensen, Torben, Jousilahti, Pekka, Jukema, J. Wouter, Kahali, Bratati, Kahn, Ren S., Khnen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Keeman, Renske, Kiemeney, Lambertus A., Kitajima, Hidetoshi, Kluivers, Kirsten B., Kocher, Thomas, Komulainen, Pirjo, Kontto, Jukka, Kooner, Jaspal S., Kooperberg, Charles, Kovacs, Peter, Kriebel, Jennifer, Kuivaniemi, Helena, Kry, Sbastien, Kuusisto, Johanna, La Bianca, Martina, Laakso, Markku, Lakka, Timo A., Lange, Ethan M., Lange, Leslie A., Langefeld, Carl D., Langenberg, Claudia, Larson, Eric B., Lee, I-Te, Lehtimki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindstrm, Jaana, Linneberg, Allan, Liu, Yeheng, Liu, Yongmei, Lophatananon, Artitaya, Luan, Jianan, Lubitz, Steven A., Lyytikinen, Leo-Pekka, Mackey, David A., Madden, Pamela A. F., Manning, Alisa K., Mnnist, Satu, Marenne, Galle, Marten, Jonathan, Martin, Nicholas G., Mazul, Angela L., Meidtner, Karina, Metspalu, Andres, Mitchell, Paul, Mohlke, Karen L., Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew D., Morris, Andrew P., Mller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Nauck, Matthias, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njlstad, Pl R., Nordestgaard, Brge G., Ntalla, Ioanna, OConnel, Jeffrey R., Oksa, Heikki, Loohuis, Loes M. Olde, Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Markus, Perry, James A., Perry, John R. B., Person, Thomas N., Pirie, Ailith, Polasek, Ozren, Posthuma, Danielle, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Renstrm, Frida, Ridker, Paul M., Rioux, John D., Robertson, Neil, Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sandow, Kevin, Sapkota, Yadav, Sattar, Naveed, Schmidt, Marjanka K., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati, Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S., Smith, Albert Vernon, Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Steinthorsdottir, Valgerdur, Stringham, Heather M., Stumvoll, Michael, Surendran, Praveen, t Hart, Leen M., Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorsteinsdottir, Unnur, Thuesen, Betina H., Tnjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, Andr G., Ulivi, Sheila, van der Laan, Sander W., Van Der Leij, Andries R., van Duijn, Cornelia M., van Schoor, Natasja M., van Setten, Jessica, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Edwards, Digna R. Velez, Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vozzi, Diego, Walker, Mark, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Wareham, Nicholas J., Warren, Helen R., Wessel, Jennifer, Willems, Sara M., Wilson, James G., Witte, Daniel R., Woods, Michael O., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Rotter, Jerome I, Boehnke, Michael, Kathiresan, Sekar, McCarthy, Mark I., Willer, Cristen J., Stefansson, Kari, Borecki, Ingrid B., Liu, Dajiang J., North, Kari E., Heard-Costa, Nancy L., Pers, Tune H., Lindgren, Cecilia M., Oxvig, Claus, Kutalik, Zoltn, Rivadeneira, Fernando, Loos, Ruth J. F., Frayling, Timothy M., Hirschhorn, Joel N., Deloukas, Panos, and Lettre, Guillaume
Subjects: Body height -- Genetic aspects, Genetic variation -- Observations, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.14.8%) and effects of up to 2centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 12centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways., Author(s): Eirini Marouli [1]; Mariaelisa Graff [2]; Carolina Medina-Gomez [3, 4]; Ken Sin Lo [5]; Andrew R. Wood [6]; Troels R. Kjaer [7]; Rebecca S. Fine [8, 9, 10]; Yingchang [...]
Published: 2017
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26. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity

Author: Wahl, Simone, Drong, Alexander, Lehne, Benjamin, Loh, Marie, Scott, William R., Kunze, Sonja, Tsai, Pei-Chien, Ried, Janina S., Zhang, Weihua, Yang, Youwen, Tan, Sili, Fiorito, Giovanni, Franke, Lude, Guarrera, Simonetta, Kasela, Silva, Kriebel, Jennifer, Richmond, Rebecca C., Adamo, Marco, Afzal, Uzma, Ala-Korpela, Mika, Albetti, Benedetta, Ammerpohl, Ole, Apperley, Jane F., Beekman, Marian, Bertazzi, Pier Alberto, Black, S. Lucas, Blancher, Christine, Bonder, Marc-Jan, Brosch, Mario, Carstensen-Kirberg, Maren, de Craen, Anton J. M., de Lusignan, Simon, Dehghan, Abbas, Elkalaawy, Mohamed, Fischer, Krista, Franco, Oscar H., Gaunt, Tom R., Hampe, Jochen, Hashemi, Majid, Isaacs, Aaron, Jenkinson, Andrew, Jha, Sujeet, Kato, Norihiro, Krogh, Vittorio, Laffan, Michael, Meisinger, Christa, Meitinger, Thomas, Mok, Zuan Yu, Motta, Valeria, Ng, Hong Kiat, Nikolakopoulou, Zacharoula, Nteliopoulos, Georgios, Panico, Salvatore, Pervjakova, Natalia, Prokisch, Holger, Rathmann, Wolfgang, Roden, Michael, Rota, Federica, Rozario, Michelle Ann, Sandling, Johanna K., Schafmayer, Clemens, Schramm, Katharina, Siebert, Reiner, Slagboom, P. Eline, Soininen, Pasi, Stolk, Lisette, Strauch, Konstantin, Tai, E-Shyong, Tarantini, Letizia, Thorand, Barbara, Tigchelaar, Ettje F., Tumino, Rosario, Uitterlinden, Andre G., van Duijn, Cornelia, van Meurs, Joyce B. J., Vineis, Paolo, Wickremasinghe, Ananda Rajitha, Wijmenga, Cisca, Yang, Tsun-Po, Yuan, Wei, Zhernakova, Alexandra, Batterham, Rachel L., Smith, George Davey, Deloukas, Panos, Heijmans, Bastiaan T., Herder, Christian, Hofman, Albert, Lindgren, Cecilia M., Milani, Lili, van der Harst, Pim, Peters, Annette, Illig, Thomas, Relton, Caroline L., Waldenberger, Melanie, Jrvelin, Marjo-Riitta, Bollati, Valentina, Soong, Richie, Spector, Tim D., Scott, James, McCarthy, Mark I., Elliott, Paul, Bell, Jordana T., Matullo, Giuseppe, Gieger, Christian, Kooner, Jaspal S., Grallert, Harald, and Chambers, John C.
Subjects: Epigenetic inheritance -- Health aspects, Obesity -- Genetic aspects, Genome-wide association studies, Body mass index -- Genetic aspects -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): Simone Wahl [1, 2, 3]; Alexander Drong [4]; Benjamin Lehne [5]; Marie Loh [5, 6, 7]; William R. Scott [5, 8]; Sonja Kunze [1, 2]; Pei-Chien Tsai [9]; Janina [...]
Published: 2017
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27. Genome-wide association scans for Type 2 diabetes: new insights into biology and therapy

Author: McCarthy, Mark I. and Zeggini, Eleftheria
Subjects: Biological sciences, Chemistry, Pharmaceuticals and cosmetics industries
Abstract: Type 2 diabetes is a complex, multifactorial disease, for which genetic and environmental factors jointly determine susceptibility. Disentangling the genetic aetiology of Type 2 diabetes has proven a challenging task, rewarded, until recently, with only limited success. However, the field of Type 2 diabetes genetics has been transformed over the past few months, with the publication of six genome-wide association scans, leading to the establishment of novel genomic regions that harbour disease susceptibility loci. Here, we provide an overview of the main recent findings and discuss their significance in providing biological insights and their translational implications.
Published: 2007

28. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Author: Burton, Paul R., Clayton, David G., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Todd, John A., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Stevens, Helen E., Taylor, Niall C., Walters, Graham R., Walker, Neil M., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Ferrier, I. Nicol, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Mohiuddin, M. Khalid, Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Marcano, Carolina A. Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Mohammed J. R., Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, and Compston, Alistair
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): The Wellcome Trust Case Control Consortium; Management Committee; Paul R. Burton [1]; David G. Clayton [2]; Lon R. Cardon [3]; Nick Craddock [4]; Panos Deloukas [5]; Audrey Duncanson [6]; [...]
Published: 2007
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29. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Author: Burton, Paul R., Clayton, David G., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Todd, John A., Barrett, Jeffrey C., Davison, Dan, Donnelly, Peter, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Stevens, Helen E., Taylor, Niall C., Walters, Graham R., Walker, Neil M., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, Caesar, Sian, Gordon-Smith, Katherine, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, Young, Allan H., Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Barbour, Jamie, Mohiuddin, M. Khalid, Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Brown, Morris J., Connell, John, Marcano, Carolina A. Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Lyons, Emily, Vannberg, Fredrik, Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Mohammed J. R., Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, Caulfield, Mark, Compston, Alistair, Farrall, Martin, Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., and Parkes, Miles
Subjects: Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract: Author(s): The Wellcome Trust Case Control Consortium; Management Committee; Paul R. Burton [1]; David G. Clayton [2]; Lon R. Cardon [3]; Nick Craddock [4]; Panos Deloukas [5]; Audrey Duncanson [6]; [...]
Published: 2007
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30. Type 2 diabetes TCF7L2 risk genotypes alter birth weight: A study of 24, 053 individuals

Author: Freathy, Rachel M., Weedon, Micahel N., Bennett, Amanda, Hypponen, Elina, Ben-Shlomo, Yoav, Strachan, David P., Power, Chris, Jarvelin, Marjo-Riitta, McCarthy, Mark I., Smith, George Davey, Hattersley, Andrew T., Frayling, Timothy M., Relton, Caroline L., Knight, Beatrice, Shields, Beverley, Parnell, Kirstie S., Groves, Christopher J., Ring, Susan M., and Pembrey, Marcus E.
Subjects: Type 2 diabetes -- Genetic aspects, Type 2 diabetes -- Research, Genotype -- Research, Birth size -- Research, Birth weight -- Research, Biological sciences
Abstract: A hypothesis that fetal TCF7L2 type-2 diabetes predisposing genotypes at rs7903146 and rs12255372 would be associated with reduced birth weight was investigated in individuals from six population-based studies. The first type-2 diabetes susceptibility allele was identified and found to be reproducibly associated with birth weight and common gene variants were found to substantially influence normal birth weight variation.
Published: 2007

31. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes

Author: Zeggini, Eleftheria, Weedon, Michael N., Lindgren, Cecilia M., Frayling, Timothy M., Elliott, Katherine S., Lango, Hana, Timpson, Nicholas J., Perry, John R.B., Rayner, Nigel W., Freathy, Rachel M., Barrett, Jeffrey C., Shields, Beverley, Morris, Andrew P., Ellard, Sian, Groves, Christopher J., Harries, Lorna W., Marchini, Jonathan L., Owen, Katharine R., Knight, Beatrice, Cardon, Lon R., Walker, Mark, Hitman, Graham A., Morris, Andrew D., Doney, Alex S.F., McCarthy, Mark I., and Hattersley, Andrew T.
Subjects: Type 2 diabetes -- Research, Type 2 diabetes -- Risk factors, Type 2 diabetes -- Genetic aspects
Published: 2007

32. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity

Author: Frayling, Timothy M., Timpson, Nicholas J., Weedon, Michael N., Zeggini, Eleftheria, Freathy, Rachel M., Lindgren, Cecilia M., Perry, John R.B., Elliott, Katherine S., Lango, Hana, Rayner, Nigel W., Shields, Beverley, Harries, Lorna W., Barrett, Jeffrey C., Ellard, Sian, Groves, Christopher J., Knight, Bridget, Patch, Ann-Marie, Ness, Andrew R., Ebrahim, Shah, Lawlor, Debbie A., Ring, Susan M., Ben-Shlomo, Yoav, Jarvelin, Marjo-Riitta, Sovio, Ulla, Bennett, Amanda J., Melzer, David, Ferrucci, Luigi, Loos, Ruth J.F., Barroso, Ines, Wareham, Nicholas J., Karpe, Fredrik, Owen, Katharine R., Cardon, Lon R., Walker, Mark, Hitman, Graham A., Palmer, Colin N.A., Doney, Alex S.F., Morris, Andrew D., Smith, George Davey, Hattersley, Andrew T., and McCarthy, Mark I.
Subjects: Obesity gene -- Research, Body mass index -- Research
Published: 2007

33. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice

Author: Dumas, Marc-Emmanuel, Barton, Richard H., Toye, Ayo, Cloarec, Olivier, Blancher, Christine, Rothwell, Alice, Fearnside, Jane, Tatoud, Roger, Blanc, Veronique, Lindon, John C., Mitchell, Steve C., Holmes, Elaine, McCarthy, Mark I., Scott, James, Gauguier, Dominique, and Nicholson, Jeremy K.
Subjects: Metabonomic analysis -- Usage, Nuclear magnetic resonance -- Usage, Liver diseases -- Genetic aspects, Liver diseases -- Research, Science and technology
Abstract: Here, we study the intricate relationship between gut microbiota and host cometabolic phenotypes associated with dietary-induced impaired glucose homeostasis and nonalcoholic fatty liver disease (NAFLD) in a mouse strain (129S6) known to be susceptible to these disease traits, using plasma and urine metabotyping, achieved by 1H NMR spectroscopy. Multivariate statistical modeling of the spectra shows that the genetic predisposition of the 129S6 mouse to impaired glucose homeostasis and NAFLD is associated with disruptions of choline metabolism, i.e., low circulating levels of plasma phosphatidylcholine and high urinary excretion of methylamines (dimethylamine, trimethylamine, and trimethylamine-Noxide), coprocessed by symbiotic gut microbiota and mammalian enzyme systems. Conversion of choline into methylamines by microbiota in strain 129S6 on a high-fat diet reduces the bioavailability of choline and mimics the effect of choline-deficient diets, causing NAFLD. These data also indicate that gut microbiota may play an active role in the development of insulin resistance. metabonomics | NMR | nonalcoholic fatty liver disease | nutritional genomics | metabolic syndrome
Published: 2006

34. Nitrogen fixation and dissimilatory nitrate reduction to ammonium (DNRA) support nitrogen dynamics in Texas estuaries

Author: Gardner, Wayne S., McCarthy, Mark J., An, Soonmo, Sobolev, Dmitri, Sell, Karen S., and Brock, David
Subjects: Estuaries -- Environmental aspects, Nitrogen -- Fixation, Nitrogen -- Environmental aspects, Earth sciences
Abstract: We conducted continuous-flow experiments on intact sediment cores from Laguna Madre, Sabine Lake, East Matagorda Bay, and Nueces Estuary to evaluate internal nitrogen (N) sources, sinks, and retention mechanisms in Texas estuaries having different salinities. Mean ammonium (N[H.sup.+.sub.4]) flux ranged from slight uptake (negative values) to N[H.sup.+.sub.4] production rates of about 300 [micro]mol [m.sup.-2] [h.sup.-1] (units used for all N rates) and increased with salinity (p = 0.10). Net nitrate (N[O.sup.-.sub.3]) flux (-20 to 32) and net [N.sub.2], flux (-70 to 100) did not relate to salinity. Mean net [N.sub.2] flux was positive but near zero, indicating that N, sources and sinks are nearly balanced. Total denitrification, N fixation, and potential dissimilatory N[O.sup.-.sub.3] reduction to N[H.sup.+.sub.4] (DNRA) rates were estimated after inflow water was enriched with [sup.15]N[O.sup.-.sub.3], (100 [micro]mol [L.sup.-1]). Total denitrification rates ranged from 0 to 90 versus N fixation rates ranging from 0 to 97. Potential DNRA, measured conservatively as [sup.15]N[H.sup.+.sub.4] accumulation, ranged from 0 to 80 and related significantly to salinity (p < 0.01). Increases in total N[H.sup.+.sub.4] release after [sup.15]N[O.sup.-.sub.3], additions were higher but closely related (r = 0.9998) to [sup.15]N[H.sup.+.sub.4] accumulation, implying exchange reactions of DNRA-regenerated [sup.15]N[H.sup.+.sub.4] with sediment-bound [sup.15]N[H.sup.+.sub.4]. The fate of N[O.sup.-.sub.3] was related to salinity, perhaps via sulfide effects on DNRA. Potential DNRA was high in southeastern Corpus Christi Bay in August during hypoxia when the sulfide transition zone was near the sediment surface. Nitrogen fixation and DNRA are important mechanisms that add and retain available N in Texas estuaries.
Published: 2006

35. Genetic epidemiology 5: what makes a good genetic association study?

Author: Hattersley, Andrew T. and McCarthy, Mark I.
Subjects: Epidemiology -- Genetic aspects, Epidemiologic methods -- Analysis
Published: 2005

36. What makes a good genetic association study?

Author: Hattersley, Andrew T. and McCarthy, Mark I.
Subjects: Genetic susceptibility -- Health aspects, Genetic susceptibility -- Research, Genetic variation -- Research
Published: 2005

37. Mutations in HNF1A result in marked alterations of plasma glycan profile

Author: Thanabalasingham, Gaya, Huffman, Jennifer E., Kattla, Jayesh J., Novokmet, Mislav, Rudan, Igor, Gloyn, Anna L., Hayward, Caroline, Adamczyk, Barbara, Reynolds, Rebecca M., Muzinic, Ana, Hassanali, Neelam, Pucic, Maja, Bennett, Amanda J., Essafi, Abdelkader, Polasek, Ozren, Mughal, Saima A., Redzic, Irma, Primorac, Dragan, Zgaga, Lina, Kolcic, Ivana, Hansen, Torben, Gasperikova, Daniela, Tjora, Erling, Strachan, Mark W.J., Nielsen, Trine, Stanik, Juraj, Klimes, Iwar, Pedersen, Oluf B., Njolstad, Pal R., Wild, Sarah H., Gyllensten, Ulf, Gornik, Olga, Wilson, James F., Hastie, Nicholas D., Campbell, Harry, McCarthy, Mark I., Rudd, Pauline M., Owen, Katharine R., Lauc, Gordan, and Wright, Alan F.
Subjects: Gene mutations -- Physiological aspects -- Research, Diabetes -- Risk factors -- Genetic aspects -- Diagnosis -- Research, Biological markers -- Physiological aspects -- Genetic aspects -- Research, Health
Abstract: A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic [greater than or equal to]0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction., Genome-wide association studies are providing novel insights into the genetic architecture and biological basis of many diseases, but immediate translation into clinical practice has been limited. We recently performed a [...]
Published: 2013
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38. Insights into the molecular mechanism for type 2 diabetes susceptibility at the KCNQ1 locus from temporal changes m imploring stares in human islets

Author: Travers, Mary E., Mackay, Deborah J.G., Nitert, Marloes Dekker, Morris, Andrew P., Lindgren, Cecilia M., Berry, Andrew, Johnson, Paul R., Hanley, Neil, Groop, Left C., McCarthy, Mark I., and Gloyn, Anna L.
Subjects: Type 2 diabetes -- Research -- Analysis -- Genetic aspects, Health
Abstract: The molecular basis of type 2 diabetes predisposition at most established susceptibility loci remains poorly understood. KCNQ1 maps within the 11p15.5 imprinted domain, a region with an established role in congenital growth phenotypes. Variants intronic to KCNQ1 influence diabetes susceptibility when maternally inherited. By use of quantitative PCR and pyrosequencing of human adult islet and fetal pancreas samples, we investigated the imprinting status of regional transcripts and aimed to determine whether type 2 diabetes risk alleles influence regional DNA methylation and gene expression. The results demonstrate that gene expression patterns differ by developmental stage. CDKNIC showed monoallelic expression in both adult and fetal tissue, whereas PHLDA2, SLC22A18, and SLC22A18AS were biallelically expressed in both tissues. Temporal changes in imprinting were observed for KCNQ1 and KCNQIOT1, with monoallelic expression in fetal tissues and biallelic expression in adult samples. Genotype at the type 2 diabetes risk variant rs2237895 influenced methylation levels of regulatory sequence in fetal pancreas but without demonstrable effects on gene expression. We demonstrate that CDKN1C, KCNQ1, andKCNQIOT1 are most likely to mediate diabetes susceptibility at the KCNQ1 locus and identify temporal differences in imprinting status and methylation effects, suggesting that diabetes risk effects may be mediated in early development., The translation of established type 2 diabetes risk variants into an improved understanding of disease pathology is challenging. Progress has been made primarily at the few loci where causal alleles [...]
Published: 2013
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39. Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21

Author: Tabassum, Rubina, Chauhan, Ganesh, Dwivedi, Om Prakash, Mahajan, Anubha, Jaiswal, Alok, Kaur, Ismeet, Bandesh, Khushdeep, Singh, Tejbir, Mathai, Benan John, Pandey, Yogesh, Chidambaram, Manickam, Sharma, Amitabh, Chavali, Sreenivas, Sengupta, Shantanu, Ramakrishnan, Lakshmi, Venkatesh, Pradeep, Aggarwal, Sanjay K., Ghosh, Saurabh, Prabhakaran, Dorairaj, Srinath, Reddy K., Saxena, Madhukar, Banerjee, Monisha, Mathur, Sandeep, Bhansali, Anti, Shah, Viral N., Madhu, Sri Venkata, Marwaha, Raman K., Basu, Analabha, Scaria, Vinod, McCarthy, Mark I., Venkatesan, Radha, Mohan, Viswanathan, Tandon, Nikhil, and Bharadwaj, Dwaipayan
Subjects: Type 2 diabetes -- Research -- Demographic aspects -- Genetic aspects, Health
Abstract: Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 x [10.sup.-9]). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 x [10.sup.-12]) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D., Type 2 diabetes (T2D) has developed into a major health problem, responsible for early morbidities and mortality that affects over a billion people worldwide (1). Developing countries such as India [...]
Published: 2013
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40. Estimation and testing of parent-of-origin effects for quantitative traits. (Report)

Author: Whittaker, John C., Gharani, Neda, Hindmarsh Peter, and McCarthy, Mark I.
Subjects: Phenotype -- Research, Phenotype -- Genetic aspects, Biological sciences
Published: 2003

41. On Walkers

Author: McCarthy, Mark
Subjects: The Walking Dead and Philosophy: Zombie Apocalypse Now (Nonfiction work) -- Wayne Yuen -- Book reviews, Books -- Book reviews, Literature/writing
Abstract: On Walkers. Wayne Yuen, ed. The Walking Dead and Philosophy: Zombie Apocalypse Now. Chicago, IL: Open Court, 2012. 288 pp. ISBN 9780812697674. $19.95 pbk. Some of philosophy's most enduring questions [...]
Published: 2014
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42. Evaluating the results of genomewide linkage scans of complex traits by locus counting. (Report)

Author: Wiltshire, Steven, Cardon, Lon R., and McCarthy, Mark I.
Subjects: Genetic disorders -- Research, Human genetics -- Research, Genetic research -- Analysis, Biological sciences
Published: 2002

43. Genetic approaches to the molecular understanding of type 2 diabetes

Author: McCarthy, Mark I. and Froguel, Philippe
Subjects: Type 2 diabetes -- Genetic aspects, Linkage (Genetics) -- Analysis, Molecular genetics -- Research, Biological sciences
Abstract: The appreciation that individual susceptibility to type 2 diabetes (T2D) and related components of the dysmetabolic syndrome has a strong inherited component provides a coherent framework within which to develop a molecular understanding of the pathogenesis of T2D. This review focuses on the main approaches currently adopted by researchers seeking to identify the inherited basis of T2D and the present state of our knowledge. One central theme that emerges is that progress in defining the genetic basis of the common, multi-factorial forms of T2D is hindered by etiological heterogeneity: T2D is likely to represent the final common pathway of diverse interacting primary disturbances. Such heterogeneity equally compromises efforts to understand the basis for T2D by use of other approaches, such as cellular biochemistry and classical physiology. Analyses that seek to ally sophisticated physiological characterization with measures of genomic variation are likely to provide powerful tools for redressing the loss of power associated with such heterogeneity. linkage; linkage disequilibrium; susceptibility genes; positional cloning
Published: 2002

44. Evidence for linkage of stature to chromosome 3p26 in a large U.K. family data set ascertained for type 2 diabetes. (Report)

Author: Wiltshire, Steven, Frayling, Timothy M., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Levy, Jonathan C., O'Rahilly, Stephen, Groves, Christopher J., Menzel, Stephan, Cardon, Lon R., and McCarthy, Mark I.
Subjects: United Kingdom -- Research, Stature -- Genetic aspects, Linkage (Genetics) -- Research, Biological sciences
Published: 2002

45. Classification of financial instruments with characteristics of both debt and equity: evidence concerning convertible redeemable preferred stock

Author: McCarthy, Mark G. and Schneider, Douglas K.
Subjects: Financial instruments -- Analysis, Preferred stocks -- Analysis, Capital stock -- Analysis, Business
Abstract: ABSTRACT This study examines the market perception of a compound financial instrument, convertible redeemable preferred stock (CRPS). CRPS has the form of preferred stock, but also possesses a redemption feature [...]
Published: 2001

46. Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes

Author: Rosengren, Anders H., Braun, Matthias, Mahdi, Taman, Andersson, Sofia A., Travers, Mary E., Shigeto, Makoto, Zhang, Enming, Almgren, Peter, Ladenvall, Claes, Axelsson, Annika S., Edlund, Anna, Pedersen, Morten Gram, Jonsson, Anna, Ramracheya, Reshma, Tang, Yunzhao, Walker, Jonathan N., Barrett, Amy, Johnson, Paul R.V., Lyssenko, Valeriya, McCarthy, Mark I., Groop, Leif, Salehi, Albert, Gloyn, Anna L., Renstrom, Erik, Rorsman, Patrik, and Eliasson, Lena
Subjects: Pancreatic beta cells -- Research -- Genetic aspects -- Physiological aspects, Type 2 diabetes -- Research -- Genetic aspects, Health
Abstract: The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet traction remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis, and structure. Variants near TCFTL2 and ADRA2A were associated with reduced glucose-induced insulin secretion, whereas susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCFTL2 were associated with reduced depolarization-evoked insulin exocytosis. KCNQ1, ADRA2A, KCNJ11, HHEX/IDE, and SLC2A2 variants affected granule docking. We combined our results to create a novel genetic risk score for β-cell dysfunction that includes aberrant granule docking, decreased [Ca.sup.2+] sensitivity of exocytosis, and reduced insulin release. Individuals with a high risk score displayed an impaired response to intravenous glucose and deteriorating insulin secretion over time. Our results underscore the importance of defects in β-cell exocytosis in T2D and demonstrate the potential of cellular phenotypic characterization in the elucidation of complex genetic disorders. Diabetes 61:1726-1733, 2012, The rapid increase in type 2 diabetes (T2D) incidence results from a combination of lifestyle factors and genetics. Recent genome-wide association studies have identified close to 50 loci associated with [...]
Published: 2012
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47. Systematic assessment of etiology in adults with a clinical diagnosis of young-onset type 2 diabetes is a successful strategy for identifying maturity-onset diabetes of the young

Author: Thanabalasingham, Gaya, Pal, Aparna, Selwood, Mary P., Dudley, Christina, Fisher, Karen, Bingley, Polly J., Ellard, Sian, Farmer, Andrew J., McCarthy, Mark I., and Owen, Katharine R.
Subjects: Diabetes -- Research -- Genetic aspects -- Development and progression, Adults, Type 2 diabetes -- Research -- Genetic aspects -- Development and progression, Genetic screening, Health, European Association for the Study of Diabetes
Abstract: OBJECTIVE--Misdiagnosis of maturity-onset diabetes of the young (MODY) remains widespread, despite the benefits of optimized management. This cross-sectional study examined diagnostic misclassification of MODY in subjects with clinically labeled young [...]
Published: 2012
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48. Association of genetic loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children

Author: Barker, Adam, Sharp, Stephen J., Timpson, Nicholas J., Bouatia-Naji, Nabila, Warrington, Nicole M., Kanoni, Stavroula, Beilin, Lawrence J., Brage, Soren, Deloukas, Panos, Evans, David M., Grontved, Anders, Hassanali, Neelam, Lawlor, Deborah A., Lecoeur, Cecile, Loos, Ruth J.F., Lye, Stephen J., McCarthy, Mark I., Mori, Trevor A., Ndiaye, Ndeye Coumba, Newnham, John P., Ntalla, Ioanna, Pennell, Craig E., St Pourcain, Beate, Prokopenko, Inga, Ring, Susan M., Sattar, Naveed, Visvikis-Siest, Sophie, Dedoussis, George V., Palmer, Lyle J., Froguel, Philippe, Smith, George Davey, Ekelund, Ulf, Wareham, Nicholas J., and Langenberg, Claudia
Subjects: Genetic variation -- Health aspects -- Research, Insulin -- Health aspects -- Genetic aspects -- Research, Blood sugar -- Health aspects -- Genetic aspects -- Research, Health
Abstract: OBJECTIVE--To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents. RESEARCH DESIGN AND METHODS--A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS--Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced β-cell function, as indicated by homeostasis model assessment of β-cell function. Analysis using a weighted risk score showed an increase β (95% CI)] in fasting glucose level of 0.026 mmol/L (0.021-0.031) for each unit increase in the score. CONCLUSIONS--Novel fasting glucose loci identified in genomewide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards. Diabetes 60:1805-1812, 2011, Fasting glucose levels in humans are tightly regulated within a narrow homeostatic range; elevated glucose levels are a sign of reduced insulin secretion or action and are used to test [...]
Published: 2011
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49. A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium

Author: Kraja, Aldi T., Vaidya, Dhananjay, Pankow, James S., Goodarzi, Mark O., Assimes, Themistocles L., Kullo, Iftikhar J., Sovio, Ulla, Mathias, Rasika A., Sun, Yan V., Franceschini, Nora, Absher, Devin, Li, Guo, Zhang, Qunyuan, Feitosa, Mary F., Glazer, Nicole L., Haritunians, Talin, Hartikainen, Anna-Liisa, Knowles, Joshua W., North, Kari E., Iribarren, Carlos, Kral, Brian, Yanek, Lisa, OReilly, Paul F., McCarthy, Mark I., Jaquish, Cashell, Couper, David J., Chakravarti, Aravinda, Psaty, Bruce M., Becker, Lewis C., Province, Michael A., Boerwinkle, Eric, Quertermous, Thomas, Palotie, Leena, Jarvelin, Marjo-Rutta, Becker, Diane M., Kardia, Sharon L.R., Rotter, Jerome I., Chen, Yii-Der Ida, and Borecki, Ingrid B.
Subjects: Metabolic syndrome X -- Complications and side effects -- Genetic aspects -- Research, Genetic variation -- Health aspects -- Research, Health
Abstract: OBJECTIVE--The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS--Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ~2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS--Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNRIB, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from -9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS--Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants. Diabetes 60:1329-1339, 2011, Metabolicsyndrome (MetS) is defined as a combination of any three metabolic abnormalities, including central obesity, dyslipidemia, insulin resistance and/or glucose intolerance, and elevated blood pressure. These abnormalities tend to cluster [...]
Published: 2011
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50. Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance

Author: De Silva, N. Maneka G., Freathy, Rachel M., Palmer, Tom M., Donnelly, Louise A., Luan, Jian'an, Gaunt, Tom, Langenberg, Claudia, Weedon, Michael N., Shields, Beverley, Knight, Beatrice A., Ward, Kirsten J., Sandhu, Manjinder S., Harbord, Roger M., McCarthy, Mark I., Smith, George Davey, Ebrahim, Shah, Hattersley, Andrew T., Wareham, Nicholas, Lawlor, Debbie A., Morris, Andrew D., Palmer, Colin N.A., and Frayling, Timothy M.
Subjects: Genes -- Physiological aspects -- Research, Insulin resistance -- Genetic aspects -- Risk factors -- Research, Triglycerides -- Physiological aspects -- Research, Type 2 diabetes -- Genetic aspects -- Risk factors -- Research, Health
Abstract: OBJECTIVE--The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance. RESEARCH DESIGN AND METHODS--We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies. RESULTS--Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in [log.sub.10] triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002). CONCLUSIONS--Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal., Raised circulating triglyceride levels are strongly correlated with insulin resistance, raised glucose levels, and type 2 diabetes (1-8), but the causal nature of these associations is unclear because of the [...]
Published: 2011
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