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1. No evidence of association between either Modic change or disc degeneration and five circulating inflammatory proteins.

Author

Compte, Roger, Freidin, Maxim B., Granville Smith, Isabelle, Le Maitre, Christine L., Vaitkute, Dovile, Nessa, Ayrun, Lachance, Genevieve, and Williams, Frances M. K.

Subjects
CHRONIC pain, BLOOD proteins, BODY mass index, BLOOD circulation, INTERVERTEBRAL disk
Abstract

Introduction: Intervertebral disc degeneration and Modic change are the main spinal structural changes associated with chronic low back pain (LBP). Both conditions are thought to manifest local inflammation and if inflammatory proteins translocate to the blood circulation could be detected systemically. The work here assesses whether the presence of disc degeneration is associated with detectable blood level changes of five inflammatory markers and whether chronic LBP is associated with these changes. Materials and Methods: Two hundred and forty TwinsUK cohort participants with both MRI disc degeneration grade and Modic change extent, and IL‐6, IL‐8, IL‐8 TNF, and CX3CL1 protein blood concentration measurements were included in this work. Linear mixed effects models were used to test the association of blood cytokine concentration with disc degeneration score and Modic change volumetric score. Association of chronic LBP status from questionnaires with disc degeneration, Modic change, and cytokine blood concentration was also tested. Results: No statistically significant association between disc degeneration or Modic change with cytokine blood concentration was found. Instead, regression analysis pointed strong association between cytokine blood concentration with body mass index for IL‐6 and with age for IL‐6 and TNF. Mild association was found between IL‐8 blood concentration and body mass index. Additionally, LBP status was associated with Modic change volumetric score but not associated with any cytokine concentration. Conclusions: We found no evidence that Modic change and disc degeneration are able to produce changes in tested blood cytokine concentration. However, age and body mass index have strong influence on cytokine concentration and both are associated with the conditions studied which may confound associations found in the literature. It is then unlikely that cytokines produced in the disc or vertebral bone marrow induce chronic LBP. [ABSTRACT FROM AUTHOR]

Published
2024
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4. The UK10K project identifies rare variants in health and disease

Author

Walter, Klaudia, Min, Josine L., Huang, Jie, Crooks, Lucy, Memari, Yasin, Perry, John R. B., Xu, ChangJiang, Futema, Marta, Lawson, Daniel, Iotchkova, Valentina, Schiffels, Stephan, Hendricks, Audrey E., Danecek, Petr, Li, Rui, Floyd, James, Wain, Louise V., Humphries, Steve E., Barrett, Jeffrey C., Bala, Senduran, Clapham, Peter, Coates, Guy, Cox, Tony, Daly, Allan, Du, Yuanping, Edkins, Sarah, Ellis, Peter, Flicek, Paul, Guo, Xiaosen, Guo, Xueqin, Huang, Liren, Jackson, David K., Joyce, Chris, Keane, Thomas, Kolb-Kokocinski, Anja, Langford, Cordelia, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Maslen, John, McCarthy, Shane, (co-chair), Muddyman, Dawn, Quail, Michael A., Stalker, Jim, (co-chair), Sun, Jianping, Tian, Jing, Wang, Guangbiao, Wang, Jun, Wang, Yu, Wong, Kim, Zhang, Pingbo, Birney, Ewan, Boustred, Chris, Chen, Lu, Clement, Gail, Cocca, Massimiliano, Smith, George Davey, Day, Ian N. M., Day-Williams, Aaron, Down, Thomas, Dunham, Ian, Evans, David M., Gaunt, Tom R., Geihs, Matthias, Hart, Deborah, Howie, Bryan, Hubbard, Tim, Hysi, Pirro, Jamshidi, Yalda, Karczewski, Konrad J., Kemp, John P., Lachance, Genevieve, Lek, Monkol, Lopes, Margarida, MacArthur, Daniel G., Marchini, Jonathan, Mangino, Massimo, Mathieson, Iain, Metrustry, Sarah, Moayyeri, Alireza, Northstone, Kate, Panoutsopoulou, Kalliope, Paternoster, Lavinia, Quaye, Lydia, Richards, Brent J., (co-chair), Ring, Susan, Ritchie, Graham R. S., Shihab, Hashem A., Shin, So-Youn, Small, Kerrin S., Artigas, María Soler, Soranzo, Nicole, (co-chair), Southam, Lorraine, Spector, Timothy D., St Pourcain, Beate, Surdulescu, Gabriela, Tachmazidou, Ioanna, Timpson, Nicholas J., (co-chair), Tobin, Martin D., Valdes, Ana M., Visscher, Peter M., Ward, Kirsten, Wilson, Scott G., Yang, Jian, Zhang, Feng, Zheng, Hou-Feng, Anney, Richard, Ayub, Muhammad, Blackwood, Douglas, Bolton, Patrick F., Breen, Gerome, Collier, David A., Craddock, Nick, Curran, Sarah, Curtis, David, Gallagher, Louise, Geschwind, Daniel, Gurling, Hugh, Holmans, Peter, Lee, Irene, Lönnqvist, Jouko, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Morris, James, OʼDonovan, Michael C., Owen, Michael J., (co-chair), Palotie, Aarno, (co-chair), Parr, Jeremy R., Paunio, Tiina, Pietilainen, Olli, Rehnström, Karola, Sharp, Sally I., Skuse, David, St Clair, David, Suvisaari, Jaana, Walters, James T. R., Williams, Hywel J., Barroso, Inês, (co-chair), Bochukova, Elena, Bounds, Rebecca, Dominiczak, Anna, Farooqi, Sadaf I., (co-chair), Keogh, Julia, Marenne, Gaëlle, Morris, Andrew, OʼRahilly, Stephen, Porteous, David J., Smith, Blair H., Wheeler, Eleanor, Al Turki, Saeed, Anderson, Carl A., Antony, Dinu, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Fitzpatrick, David R., (co-chair), Foley, Reghan A., Franklin, Christopher S., Grozeva, Detelina, Hurles, Matthew E., (co-chair), Mitchison, Hannah M., Muntoni, Francesco, Onoufriadis, Alexandros, Parker, Victoria, Payne, Felicity, Raymond, Lucy F., Roberts, Nicola, Savage, David B., Scambler, Peter, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Spasic-Boskovic, Olivera, Stevens, Elizabeth, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Williamson, Kathleen A., Wilson, Crispian, Whyte, Tamieka, Ciampi, Antonio, Greenwood, Celia M. T., (co-chair), Oualkacha, Karim, Zeggini, Eleftheria, (co-chair), Bobrow, Martin, Griffin, Heather, Kaye, Jane, (co-chair), Kennedy, Karen, Kent, Alastair, Smee, Carol, Charlton, Ruth, Ekong, Rosemary, Khawaja, Farrah, Lopes, Luis R., Migone, Nicola, Payne, Stewart J., Plagnol, Vincent, (chair), Pollitt, Rebecca C., Povey, Sue, Ridout, Cheryl K., Robinson, Rachel L., Scott, Richard H., Shaw, Adam, Syrris, Petros, Taylor, Rohan, Vandersteen, Anthony M., Durbin, Richard, (chair), Amuzu, Antoinette, Casas, Juan Pablo, Chambers, John C., Dedoussis, George, Gambaro, Giovanni, Gasparini, Paolo, Isaacs, Aaron, Johnson, Jon, Kleber, Marcus E., Kooner, Jaspal S., Langenberg, Claudia, Luan, Jianʼan, Malerba, Giovanni, März, Winfried, Matchan, Angela, Morris, Richard, Nordestgaard, Børge G., Benn, Marianne, Scott, Robert A., Toniolo, Daniela, Traglia, Michela, Tybjaerg-Hansen, Anne, van Duijn, Cornelia M., van Leeuwen, Elisabeth M., Varbo, Anette, Whincup, Peter, Zaza, Gianluigi, and Zhang, Weihua

Published
2015
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8. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author

Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaëlle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Körner, Antje, Muddyman, Dawn, McCarthy, Shane, Hinney, Anke, Hebebrand, Johannes, Scott, Robert A., Langenberg, Claudia, Wareham, Nick J., Surendran, Praveen, Howson, Joanna M M, Butterworth, Adam S., Danesh, John, Nordestgaard, Børge G., Nielsen, Sune F., Afzal, Shoaib, Papadia, Sofia, Ashford, Sofie, Garg, Sumedha, Millhauser, Glenn L., Palomino, Rafael I., Kwasniewska, Alexandra, Tachmazidou, Ioanna, O'Rahilly, Stephen, Zeggini, Eleftheria, Barroso, Inês, Farooqi, I. Sadaf, Benzeval, Michaela, Burton, Jonathan, Buck, Nicholas, Jäckle, Annette, Kumari, Meena, Laurie, Heather, Lynn, Peter, Pudney, Stephen, Rabe, Birgitta, Wolke, Dieter, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogha, Vittorio, Panico, Salvatore, Tuminoa, Rosario, Matullo, Giuseppe, Boer, Jolanda Ma, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Al-Turki, Saeed, Anderson, Carl A, Anney, Richard, Antony, Dinu, Soler Artigas, María, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C, Beales, Phil, Bentham, Jamie, Bhattacharyaa, Shoumo, Birney, Ewan, Blackwooda, Douglas, Bobrow, Martin, Bolton, Patrick F., Boustred, Chris, Breen, Gerome, Calissanoa, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampia, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Coccaa, Massimiliano, Collier, David A, Cosgrove, Catherine, Coxa, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N M, Day-Williams, Aaron G, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., FitzPatrick, David R., Flicek, Paul, Floyd, James S., Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel H., Greenwood, Celia M.T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah J., Holmans, Peter A, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro G., Iotchkova, Valentina, Jackson, David K., Jamshidi, Yalda, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Khawaja, Farrah, Van Kogelenberg, Margriet, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lönnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, MacArthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Maslen, John, Mathieson, Iain, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Min, Josine L., Mitchison, Hannah M, Moayyeri, Alireza, Morris, Andrew D., Morris, James, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnström, Karola, Richards, J Brent, Ridout, Cheryl K., Ring, Susan M., Ritchie, Graham R.S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So Youn, Skuse, David, Small, Kerrin S, Smee, Carol, Smith, Blair H., Davey Smith, George, Soranzo, Nicole, Southam, Lorraine, Spasic-Boskovic, Olivera, Spector, Timothy D, St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela L, Suvisaari, Jaana, Syrris, Petros, Taylor, Rohan, Tian, Jing, Timpson, Nicholas J., Tobin, Martin D, Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Walters, James T.R., Wang, Guangbiao, Wang, Jun, Wang, Nai-Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, Zheng, Hou Feng, Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaã«lle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Kã¶rner, Antje, Muddyman, Dawn, Mccarthy, Shane, Hinney, Anke, Hebebrand, Johanne, Scott, Robert A., Langenberg, Claudia, Wareham, Nick J., Surendran, Praveen, Howson, Joanna M., Butterworth, Adam S., Danesh, John, Nordestgaard, Bã¸rge G, Nielsen, Sune F, Afzal, Shoaib, Papadia, Sofia, Ashford, Sofie, Garg, Sumedha, Millhauser, Glenn L., Palomino, Rafael I., Kwasniewska, Alexandra, Tachmazidou, Ioanna, O'Rahilly, Stephen, Zeggini, Eleftheria, Barroso, Inãª, Farooqi, I. Sadaf, Benzeval, Michaela, Burton, Jonathan, Buck, Nichola, Jã¤ckle, Annette, Kumari, Meena, Laurie, Heather, Lynn, Peter, Pudney, Stephen, Rabe, Birgitta, Wolke, Dieter, Overvad, Kim, Tjã¸nneland, Anne, Clavel chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogha, Vittorio, Panico, Salvatore, Tuminoa, Rosario, Matullo, Giuseppe, Boer, Jolanda, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sã¡nchez, Marã­a josã©, Navarro, Carmen, Moreno iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Turki, Saeed Al, Anderson, Carl A., Anney, Richard, Antony, Dinu, Soler Artigas, Marã­a, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C., Beales, Phil, Bentham, Jamie, Bhattacharyaa, Shoumo, Birney, Ewan, Blackwooda, Dougla, Bobrow, Martin, Bolton, Patrick F., Boustred, Chri, Breen, Gerome, Calissanoa, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampia, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Coccaa, Massimiliano, Collier, David A., Cosgrove, Catherine, Coxa, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N. M., Day williams, Aaron, Dominiczak, Anna, Down, Thoma, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., Fitzpatrick, David R., Flicek, Paul, Floyd, Jame, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthia, Geschwind, Daniel, Greenwood, Celia M. T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah, Holmans, Peter, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Iotchkova, Valentina, Jackson, David K., Jamshidi, Yalda, Joyce, Chri, Karczewski, Konrad J., Kaye, Jane, Keane, Thoma, Kemp, John P., Kennedy, Karen, Kent, Alastair, Khawaja, Farrah, Van Kogelenberg, Margriet, Kolb kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lã¶nnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, Macarthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Maslen, John, Mathieson, Iain, Mcguffin, Peter, Mcintosh, Andrew M., Mckechanie, Andrew G., Mcquillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Min, Josine L., Mitchison, Hannah M., Moayyeri, Alireza, Morris, Andrew, Morris, Jame, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., Onoufriadis, Alexandro, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnstrã¶m, Karola, Richards, J. Brent, Ridout, Cheryl K., Ring, Susan, Ritchie, Graham R. S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So youn, Skuse, David, Small, Kerrin S., Smee, Carol, Smith, Blair H., Davey Smith, George, Soranzo, Nicole, Southam, Lorraine, Spasic boskovic, Olivera, Spector, Timothy D., St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela, Suvisaari, Jaana, Syrris, Petro, Taylor, Rohan, Tian, Jing, Timpson, Nicholas J., Tobin, Martin D., Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Walters, James T. R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, and Zheng, Hou feng

Subjects
Multidisciplinary, Journal Article, General
Abstract

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as describedw previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

Published
2017

9. Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Author

Yang, Yongjie, van der Klaauw, Agatha A., Zhu, Liangru, Cacciottolo, Tessa M., He, Yanlin, Stadler, Lukas K. J., Wang, Chunmei, Xu, Pingwen, Saito, Kenji, Hinton, Antentor, Yan, Xiaofeng, Keogh, Julia M., Henning, Elana, Banton, Matthew C., Hendricks, Audrey E., Bochukova, Elena G., Mistry, Vanisha, Lawler, Katherine L., Liao, Lan, Xu, Jianming, O'Rahilly, Stephen, Tong, Qingchun, Barroso, Ines, O'Malley, Bert W., Farooqi, I. Sadaf, Xu, Yong, Balasubramanian, Senduran, Clapham, Peter, Coates, Guy, Cox, Tony, Daly, Allan, Danecek, Petr, Du, Yuanping, Durbin, Richard, Edkins, Sarah, Ellis, Peter, Flicek, Paul, Guo, Xiaosen, Guo, Xueqin, Huang, Liren, Jackson, David K., Joyce, Chris, Keane, Thomas, Kolb-Kokocinski, Anja, Langford, Cordelia, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Maslen, John, McCarthy, Shane, Muddyman, Dawn, Quail, Michael A., Stalker, Jim, Sun, Jianping, Tian, Jing, Wang, Guangbiao, Wang, Jun, Wang, Yu, Wong, Kim, Zhang, Pingbo, Birney, Ewan, Boustred, Chris, Brion, Marie-Jo, Chen, Lu, Clement, Gail, Smith, George Davey, Day, Ian N. M., Day-Williams, Aaron, Down, Thomas, Dunham, Ian, Evans, David M., Fatemifar, Ghazaleh, Gaunt, Tom R., Geihs, Matthias, Greenwood, Celia M. T., Hart, Deborah, Howie, Bryan, Huang, Jie, Hubbard, Tim, Hysi, Pirro, Iotchkova, Valentina, Jamshidi, Yalda, Kemp, John P., Lachance, Genevieve, Lawson, Daniel, Lek, Monkol, Lopes, Margarida, MacArthur, Daniel G., Marchini, Jonathan, Massimo, Mangino, Mathieson, Iain, Memari, Yasin, Metrustry, Sarah, Min, Josine L., Moayyeri, Alireza, Northstone, Kate, Panoutsopoulou, Kalliope, Paternoster, Lavinia, Perry, John R. B., Quaye, Lydia, Richards, J. Brent, Ring, Susan, Ritchie, Graham R. S., Schiffels, Stephan, Shihab, Hashem A., Shin, So-Youn, Small, Kerrin S., Artigas, Maria Soler, Soranzo, Nicole, Southam, Lorraine, Spector, Timothy D., St Pourcain, Beate, Surdulescu, Gabriela, Tachmazidou, Ioanna, Timpson, Nicholas J., Tobin, Martin D., Valdes, Ana M., Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Ward, Kirsten, Wilson, Scott G., Yang, Jian, Zeggini, Eleftheria, Zhang, Feng, Zheng, Hou-Feng, Anney, Richard, Ayub, Muhammad, Barrett, Jeffrey C., Blackwood, Douglas, Bolton, Patrick F., Breen, Gerome, Collier, David A., Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Gallagher, Louise, Geschwind, Daniel, Gurling, Hugh, Holmans, Peter, Lee, Irene, Lonnqvist, Jouko, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Morris, James, O'Donovan, Michael C., Owen, Michael J., Palotie, Aarno, Parr, Jeremy R., Paunio, Tiina, Pietilainen, Olli, Rehnstrom, Karola, Sharp, Sally I., Skuse, David, St Clair, David, Suvisaari, Jaana, Walters, James T. R., Williams, Hywel J., Bochukova, Elena, Bounds, Rebecca, Dominiczak, Anna, Keogh, Julia, Marenne, Gaelle, Morris, Andrew, Porteous, David J., Smith, Blair H., Wheeler, Eleanor, Al Turki, Saeed, Anderson, Carl A., Antony, Dinu, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Fitzpatrick, David R., Floyd, James, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Grozeva, Detelina, Humphries, Steve E., Hurles, Matthew E., Mitchison, Hannah M., Muntoni, Francesco, Onoufriadis, Alexandros, Parker, Victoria, Payne, Felicity, Plagnol, Vincent, Raymond, F. Lucy, Roberts, Nicola, Savage, David B., Scambler, Peter, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Spasic-Boskovic, Olivera, Stevens, Elizabeth, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Williamson, Kathleen A., Wilson, Crispian, Whyte, Tamieka, Ciampi, Antonio, Li, Rui, Oualkacha, Karim, Xu, ChangJiang, Bobrow, Martin, Griffin, Heather, Kaye, Jane, Kennedy, Karen, Kent, Alastair, Smee, Carol, Charlton, Ruth, Ekong, Rosemary, Khawaja, Farrah, Lopes, Luis R., Migone, Nicola, Payne, Stewart J., Pollitt, Rebecca C., Povey, Sue, Ridout, Cheryl K., Robinson, Rachel L., Scott, Richard H., Shaw, Adam, Syrris, Petros, Taylor, Rohan, Vandersteen, Anthony M., Amuzu, Antoinette, Casas, Juan Pablo, Chambers, John C., Cocca, Massimiliano, Dedoussis, George, Gambaro, Giovanni, Gasparini, Paolo, Isaacs, Aaron, Johnson, Jon, Kleber, Marcus E., Kooner, Jaspal S., Langenberg, Claudia, Luan, Jian'an, Malerba, Giovanni, Marz, Winfried, Matchan, Angela, Morris, Richard, Nordestgaard, Børge G., Benn, Marianne, Scott, Robert A., Toniolo, Daniela, Traglia, Michela, Tybjaerg-Hansen, Anne, van Duijn, Cornelia M., van Leeuwen, Elisabeth M., Varbo, Anette, Whincup, Peter, Zaza, Gianluigi, and Zhang, Weihua

Published
2019

10. An association between chronic widespread pain and the gut microbiome.

Author

Freidin, Maxim B, Stalteri, Maria A, Wells, Philippa M, Lachance, Genevieve, Baleanu, Andrei-Florin, Bowyer, Ruth C E, Kurilshikov, Alexander, Zhernakova, Alexandra, Steves, Claire J, and Williams, Frances M K

Subjects
CHRONIC pain, CHROMOSOMES, MYALGIA, PAIN measurement, SEQUENCE analysis, META-analysis, GUT microbiome, CASE-control method, MANN Whitney U Test, DIET, GENETIC variation, RNA, RISK assessment, FECES, COMPARATIVE studies, QUESTIONNAIRES, DESCRIPTIVE statistics, GENOMES, STATISTICAL models, BODY mass index, LONGITUDINAL method, BACTERIA, DISEASE risk factors
Abstract

Objectives Chronic widespread musculoskeletal pain (CWP) is a characteristic symptom of fibromyalgia, which has been shown to be associated with an altered gut microbiome. Microbiome studies to date have not examined the milder CWP phenotype specifically nor have they explored the role of raised BMI. The aim of this study was to investigate whether the microbiome is abnormal in CWP. Methods CWP was assessed using a standardized screening questionnaire in female volunteers from the TwinsUK cohort including 113 CWP cases and 1623 controls. The stool microbiome was characterized using 16S rRNA amplicon sequencing and amplicon sequence variants, and associations with CWP examined using linear mixed-effects models adjusting for BMI, age, diet, family relatedness and technical factors. Results Alpha diversity was significantly lower in CWP cases than controls (Mann–Whitney test, P -values 2.3e-04 and 1.2e-02, for Shannon and Simpson indices respectively). The species Coprococcus comes was significantly depleted in CWP cases (P adj = 3.04e-03). A genome-wide association study (GWAS) performed for C. comes in TwinsUK followed by meta-analysis with three Dutch cohorts (total n  = 3521) resulted in nine suggestive regions, with the most convincing on chromosome 4 near the TRAM1L1 gene (rs76957229, P  = 7.4e-8). A Mendelian randomization study based on the results of the GWAS did not support a causal role for C. comes on the development of CWP. Conclusions We have demonstrated reduced diversity in the microbiome in CWP, indicating an involvement of the gut microbiota in CWP; prospectively the microbiome may offer therapeutic opportunities for this condition. [ABSTRACT FROM AUTHOR]

Published
2021
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11. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Author

Int Multiple Sclerosis Genetics, Mitrovic, Mitja, Patsopoulos, Nikoloas, Beecham, Ashley, Dankowski, Theresa, Goris, An, Dubois, Bénédicte, D'hooghe, Marie B, Lemmens, Robin, Van Damme, Philip, Bach Sondergaard, Helle, Sellebjerg, Finn, Soelberg Sorensen, Per, Ullum, Henrik, Thorner, Lise W, Werge, Thomas, Saarela, Janna, Cournu-Rebeix, Isabelle, Damotte, Vincent, Fontaine, Bertrand, Guillot-Noel, Lena, Lathrop, Mark, Vukusik, Sandra, Gourraud, Pierre-Antoine, Andlauer, Till FM, Pongratz, Viola, Buck, Dorothea, Gasperi, Christiane, Bayas, Antonios, Heesen, Christoph, Kümpfel, Tania, Linker, Ralf, Friedemann, Paul, Stangel, Martin, Tackenberg, Björn, Then Bergh, Florian, Warnke, Clemens, Wiendl, Heinz, Wildemann, Brigitte, Zettl, Uwe, Ziemann, Ulf, Tumani, Hayrettin, Gold, Ralf, Grummel, Verena, Hemmer, Bernhard, Knier, Benjamin, Lill, Christina, Luessi, Felix, Dardiotis, Efthimios, Agliardi, Cristina, Barizzone, Nadia, Mascia, Elisabetta, Bernardinelli, Luisa, Comi, Giancarlo, Cusi, Daniele, Esposito, Federica, Ferrè, Laura, Comi, Cristoforo, Galimberti, Daniela, Leone, Maurizio A, Sorosina, Melissa, Mescheriakova, Julia, Hintzen, Rogier, van Duijn, Cornelia, Theunissen, Charlotte E, Bos, Steffan D, Myhr, Kjell-Morten, Celius, Elisabeth G, Lie, Benedicte A, Spurkland, Anne, Comabella, Manuel, Montalban, Xavier, Alfredsson, Lars, Stridh, Pernilla, Hillert, Jan, Jagodic, Maja, Piehl, Fredrik, Jelcic, Ilijas, Martin, Roland, Sospedra, Mireia, Ban, Maria, Hawkins, Clive, Hysi, Pirro, Kalra, Seema, Karpe, Fredrik, Khadake, Jyoti, Lachance, Genevieve, Neville, Matthew, Santaniello, Adam, Caillier, Stacy J, Calavresi, Peter A, Cree, Bruce AC, Cross, Anne, Davis, Mary F, Haines, Jonathan L, de Bakker, Paul IW, Delgado, Silvia, Dembele, Marieme, Edwards, Keith, Fitzgerald, Kathryn C, Hakonarson, Hakon, Konidari, Ioanna, Lathi, Ellen, Manrique, Clara P, Pericak-Vance, Margaret A, Piccio, Laura, Schaefer, Cathy, McCabe, Cristin, Weiner, Howard, Goldstein, Jacqueline, Olsson, Tomas, Hadjigeorgiou, Georgios, Taylor, Bruce, Tajouri, Lotti, Charlesworth, Jac, Booth, David R, HArbo, Hanne F, Ivinson, Adrian J, Hauser, Stephen L, Compston, Alistair, Stewart, Graeme, Zipp, Frauke, Barcellos, Lisa F, Baranzini, Sergio E, Martinelli-Boneschi, Filippo, D'Alfonso, Sandra, Ziegler, Andreas, Oturai, Annette, McCauley, Jacob L, Sawcer, Stephen J, Oksenberg, Jorge R, De Jager, Philip L, Kockum, Ingrid, Hafler, David A, and Cotsapas, Chris

Subjects
Biochemistry & Molecular Biology, Science & Technology, REPLICATION, LINKAGE, Cell Biology, GENETIC RISK, GENOME-WIDE ASSOCIATION, VARIANTS, Life Sciences & Biomedicine, METAANALYSIS, POPULATION
Abstract

Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS. ispartof: CELL vol:175 issue:6 pages:1679-1695 ispartof: location:United States status: published

Published
2018

12. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Author

Mitrovič, Mitja, Patsopoulos, Nikolaos, Beecham, Ashley, Dankowski, Theresa, Goris, An, Dubois, Bénédicte, D’hooghe, Marie, Lemmens, Robin, Van Damme, Philip, Søndergaard, Helle Bach, Sellebjerg, Finn, Sorensen, Per Soelberg, Ullum, Henrik, Thørner, Lise, Werge, Thomas, Saarela, Janna, Cournu-Rebeix, Isabelle, Damotte, Vincent, Fontaine, Bertrand, Guillot-Noel, Lena, Lathrop, Mark, Vukusik, Sandra, Gourraud, Pierre-Antoine, Andlauer, Till F.M., Pongratz, Viola, Buck, Dorothea, Gasperi, Christiane, Bayas, Antonios, Heesen, Christoph, Kümpfel, Tania, Linker, Ralf, Paul, Friedemann, Stangel, Martin, Tackenberg, Björn, Bergh, Florian Then, Warnke, Clemens, Wiendl, Heinz, Wildemann, Brigitte, Zettl, Uwe, Ziemann, Ulf, Tumani, Hayrettin, Gold, Ralf, Grummel, Verena, Hemmer, Bernhard, Knier, Benjamin, Lill, Christina, Luessi, Felix, Dardiotis, Efthimios, Agliardi, Cristina, Barizzone, Nadia, Mascia, Elisabetta, Bernardinelli, Luisa, Comi, Giancarlo, Cusi, Daniele, Esposito, Federica, Ferrè, Laura, Comi, Cristoforo, Galimberti, Daniela, Leone, Maurizio, Sorosina, Melissa, Mescheriakova, Julia, Hintzen, Rogier, Van Duijn, Cornelia, Teunissen, Charlotte, Bos, Steffan, Myhr, Kjell-Morten, Celius, Elisabeth, Lie, Benedicte, Spurkland, Anne, Comabella, Manuel, Montalban, Xavier, Alfredsson, Lars, Stridh, Pernilla, Hillert, Jan, Jagodic, Maja, Piehl, Fredrik, Jelčić, Ilijas, Martin, Roland, Sospedra, Mireia, Ban, Maria, Hawkins, Clive, Hysi, Pirro, Kalra, Seema, Karpe, Fredrik, Khadake, Jyoti, Lachance, Genevieve, Neville, Matthew, Santaniello, Adam, Caillier, Stacy, Calabresi, Peter, Cree, Bruce A.C., Cross, Anne, Davis, Mary, Haines, Jonathan, de Bakker, Paul I.W., Delgado, Silvia, Dembele, Marieme, Edwards, Keith, Fitzgerald, Kathryn, Hakonarson, Hakon, Konidari, Ioanna, Lathi, Ellen, Manrique, Clara, Pericak-Vance, Margaret, Piccio, Laura, Schaefer, Cathy, McCabe, Cristin, Weiner, Howard, Goldstein, Jacqueline, Olsson, Tomas, Hadjigeorgiou, Georgios, Taylor, Bruce, Tajouri, Lotti, Charlesworth, Jac, Booth, David, Harbo, Hanne, Ivinson, Adrian, Hauser, Stephen, Compston, Alastair, Stewart, Graeme, Zipp, Frauke, Barcellos, Lisa, Baranzini, Sergio, Martinelli-Boneschi, Filippo, D’Alfonso, Sandra, Ziegler, Andreas, Oturai, Annette, McCauley, Jacob, Sawcer, Stephen, Oksenberg, Jorge, De Jager, Philip, Kockum, Ingrid, Hafler, David, Cotsapas, Chris, Søndergaard, Helle, Sorensen, Per, Andlauer, Till, Bergh, Florian, Cree, Bruce, De Bakker, Paul, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Centre de Recherche en Myologie

Subjects
[SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
Abstract

International audience; Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.

Published
2018

13. TwinsUK: The UK Adult Twin Registry Update.

Author

Verdi, Serena, Abbasian, Golboo, Bowyer, Ruth C. E., Lachance, Genevieve, Yarand, Darioush, Christofidou, Paraskevi, Mangino, Massimo, Menni, Cristina, Bell, Jordana T., Falchi, Mario, Small, Kerrin S., Williams, Frances M. K., Hammond, Christopher J., Hart, Deborah J., Spector, Timothy D., and Steves, Claire J.

Subjects
TWIN studies, BIRTH certificates, HUMAN microbiota, EPIDEMIOLOGY, EPIGENETICS
Abstract

TwinsUK is the largest cohort of community-dwelling adult twins in the UK. The registry comprises over 14,000 volunteer twins (14,838 including mixed, single and triplets); it is predominantly female (82%) and middle-aged (mean age 59). In addition, over 1800 parents and siblings of twins are registered volunteers. During the last 27 years, TwinsUK has collected numerous questionnaire responses, physical/cognitive measures and biological measures on over 8500 subjects. Data were collected alongside four comprehensive phenotyping clinical visits to the Department of Twin Research and Genetic Epidemiology, King's College London. Such collection methods have resulted in very detailed longitudinal clinical, biochemical, behavioral, dietary and socioeconomic cohort characterization; it provides a multidisciplinary platform for the study of complex disease during the adult life course, including the process of healthy aging. The major strength of TwinsUK is the availability of several 'omic' technologies for a range of sample types from participants, which includes genomewide scans of single-nucleotide variants, next-generation sequencing, metabolomic profiles, microbiomics, exome sequencing, epigenetic markers, gene expression arrays, RNA sequencing and telomere length measures. TwinsUK facilitates and actively encourages sharing the 'TwinsUK' resource with the scientific community - interested researchers may request data via the TwinsUK website (http://twinsuk.ac.uk/resources-for-researchers/access-our-data/) for their own use or future collaboration with the study team. In addition, further cohort data collection is planned via the Wellcome Open Research gateway (https://wellcomeopenresearch.org/gateways). The current article presents an up-to-date report on the application of technological advances, new study procedures in the cohort and future direction of TwinsUK. [ABSTRACT FROM AUTHOR]

Published
2019
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15. Food Preference Patterns in a UK Twin Cohort.

Author

Pallister, Tess, Sharafi, Mastaneh, Lachance, Genevieve, Pirastu, Nicola, Mohney, Robert P., MacGregor, Alex, Feskens, Edith J. M., Duffy, Valerie, Spector, Tim D., and Menni, Cristina

Subjects
FOOD preferences, TWIN psychology, COHORT analysis, LIFESTYLES & health, STRUCTURAL equation modeling, BIOCHEMISTRY, COMPARATIVE studies, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, RESEARCH, EVALUATION research
Abstract

Food liking-disliking patterns may strongly influence food choices and health. Here we assess: (1) whether food preference patterns are genetic/environmentally driven; and (2) the relationship between metabolomics profiles and food preference patterns in a large population of twins. 2,107 individuals from TwinsUK completed an online food and lifestyle preference questionnaire. Principle components analysis was undertaken to identify patterns of food liking-disliking. Heritability estimates for each liking pattern were obtained by structural equation modeling. The correlation between blood metabolomics profiles (280 metabolites) and each food liking pattern was assessed in a subset of 1,491 individuals and replicated in an independent subset of monozygotic twin pairs discordant for the liking pattern (65 to 88 pairs). Results from both analyses were meta-analyzed. Four major food-liking patterns were identified (Fruit and Vegetable, Distinctive Tastes, Sweet and High Carbohydrate, and Meat) accounting for 26% of the total variance. All patterns were moderately heritable (Fruit and Vegetable, h2[95% CI]: 0.36 [0.28; 0.44]; Distinctive Tastes: 0.58 [0.52; 0.64]; Sweet and High Carbohydrate: 0.52 [0.45, 0.59] and Meat: 0.44 [0.35; 0.51]), indicating genetic factors influence food liking-disliking. Overall, we identified 14 significant metabolite associations (Bonferroni p < 4.5 × 10−5) with Distinctive Tastes (8 metabolites), Sweet and High Carbohydrate (3 metabolites), and Meat (3 metabolites). Food preferences follow patterns based on similar taste and nutrient characteristics and these groupings are strongly determined by genetics. Food preferences that are strongly genetically determined (h2 ≥ 0.40), such as for meat and distinctive-tasting foods, may influence intakes more substantially, as demonstrated by the metabolomic associations identified here. [ABSTRACT FROM PUBLISHER]

Published
2015
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17. A Discordant Monozygotic-Twin Approach to Potential Risk Factors for Chronic Widespread Pain in Females.

Author

Burri, Andrea, Lachance, Genevieve, and Williams, Frances

Subjects
*TWIN psychology, *DISEASES in twins, *FEMALES, *SYMPTOMS, *MEDICAL screening, *QUESTIONNAIRES, *DISEASES, PAIN risk factors
Abstract

Chronic widespread pain (CWP) is a common disorder affecting up to 15% of the general population. The objective of the present study was to explore the role of previously reported psychosocial and interpersonal risk factors on variation in CWP by investigating CWP discordant monozygotic (MZ) twins. This approach allows separation of cause and effect relationships, albeit imperfectly, as well the control for critical confounding variables such as common environment or genetics. In a total sample of N = 3,266 female twins aged 18–89 years, MZ (113 full pairs) and DZ twins (180 full pairs) discordant for CWP were selected. Items from the London fibromyalgia symptom screening questionnaire were used to discriminate cases from controls. To assess potential risk factors, including body mass index, anxiety sensitivity (AS), emotional intelligence, personality, obsessive-compulsive behavior, and coping, validated questionnaires were used. A set of univariate and multivariate logistic regression analyses were conducted. Of the variables showing significant links with CWP in the univariate individual-level analyses, including age, AS, and emotional intelligence, only emotional intelligence turned out to an independent predictor to the pathogenesis of CWP in both the individual level and discordant MZ analyses. These data indicate that in women having identical genetic risk, emotional intelligence seems to play a key role, although of small effect, in the development and/or maintenance of CWP. It further seems that many of the previously reported risk factors for CWP suffer from genetic confounding. [ABSTRACT FROM AUTHOR]

Published
2015
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20. Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Author

Huang, Jie, Howie, Bryan, McCarthy, Shane, Memari, Yasin, Walter, Klaudia, Min, Josine L., Danecek, Petr, Malerba, Giovanni, Trabetti, Elisabetta, Zheng, Hou-Feng, Al Turki, Saeed, Amuzu, Antoinette, Anderson, Carl A., Anney, Richard, Antony, Dinu, Artigas, María Soler, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C., Barroso, Inês, Beales, Phil, Benn, Marianne, Bentham, Jamie, Bhattacharya, Shoumo, Birney, Ewan, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick F., Bounds, Rebecca, Boustred, Chris, Breen, Gerome, Calissano, Mattia, Carss, Keren, Pablo Casas, Juan, Chambers, John C., Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampi, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Cocca, Massimiliano, Collier, David A., Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Day, Ian N. M., Day-Williams, Aaron, Dedoussis, George, Down, Thomas, Du, Yuanping, van Duijn, Cornelia M., Dunham, Ian, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evans, David M., Farooqi, I. Sadaf, Fitzpatrick, David R., Flicek, Paul, Floyd, James, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gasparini, Paolo, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel, Greenwood, Celia, Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey E., Holmans, Peter, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Iotchkova, Valentina, Isaacs, Aaron, Jackson, David K., Jamshidi, Yalda, Johnson, Jon, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Keogh, Julia, Khawaja, Farrah, Kleber, Marcus E., van Kogelenberg, Margriet, Kolb-Kokocinski, Anja, Kooner, Jaspal S., Lachance, Genevieve, Langenberg, Claudia, Langford, Cordelia, Lawson, Daniel, Lee, Irene, van Leeuwen, Elisabeth M., Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lönnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, Luan, Jian'an, MacArthur, Daniel G., Mangino, Massimo, Marenne, Gaëlle, März, Winfried, Maslen, John, Matchan, Angela, Mathieson, Iain, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Metrustry, Sarah, Migone, Nicola, Mitchison, Hannah M., Moayyeri, Alireza, Morris, James, Morris, Richard, Muddyman, Dawn, Muntoni, Francesco, Nordestgaard, Børge G., Northstone, Kate, O'Donovan, Michael C., O'Rahilly, Stephen, Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Ridout, Cheryl K., Ring, Susan, Ritchie, Graham R. S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Scott, Robert A., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So-Youn, Skuse, David, Small, Kerrin S., Smee, Carol, Smith, George Davey, Southam, Lorraine, Spasic-Boskovic, Olivera, Spector, Timothy D., St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela, Suvisaari, Jaana, Syrris, Petros, Tachmazidou, Ioanna, Taylor, Rohan, Tian, Jing, Tobin, Martin D., Toniolo, Daniela, Traglia, Michela, Tybjaerg-Hansen, Anne, Valdes, Ana M., Vandersteen, Anthony M., Varbo, Anette, Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walters, James T. R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Wheeler, Eleanor, Whincup, Peter, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, ChangJiang, Yang, Jian, Zaza, Gianluigi, Zeggini, Eleftheria, Zhang, Feng, Zhang, Pingbo, Zhang, Weihua, Gambaro, Giovanni, Richards, J. Brent, Durbin, Richard, Timpson, Nicholas J., Marchini, Jonathan, and Soranzo, Nicole

Abstract

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.

Published
2015
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21. TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Author

Schmidts, Miriam, Hou, Yuqing, Cortés, Claudio R., Mans, Dorus A., Huber, Celine, Boldt, Karsten, Patel, Mitali, van Reeuwijk, Jeroen, Plaza, Jean-Marc, van Beersum, Sylvia E. C., Yap, Zhi Min, Letteboer, Stef J. F., Taylor, S. Paige, Herridge, Warren, Johnson, Colin A., Scambler, Peter J., Ueffing, Marius, Kayserili, Hulya, Krakow, Deborah, King, Stephen M., Beales, Philip L., Al-Gazali, Lihadh, Wicking, Carol, Cormier-Daire, Valerie, Roepman, Ronald, Mitchison, Hannah M., Witman, George B., Al-Turki, Saeed, Anderson, Carl, Anney, Richard, Antony, Dinu, Asimit, Jennifer, Ayub, Mohammad, Barrett, Jeff, Barroso, Inês, Bentham, Jamie, Bhattacharya, Shoumo, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Boustred, Chris, Breen, Gerome, Brion, Marie-Jo, Brown, Andrew, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Chen, Lu, Cirak, Sebhattin, Clapham, Peter, Clement, Gail, Coates, Guy, Collier, David, Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Daly, Allan, Danecek, Petr, Smith, George Davey, Day-Williams, Aaron, Day, Ian, Durbin, Richard, Edkins, Sarah, Ellis, Peter, Evans, David, Farooqi, I. Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David, Flicek, Paul, Floyd, Jamie, Foley, A. Reghan, Franklin, Chris, Futema, Marta, Gallagher, Louise, Gaunt, Tom, Geschwind, Daniel, Greenwood, Celia, Grozeva, Detelina, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Huang, Jie, Humphries, Steve E., Hurles, Matt, Hysi, Pirro, Jackson, David, Jamshidi, Yalda, Jewell, David, Chris, Joyce, Kaye, Jane, Keane, Thomas, Kemp, John, Kennedy, Karen, Kent, Alastair, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lee, Irene, Li, Rui, Li, Yingrui, Ryan, Liu, Lönnqvist, Jouko, Lopes, Margarida, MacArthur, Daniel G., Massimo, Mangino, Marchini, Jonathan, Maslen, John, McCarthy, Shane, McGuffin, Peter, McIntosh, Andrew, McKechanie, Andrew, McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Min, Josine, Moayyeri, Alireza, Morris, James, Muddyman, Dawn, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael, O'Rahilly, Stephen, Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy, Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Perry, John, Pietilainen, Olli, Plagnol, Vincent, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Brent Richards, J., Ring, Sue, Ritchie, Graham R S, Savage, David B., Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Shihab, Hashem, Shin, So-Youn, Skuse, David, Small, Kerrin, Smee, Carol, Soler, Artigas María, Soranzo, Nicole, Southam, Lorraine, Spector, Tim, St Pourcain, Beate, St. Clair, David, Stalker, Jim, Surdulescu, Gabriela, Suvisaari, Jaana, Tachmazidou, Ioanna, Tian, Jing, Timpson, Nic, Tobin, Martin, Valdes, Ana, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Wain, Louise, Walter, Klaudia, Wang, Jun, Ward, Kirsten, Wheeler, Ellie, Whittall, Ros, Williams, Hywel, Williamson, Kathy, Wilson, Scott G., Wong, Kim, Whyte, Tamieka, ChangJiang, Xu, Zeggini, Eleftheria, Zhang, Feng, and Zheng, Hou-Feng

Abstract

The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.

Published
2015
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22. Whole-genome sequence-based analysis of thyroid function

Author

Taylor, Peter N., Porcu, Eleonora, Chew, Shelby, Campbell, Purdey J., Traglia, Michela, Brown, Suzanne J., Mullin, Benjamin H., Shihab, Hashem A., Min, Josine, Walter, Klaudia, Memari, Yasin, Huang, Jie, Barnes, Michael R., Beilby, John P., Charoen, Pimphen, Danecek, Petr, Dudbridge, Frank, Forgetta, Vincenzo, Greenwood, Celia, Grundberg, Elin, Johnson, Andrew D., Hui, Jennie, Lim, Ee M., McCarthy, Shane, Muddyman, Dawn, Panicker, Vijay, Perry, John R.B., Bell, Jordana T., Yuan, Wei, Relton, Caroline, Gaunt, Tom, Schlessinger, David, Abecasis, Goncalo, Cucca, Francesco, Surdulescu, Gabriela L., Woltersdorf, Wolfram, Zeggini, Eleftheria, Zheng, Hou-Feng, Toniolo, Daniela, Dayan, Colin M., Naitza, Silvia, Walsh, John P., Spector, Tim, Davey Smith, George, Durbin, Richard, Brent Richards, J., Sanna, Serena, Soranzo, Nicole, Timpson, Nicholas J., Wilson, Scott G., Turki, Saeed Al, Anderson, Carl, Anney, Richard, Antony, Dinu, Artigas, Maria Soler, Ayub, Muhammad, Balasubramaniam, Senduran, Barrett, Jeffrey C., Barroso, Inês, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Birney, Ewan, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Bounds, Rebecca, Boustred, Chris, Breen, Gerome, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Chen, Lu, Ciampi, Antonio, Cirak, Sebhattin, Clapham, Peter, Clement, Gail, Coates, Guy, Collier, David, Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Day-Williams, Aaron, Day, Ian N.M., Down, Thomas, Du, Yuanping, Dunham, Ian, Edkins, Sarah, Ellis, Peter, Evans, David, Faroogi, Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David R., Flicek, Paul, Flyod, James, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Geihs, Matthias, Geschwind, Daniel, Griffin, Heather, Grozeva, Detelina, Guo, Xueqin, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Howie, Bryan, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Jackson, David K., Jamshidi, Yalda, Jing, Tian, Joyce, Chris, Kaye, Jane, Keane, Thomas, Keogh, Julia, Kemp, John, Kennedy, Karen, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Liang, Jieqin, Lin, Hong, Li, Rui, Li, Yingrui, Liu, Ryan, Lönnqvist, Jouko, Lopes, Margarida, Lotchkova, Valentina, MacArthur, Daniel, Marchini, Jonathan, Maslen, John, Massimo, Mangino, Mathieson, Iain, Marenne, Gaëlle, McGuffin, Peter, McIntosh, Andrew, McKechanie, Andrew G., McQuillin, Andrew, Metrustry, Sarah, Mitchison, Hannah, Moayyeri, Alireza, Morris, James, Muntoni, Francesco, Northstone, Kate, O'Donnovan, Michael, Onoufriadis, Alexandros, O'Rahilly, Stephen, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Pietilainen, Olli, Plagnol, Vincent, Quaye, Lydia, Quai, Michael A., Raymond, Lucy, Rehnström, Karola, Richards, Brent, Ring, Susan, Ritchie, Graham R.S., Roberts, Nicola, Savage, David B., Scambler, Peter, Schiffels, Stephen, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Sharp, Sally I., Shin, So-Youn, Skuse, David, Small, Kerrin, Southam, Lorraine, Spasic-Boskovic, Olivera, Clair, David St, Stalker, Jim, Stevens, Elizabeth, Pourcian, Beate St, Sun, Jianping, Suvisaari, Jaana, Tachmazidou, Ionna, Tobin, Martin D., Valdes, Ana, Kogelenberg, Margriet Van, Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walters, James T.R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Wheeler, Elanor, Whyte, Tamieka, Williams, Hywel, Williamson, Kathleen A., Wilson, Crispian, Wong, Kim, Xu, ChangJiang, Yang, Jian, Zhang, Fend, and Zhang, Pingbo

Abstract

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10−9) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10−14). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10−9) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10−11). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.

Published
2015
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23. A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

Author

Timpson, Nicholas J., Walter, Klaudia, Min, Josine L., Tachmazidou, Ioanna, Malerba, Giovanni, Shin, So-Youn, Chen, Lu, Futema, Marta, Southam, Lorraine, Iotchkova, Valentina, Cocca, Massimiliano, Huang, Jie, Memari, Yasin, McCarthy, Shane, Danecek, Petr, Muddyman, Dawn, Mangino, Massimo, Menni, Cristina, Perry, John R. B., Ring, Susan M., Gaye, Amadou, Dedoussis, George, Farmaki, Aliki-Eleni, Burton, Paul, Talmud, Philippa J., Gambaro, Giovanni, Spector, Tim D., Smith, George Davey, Durbin, Richard, Richards, J Brent, Humphries, Steve E., Zeggini, Eleftheria, Soranzo, Nicole, Al Turki, Saeed, Anderson, Carl, Anney, Richard, Antony, Dinu, Soler Artigas, Maria, Ayub, Muhammad, Balasubramaniam, Senduran, Barrett, Jeffrey C., Barroso, Inês, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Birney, Ewan, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Bounds, Rebecca, Boustred, Chris, Breen, Gerome, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Ciampi, Antonio, Cirak, Sebhattin, Clapham, Peter, Clement, Gail, Coates, Guy, Collier, David, Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Davey Smith, George, Day-Williams, Aaron, Day, Ian N. M., Down, Thomas, Du, Yuanping, Dunham, Ian, Edkins, Sarah, Ellis, Peter, Evans, David, Faroogi, Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David R., Flicek, Paul, Flyod, James, Foley, A Reghan, Franklin, Christopher S, Gallagher, Louise, Gaunt, Tom, Geihs, Matthias, Geschwind, Daniel, Greenwood, Celia, Griffin, Heather, Grozeva, Detelina, Guo, Xueqin, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Howie, Bryan, Huang, Liren, Hubbard, Tim, Hurles, Matthew E., Hysi, Pirro, Jackson, David K., Jamshidi, Yalda, Jing, Tian, Joyce, Chris, Kaye, Jane, Keane, Thomas, Keogh, Julia, Kemp, John, Kennedy, Karen, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Liang, Jieqin, Lin, Hong, Li, Rui, Li, Yingrui, Liu, Ryan, Lönnqvist, Jouko, Lopes, Margarida, Lotchkova, Valentina, MacArthur, Daniel, Marchini, Jonathan, Maslen, John, Massimo, Mangino, Mathieson, Iain, Marenne, Gaëlle, McGuffin, Peter, McIntosh, Andrew, McKechanie, Andrew G., McQuillin, Andrew, Metrustry, Sarah, Min, Josine, Mitchison, Hannah, Moayyeri, Alireza, Morris, James, Muntoni, Francesco, Northstone, Kate, O'Donnovan, Michael, Onoufriadis, Alexandros, O'Rahilly, Stephen, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Perry, John, Pietilainen, Olli, Plagnol, Vincent, Quaye, Lydia, Quail, Michael A., Raymond, Lucy, Rehnström, Karola, Richards, Brent, Ring, Susan, Ritchie, Graham R. S., Roberts, Nicola, Savage, David B., Scambler, Peter, Schiffels, Stephen, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Sharp, Sally I., Shihab, Hasheem, Skuse, David, Small, Kerrin, Spasic-Boskovic, Olivera, Spector, Tim, St Clair, David, Stalker, Jim, Stevens, Elizabeth, St Pourcian, Beate, Sun, Jianping, Surdulescu, Gabriela, Suvisaari, Jaana, Tachmazidou, Ionna, Timpson, Nicholas, Tobin, Martin D., Valdes, Ana, Van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walters, James T. R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Wheeler, Elanor, Whyte, Tamieka, Williams, Hywel, Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, ChangJiang, Yang, Jian, Zhang, Fend, Zhang, Pingbo, and Zheng, Hou-Feng

Abstract

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (−1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10−8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (−1.0 s.d. (s.e.=0.173), P-value=7.32 × 10−9). This is consistent with an effect between 0.5 and 1.5 mmol l−1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.

Published
2014
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24. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Author

Ligthart, Symen, Vaez, Ahmad, Võsa, Urmo, Stathopoulou, Maria G, De Vries, Paul S, Prins, Bram P, Van Der Most, Peter J, Tanaka, Toshiko, Naderi, Elnaz, Rose, Lynda M, Wu, Ying, Karlsson, Robert, Barbalic, Maja, Lin, Honghuang, Pool, René, Zhu, Gu, Macé, Aurélien, Sidore, Carlo, Trompet, Stella, Mangino, Massimo, Sabater-Lleal, Maria, Kemp, John P, Abbasi, Ali, Kacprowski, Tim, Verweij, Niek, Smith, Albert V, Huang, Tao, Marzi, Carola, Feitosa, Mary F, Lohman, Kurt K, Kleber, Marcus E, Milaneschi, Yuri, Mueller, Christian, Huq, Mahmudul, Vlachopoulou, Efthymia, Lyytikäinen, Leo-Pekka, Oldmeadow, Christopher, Deelen, Joris, Perola, Markus, Zhao, Jing Hua, Feenstra, Bjarke, Amini, Marzyeh, Lahti, Jari, Schraut, Katharina E, Fornage, Myriam, Suktitipat, Bhoom, Chen, Wei-Min, Li, Xiaohui, Nutile, Teresa, Malerba, Giovanni, Luan, Jian'an, Bak, Tom, Schork, Nicholas, Del Greco M, Fabiola, Thiering, Elisabeth, Mahajan, Anubha, Marioni, Riccardo E, Mihailov, Evelin, Eriksson, Joel, Ozel, Ayse Bilge, Zhang, Weihua, Nethander, Maria, Cheng, Yu-Ching, Aslibekyan, Stella, Ang, Wei, Gandin, Ilaria, Yengo, Loïc, Portas, Laura, Kooperberg, Charles, Hofer, Edith, Rajan, Kumar B, Schurmann, Claudia, Den Hollander, Wouter, Ahluwalia, Tarunveer S, Zhao, Jing, Draisma, Harmen H M, Ford, Ian, Timpson, Nicholas, Teumer, Alexander, Huang, Hongyan, Wahl, Simone, Liu, YongMei, Huang, Jie, Uh, Hae-Won, Geller, Frank, Joshi, Peter K, Yanek, Lisa R, Trabetti, Elisabetta, Lehne, Benjamin, Vozzi, Diego, Verbanck, Marie, Biino, Ginevra, Saba, Yasaman, Meulenbelt, Ingrid, O'Connell, Jeff R, Laakso, Markku, Giulianini, Franco, Magnusson, Patrik K E, Ballantyne, Christie M, Hottenga, Jouke Jan, Montgomery, Grant W, Rivadineira, Fernando, Rueedi, Rico, Steri, Maristella, Herzig, Karl-Heinz, Stott, David J, Menni, Cristina, Frånberg, Mattias, St Pourcain, Beate, Felix, Stephan B, Pers, Tune H, Bakker, Stephan J L, Kraft, Peter, Peters, Annette, Vaidya, Dhananjay, Delgado, Graciela, Smit, Johannes H, Großmann, Vera, Sinisalo, Juha, Seppälä, Ilkka, Williams, Stephen R, Holliday, Elizabeth G, Moed, Matthijs, Langenberg, Claudia, Räikkönen, Katri, Ding, Jingzhong, Campbell, Harry, Sale, Michele M, Chen, Yii-Der I, James, Alan L, Ruggiero, Daniela, Soranzo, Nicole, Hartman, Catharina A, Smith, Erin N, Berenson, Gerald S, Fuchsberger, Christian, Hernandez, Dena, Tiesler, Carla M T, Giedraitis, Vilmantas, Liewald, David, Fischer, Krista, Mellström, Dan, Larsson, Anders, Wang, Yunmei, Scott, William R, Lorentzon, Matthias, Beilby, John, Ryan, Kathleen A, Pennell, Craig E, Vuckovic, Dragana, Balkau, Beverly, Concas, Maria Pina, Schmidt, Reinhold, Mendes De Leon, Carlos F, Bottinger, Erwin P, Kloppenburg, Margreet, Paternoster, Lavinia, Boehnke, Michael, Musk, A W, Willemsen, Gonneke, Evans, David M, Madden, Pamela A F, Kähönen, Mika, Kutalik, Zoltán, Zoledziewska, Magdalena, Karhunen, Ville, Kritchevsky, Stephen B, Sattar, Naveed, Lachance, Genevieve, Clarke, Robert, Harris, Tamara B, Raitakari, Olli T, Attia, John R, Van Heemst, Diana, Kajantie, Eero, Sorice, Rossella, Gambaro, Giovanni, Scott, Robert A, Hicks, Andrew A, Ferrucci, Luigi, Standl, Marie, Lindgren, Cecilia M, Starr, John M, Karlsson, Magnus, Lind, Lars, Li, Jun Z, Chambers, John C, Mori, Trevor A, De Geus, Eco J C N, Heath, Andrew C, Martin, Nicholas G, Auvinen, Juha, Buckley, Brendan M, De Craen, Anton J M, Waldenberger, Melanie, Strauch, Konstantin, Meitinger, Thomas, Scott, Rodney J, McEvoy, Mark, Beekman, Marian, Bombieri, Cristina, Ridker, Paul M, Mohlke, Karen L, Pedersen, Nancy L, Morrison, Alanna C, Boomsma, Dorret I, Whitfield, John B, Strachan, David P, Hofman, Albert, Vollenweider, Peter, Cucca, Francesco, Jarvelin, Marjo-Riitta, Jukema, J Wouter, Spector, Tim D, Hamsten, Anders, Zeller, Tanja, Uitterlinden, André G, Nauck, Matthias, Gudnason, Vilmundur, Qi, Lu, Grallert, Harald, Borecki, Ingrid B, Rotter, Jerome I, März, Winfried, Wild, Philipp S, Lokki, Marja-Liisa, Boyle, Michael, Salomaa, Veikko, Melbye, Mads, Eriksson, Johan G, Wilson, James F, Penninx, Brenda W J H, Becker, Diane M, Worrall, Bradford B, Gibson, Greg, Krauss, Ronald M, Ciullo, Marina, Zaza, Gianluigi, Wareham, Nicholas J, Oldehinkel, Albertine J, Palmer, Lyle J, Murray, Sarah S, Pramstaller, Peter P, Bandinelli, Stefania, Heinrich, Joachim, Ingelsson, Erik, Deary, Ian J, Mägi, Reedik, Vandenput, Liesbeth, Van Der Harst, Pim, Desch, Karl C, Kooner, Jaspal S, Ohlsson, Claes, Hayward, Caroline, Lehtimäki, Terho, Shuldiner, Alan R, Arnett, Donna K, Beilin, Lawrence J, Robino, Antonietta, Froguel, Philippe, Pirastu, Mario, Jess, Tine, Koenig, Wolfgang, Loos, Ruth J F, Evans, Denis A, Schmidt, Helena, Smith, George Davey, Slagboom, P Eline, Eiriksdottir, Gudny, Morris, Andrew P, Psaty, Bruce M, Tracy, Russell P, Nolte, Ilja M, Boerwinkle, Eric, Visvikis-Siest, Sophie, Reiner, Alex P, Gross, Myron, Bis, Joshua C, Franke, Lude, Franco, Oscar H, Benjamin, Emelia J, Chasman, Daniel I, Dupuis, Josée, Snieder, Harold, Dehghan, Abbas, and Alizadeh, Behrooz Z

Subjects
2. Zero hunger, 610 Medicine & health, 360 Social problems & social services, 3. Good health
Abstract

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

25. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Author

Martin, Nicholas G., Gudbjartsson, Daniel F., Nutile, Teresa, De Mutsert, Renée, Ong, Ken K., Tung, Joyce Y., Timpson, Nicholas J., Easton, Douglas F., Meitinger, Thomas, Franceschini, Nora, Crisponi, Laura, Ulivi, Sheila, Sulem, Patrick, Völzke, Henry, Völker, Uwe, Flesch-Janys, Dieter, Mulligan, Anna M., Perjakova, Natalia, Karasik, David, Chenevix-Trench, Georgia, Bandinelli, Stefania, Järvelin, Marjo-Riitta, Pharoah, Paul D.P., Vitart, Veronique, Scott, Robert A., Tanaka, Toshiko, Paternoster, Lavinia, Rueedi, Rico, Altmaier, Elisabeth, Murray, Anna, Palotie, Aarno, Mägi, Reedik, Catamo, Eulalia, Grallert, Harald, McMahon, George, Mbarek, Hamdi, Joshi, Peter K., Tyrer, Jonathan P., Giri, Ayush, Hopper, John L., Boerwinkle, Eric, Spector, Tim D., Loh, Po-Ru, Alizadeh, Behrooz Z., Barbieri, Caterina M., Rahman, Iffat, Ikram, M. Arfan, Amini, Marzyeh, Magnusson, Patrik K.E., Wang, Qin, Lawlor, Debbie A., Hu, Frank, Hartman, Catharina A., Willemsen, Gonneke, Padmanabhan, Sandosh, Southey, Melissa C., Schraut, Katharina E., Montgomery, Grant W., Brauch, Hiltrud, Couch, Fergus J., Heiss, Gerardo, Luan, Jian'An, Murabito, Joanne M., Pedersen, Nancy, Beckmann, Matthias W., Thorsteindottir, Unnur, Wareham, Nicholas J., Cucca, Francesco, Noordam, Raymond, Im, Hae Kyung, Visser, Jenny A., Teumer, Alexander, McCarthy, Mark I., Liu, Yongmei, Oldehinkel, Albertine J., Rudan, Igor, Czene, Kamila, Hamann, Ute, Menni, Cristina, Medland, Sarah E., Kolcic, Ivana, Polasek, Ozren, Demerath, Ellen, Li, Jingmei, Mook-Kanamori, Dennis O., Smith, Albert V., Toniolo, Daniela, Lenarduzzi, Stefania, Zhao, Jing Hua, Uitterlinden, André G., Campbell, Harry, Stöckl, Doris, Segrè, Ayellet V., Day, Felix R., Benitez, Javier, Andrulis, Irene L., Ridker, Paul M., Nyholt, Dale R., Edwards, Digna R. Velez, Mannermaa, Arto, Gabrielson, Marike, Boutin, Thibaud, Wolffenbuttel, Bruce H.R., Launer, Lenore J., Lindstrom, Sara, Meisinger, Christa, Buring, Julie E., Whalen, Sean, Zoledziewska, Magdalena, Milne, Roger L., Rosendaal, Frits R., Helgason, Hannes, Lunetta, Kathryn L., Mangino, Massimo, Tikkanen, Emmi, Hallberg, Emily, Cox, Angela, Strauch, Konstantin, Pollard, Katherine S., Hottenga, Jouke J., Widen, Elisabeth, Gieger, Christian, Gandin, Ilaria, Dunning, Alison M., Kraft, Peter, Dos-Santos-Silva, Isabel, Van Dijk, Ko Willems, Brand, Judith S., Giles, Graham G., Stolk, Lisette, Michailidou, Kyriaki, Bolla, Manjeet K., Fernández-Rhodes, Lindsay, Hinds, David, Davey Smith, George, Bochud, Murielle, Radice, Paolo, Marco, Brumat, Fasching, Peter A., Chang-Claude, Jenny, Price, Alkes L., Lind, Penelope A., Ruggiero, Daniela, Campbell, Archie, Robino, Antonietta, Hall, Per, Laven, Joop S.E., Metspalu, Andres, Finucane, Hilary, Lambrechts, Diether, Navarro, Pau, Devilee, Peter, Nevanlinna, Heli, O'Mara, Tracy A., Peto, Julian, Ferrucci, Luigi, Schmidt, Marjanka K., Corre, Tanguy, Sorice, Rossella, Ring, Susan M., Winqvist, Robert, Harris, Tamara B., Hayward, Caroline, De Vivo, Immaculata, Dennis, Joe, Porteous, David, Brenner, Hermann, Guénel, Pascal, Kutalik, Zoltan, Truong, Thérèse, Nohr, Ellen A., Perry, John R.B., Porcu, Eleonora, Eriksson, Johan G., Karlsson, Robert, Chanock, Stephen, Esko, Tõnu, Zygmunt, Marek, Nalls, Mike A., Stampfer, Meir, De Geus, Eco J.C.N., Snieder, Harold, Franke, Lude, Boomsma, Dorret I., Bojesen, Stig E., Sala, Cinzia F., Spurdle, Amanda B., Sarkar, Abhishek K., Brüning, Thomas, Hunter, David J., Gudnason, Vilmundur, Chasman, Daniel I., Stefansson, Kari, Vollenweider, Peter, Cousminer, Diana L., Albrecht, Eva, Steri, Maristella, Milani, Lili, Thompson, Deborah J., Broer, Linda, Rose, Lynda M., Lachance, Genevieve, Shah, Mitul, Bergmann, Sven, Ciullo, Marina, Peters, Annette, Pouta, Anneli, Hooning, Maartje J., Langenberg, Claudia, Ruth, Katherine S., Sovio, Ulla, Traglia, Michela, Nolte, Ilja M., He, Chunyan, Wilson, James F., and Kellis, Manolis

Subjects
2. Zero hunger, 3. Good health
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P

26. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Author

Emmi Tikkanen, Pascal Guénel, Rico Rueedi, Hamdi Mbarek, Gerardo Heiss, Hilary K. Finucane, Jing Hua Zhao, Peter K. Joshi, Mark I. McCarthy, Frank B. Hu, Stephen J. Chanock, Manjeet K. Bolla, Sandosh Padmanabhan, Vilmundur Gudnason, Chunyan He, Aarno Palotie, Reedik Mägi, Joe Dennis, Nicholas G. Martin, Behrooz Z. Alizadeh, Elisabeth Widen, Caroline Hayward, Penelope A. Lind, Magdalena Zoledziewska, Ayellet V. Segrè, Fergus J. Couch, Massimo Mangino, Melissa C. Southey, Immaculata De Vivo, Yongmei Liu, Ute Hamann, Angela Cox, Maartje J. Hooning, Iffat Rahman, Mitul Shah, Eric Boerwinkle, Matthias W. Beckmann, Catharina A. Hartman, Tanguy Corre, Kathryn L. Lunetta, Thérèse Truong, Anna Marie Mulligan, Caterina Barbieri, Robert Winqvist, Lili Milani, Cristina Menni, Frits R. Rosendaal, Pau Navarro, Christian Gieger, Ken K. Ong, Stig E. Bojesen, Susan M. Ring, Marjanka K. Schmidt, George McMahon, Deborah J. Thompson, Robert Karlsson, Nicholas J. Timpson, M. Arfan Ikram, Alexander Teumer, Jingmei Li, Christa Meisinger, Diana L. Cousminer, Doris Stöckl, Heli Nevanlinna, Teresa Nutile, Tim D. Spector, Eva Albrecht, Murielle Bochud, Linda Broer, Felix R. Day, Sven Bergmann, Renée de Mutsert, Nicholas J. Wareham, Marjo-Riitta Järvelin, Marzyeh Amini, Elisabeth Altmaier, Isabel dos-Santos-Silva, Peter Vollenweider, Douglas F. Easton, Tamara B. Harris, Ellen A. Nohr, Paul D.P. Pharoah, David J. Porteous, Jenny A. Visser, Ilja M. Nolte, Genevieve Lachance, Thomas Meitinger, Archie Campbell, Thomas Brüning, Graham G. Giles, Johan G. Eriksson, Nancy L. Pedersen, George Davey Smith, Gonneke Willemsen, Joanne M. Murabito, Francesco Cucca, Daniel I. Chasman, Eleonora Porcu, Nora Franceschini, Thibaud Boutin, Ulla Sovio, Roger L. Milne, Annette Peters, Lisette Stolk, Paul M. Ridker, Claudia Langenberg, Patrick Sulem, Toshiko Tanaka, Marike Gabrielson, Judith S. Brand, Unnur Thorsteindottir, Alison M. Dunning, Marina Ciullo, Julie E. Buring, Harold Snieder, Lude Franke, Meir J. Stampfer, Po-Ru Loh, Julian Peto, Ellen W. Demerath, Sheila Ulivi, Ivana Kolcic, Maristella Steri, Jouke J. Hottenga, Amanda B. Spurdle, Tõnu Esko, Katherine S. Pollard, Eulalia Catamo, Anneli Pouta, Kyriaki Michailidou, Dieter Flesch-Janys, James F. Wilson, Kamila Czene, Sean Whalen, Diether Lambrechts, Abhishek Sarkar, Laura Crisponi, Jonathan Tyrer, Antonietta Robino, Sara Lindström, Harald Grallert, Stefania Lenarduzzi, Peter Kraft, Patrik K. E. Magnusson, Lavinia Paternoster, Digna R. Velez Edwards, Mike A. Nalls, Per Hall, Joyce Y. Tung, Cinzia Sala, Lindsay Fernández-Rhodes, Ayush Giri, Hiltrud Brauch, André G. Uitterlinden, Alkes L. Price, Tracy A. O'Mara, Lynda M. Rose, John L. Hopper, David A. Hinds, Katherine S. Ruth, Arto Mannermaa, Uwe Völker, Rossella Sorice, Zoltán Kutalik, Debbie A Lawlor, Georgia Chenevix-Trench, Anna Murray, Albertine J. Oldehinkel, Bruce H. R. Wolffenbuttel, Hae Kyung Im, Dale R. Nyholt, Lenore J. Launer, Andres Metspalu, Irene L. Andrulis, Konstantin Strauch, Albert V. Smith, Daniela Toniolo, Eco J. C. de Geus, Jenny Chang-Claude, Marek Zygmunt, Dorret I. Boomsma, Harry Campbell, Peter Devilee, Henry Völzke, Daniela Ruggiero, Dennis O. Mook-Kanamori, John R. B. Perry, Javier Benitez, Grant W. Montgomery, David J. Hunter, David Karasik, Luigi Ferrucci, Emily Hallberg, Stefania Bandinelli, Hermann Brenner, Raymond Noordam, Sarah E. Medland, Peter A. Fasching, Qin Wang, Ilaria Gandin, Manolis Kellis, Hannes Helgason, Igor Rudan, Paolo Radice, Michela Traglia, Jian'an Luan, Robert A. Scott, Brumat Marco, Veronique Vitart, Kari Stefansson, Katharina E. Schraut, Ko Willems van Dijk, Ozren Polasek, Daniel F. Gudbjartsson, Natalia Perjakova, Joop S.E. Laven, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Art and Culture, History, Antiquity, Day, Felix R., Thompson, Deborah J., Helgason, Hanne, Chasman, Daniel I., Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S., Whalen, Sean, Sarkar, Abhishek K., Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, CATERINA MARIA, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J., Karlsson, Robert, Kolcic, Ivana, Loh, Po Ru, Lunetta, Kathryn L., Mangino, Massimo, Brumat, Marco, Mcmahon, George, Medland, Sarah E., Nolte, Ilja M., Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M., Schraut, Katharina E., Segrã¨, Ayellet V., Smith, Albert V., Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L., Bandinelli, Stefania, Beckmann, Matthias W., Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brã¼ning, Thoma, Buring, Julie E., Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix Trench, Georgia, Corre, Tanguy, Couch, Fergus J., Cousminer, Diana L., Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, De Geus, Eco J. C. N., De Mutsert, Renã©e, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos Santos Silva, Isabel, Dunning, Alison M., Eriksson, Johan G., Fasching, Peter A., Fernández Rhodes, Lindsay, Ferrucci, Luigi, Flesch Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Guã©nel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B., Hartman, Catharina A., Heiss, Gerardo, Hooning, Maartje J., Hopper, John L., Hu, Frank, Hunter, David J., Ikram, M. Arfan, Im, Hae Kyung, Jã¤rvelin, Marjo Riitta, Joshi, Peter K., Karasik, David, Kellis, Manoli, Kutalik, Zoltan, Lachance, Genevieve, Lambrechts, Diether, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lenarduzzi, Stefania, Li, Jingmei, Lind, Penelope A., Lindstrom, Sara, Liu, Yongmei, Luan, Jian'An, Mã¤gi, Reedik, Mannermaa, Arto, Mbarek, Hamdi, Mccarthy, Mark I., Meisinger, Christa, Meitinger, Thoma, Menni, Cristina, Metspalu, Andre, Michailidou, Kyriaki, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mulligan, Anna M., Nalls, Mike A., Navarro, Pau, Nevanlinna, Heli, Nyholt, Dale R., Oldehinkel, Albertine J., O'Mara, Tracy A., Padmanabhan, Sandosh, Palotie, Aarno, Pedersen, Nancy, Peters, Annette, Peto, Julian, Pharoah, Paul D. P., Pouta, Anneli, Radice, Paolo, Rahman, Iffat, Ring, Susan M., Robino, Antonietta, Rosendaal, Frits R., Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Schmidt, Marjanka K., Scott, Robert A., Shah, Mitul, Sorice, Rossella, Southey, Melissa C., Sovio, Ulla, Stampfer, Meir, Steri, Maristella, Strauch, Konstantin, Tanaka, Toshiko, Tikkanen, Emmi, Timpson, Nicholas J., Traglia, Michela, Truong, Thã©rã¨se, Tyrer, Jonathan P., Uitterlinden, André G., Edwards, Digna R. Velez, Vitart, Veronique, Vã¶lker, Uwe, Vollenweider, Peter, Wang, Qin, Widen, Elisabeth, Van Dijk, Ko Willem, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R., Zhao, Jing Hua, Zoledziewska, Magdalena, Zygmunt, Marek, Alizadeh, Behrooz Z., Boomsma, Dorret I., Ciullo, Marina, Cucca, Francesco, Esko, Tãµnu, Franceschini, Nora, Gieger, Christian, Gudnason, Vilmundur, Hayward, Caroline, Kraft, Peter, Lawlor, Debbie A., Magnusson, Patrik K. E., Martin, Nicholas G., Mook Kanamori, Dennis O., Nohr, Ellen A., Polasek, Ozren, Porteous, David, Price, Alkes L., Ridker, Paul M., Snieder, Harold, Spector, Tim D., Stã¶ckl, Dori, Toniolo, Daniela, Ulivi, Sheila, Visser, Jenny A., Vã¶lzke, Henry, Wareham, Nicholas J., Wilson, James F., LifeLines Cohort, Study, Interact, Consortium, Kconfab/aocs, Investigator, Endometrial Cancer Association, Consortium, Ovarian Cancer Association, Consortium, Practical, Consortium, Spurdle, Amanda B., Thorsteindottir, Unnur, Pollard, Katherine S., Easton, Douglas F., Tung, Joyce Y., Chang Claude, Jenny, Hinds, David, Murray, Anna, Murabito, Joanne M., Stefansson, Kari, Ong, Ken K., Perry, John R. B., Internal Medicine, Erasmus MC other, Medical Oncology, Epidemiology, Obstetrics & Gynecology, Day, Felix [0000-0003-3789-7651], Thompson, Deborah [0000-0003-1465-5799], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Pharoah, Paul [0000-0001-8494-732X], Sovio, Ulla [0000-0002-0799-1105], Tyrer, Jonathan [0000-0003-3724-4757], Zhao, Jing Hua [0000-0003-4930-3582], Wareham, Nicholas [0000-0003-1422-2993], Easton, Douglas [0000-0003-2444-3247], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Massachusetts Institute of Technology. Department of Mathematics, and Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Ovarian Cancer Association Consortium, LOCI, Genome-wide association study, cancer risk, Menarche/genetics, Bioinformatics, GWAS, menarche, puberty, Body Mass Index, Risk Factors, Neoplasms, Databases, Genetic, WIDE ASSOCIATION, Endometrial Cancer Association Consortium, Ribonucleoproteins/genetics, 2. Zero hunger, Genetics, Age Factors, Genetics GWAS menarche, reproductive disorders, Neoplasms/genetics, 3. Good health, Ribonucleoproteins, Menarche, MENDELIAN RANDOMIZATION, Intercellular Signaling Peptides and Proteins, GROWTH, Female, TRAITS, Population variance, Intercellular Signaling Peptides and Proteins/genetics, Adolescent, Ubiquitin-Protein Ligases, kConFab/AOCS Investigators, Quantitative Trait Loci, Quantitative trait locus, Biology, METABOLISM, INHERITANCE, Polymorphism, Single Nucleotide, PRACTICAL consortium, 03 medical and health sciences, Genomic Imprinting, SDG 3 - Good Health and Well-being, Mendelian randomization, REGRESSION, medicine, Journal Article, Humans, cancer, Genetic Predisposition to Disease, 1000 Genomes Project, Membrane Proteins/genetics, METAANALYSIS, Puberty, Calcium-Binding Proteins, Membrane Proteins, Cancer, InterAct Consortium, Heritability, medicine.disease, BODY-MASS INDEX, 030104 developmental biology, genome-wide association studies, Puberty/genetics, LifeLines Cohort Study, Genome-Wide Association Study
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P

Published
2017

27. Diverging destinies: 'social' data within the TwinsUK cohort.

Author

Bowyer RCE, Abbasian G, García MP, Anastasiou A, Lachance G, Thompson EJ, Hart D, Dowd JB, and Steves CJ

Abstract

Background : Twins offer social scientists a unique opportunity to understand the interplay of social factors and physical and mental well-being. TwinsUK is the largest UK registry of adult mono- and dy-zygotic twins, but most of the research that utilises the cohorts' data to date has focused on the genetic underpinnings of complex disease. Methods : Following formal unstructured discussions with social scientists we identified key areas of research interest and annotated the historical data collections in TwinsUK where they could be applied to these research aims. Results : We present a summary of variables identified as of key interest to researchers from the social science sphere, spanning the following domains: 1: Parenting, child rearing and pregnancies; 2: Working habits and patterns; 3: Sleeping habits and patterns; 4: Social support; 5: Negative life events; 6: Spousal relationships. Conclusions : TwinsUK has a wide range of genetic and health data that would allow investigation of research questions focusing on these domains., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Bowyer RCE et al.)

Published
2022
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28. Genetic insights into biological mechanisms governing human ovarian ageing.

Author

Ruth KS, Day FR, Hussain J, Martínez-Marchal A, Aiken CE, Azad A, Thompson DJ, Knoblochova L, Abe H, Tarry-Adkins JL, Gonzalez JM, Fontanillas P, Claringbould A, Bakker OB, Sulem P, Walters RG, Terao C, Turon S, Horikoshi M, Lin K, Onland-Moret NC, Sankar A, Hertz EPT, Timshel PN, Shukla V, Borup R, Olsen KW, Aguilera P, Ferrer-Roda M, Huang Y, Stankovic S, Timmers PRHJ, Ahearn TU, Alizadeh BZ, Naderi E, Andrulis IL, Arnold AM, Aronson KJ, Augustinsson A, Bandinelli S, Barbieri CM, Beaumont RN, Becher H, Beckmann MW, Benonisdottir S, Bergmann S, Bochud M, Boerwinkle E, Bojesen SE, Bolla MK, Boomsma DI, Bowker N, Brody JA, Broer L, Buring JE, Campbell A, Campbell H, Castelao JE, Catamo E, Chanock SJ, Chenevix-Trench G, Ciullo M, Corre T, Couch FJ, Cox A, Crisponi L, Cross SS, Cucca F, Czene K, Smith GD, de Geus EJCN, de Mutsert R, De Vivo I, Demerath EW, Dennis J, Dunning AM, Dwek M, Eriksson M, Esko T, Fasching PA, Faul JD, Ferrucci L, Franceschini N, Frayling TM, Gago-Dominguez M, Mezzavilla M, García-Closas M, Gieger C, Giles GG, Grallert H, Gudbjartsson DF, Gudnason V, Guénel P, Haiman CA, Håkansson N, Hall P, Hayward C, He C, He W, Heiss G, Høffding MK, Hopper JL, Hottenga JJ, Hu F, Hunter D, Ikram MA, Jackson RD, Joaquim MDR, John EM, Joshi PK, Karasik D, Kardia SLR, Kartsonaki C, Karlsson R, Kitahara CM, Kolcic I, Kooperberg C, Kraft P, Kurian AW, Kutalik Z, La Bianca M, LaChance G, Langenberg C, Launer LJ, Laven JSE, Lawlor DA, Le Marchand L, Li J, Lindblom A, Lindstrom S, Lindstrom T, Linet M, Liu Y, Liu S, Luan J, Mägi R, Magnusson PKE, Mangino M, Mannermaa A, Marco B, Marten J, Martin NG, Mbarek H, McKnight B, Medland SE, Meisinger C, Meitinger T, Menni C, Metspalu A, Milani L, Milne RL, Montgomery GW, Mook-Kanamori DO, Mulas A, Mulligan AM, Murray A, Nalls MA, Newman A, Noordam R, Nutile T, Nyholt DR, Olshan AF, Olsson H, Painter JN, Patel AV, Pedersen NL, Perjakova N, Peters A, Peters U, Pharoah PDP, Polasek O, Porcu E, Psaty BM, Rahman I, Rennert G, Rennert HS, Ridker PM, Ring SM, Robino A, Rose LM, Rosendaal FR, Rossouw J, Rudan I, Rueedi R, Ruggiero D, Sala CF, Saloustros E, Sandler DP, Sanna S, Sawyer EJ, Sarnowski C, Schlessinger D, Schmidt MK, Schoemaker MJ, Schraut KE, Scott C, Shekari S, Shrikhande A, Smith AV, Smith BH, Smith JA, Sorice R, Southey MC, Spector TD, Spinelli JJ, Stampfer M, Stöckl D, van Meurs JBJ, Strauch K, Styrkarsdottir U, Swerdlow AJ, Tanaka T, Teras LR, Teumer A, Þorsteinsdottir U, Timpson NJ, Toniolo D, Traglia M, Troester MA, Truong T, Tyrrell J, Uitterlinden AG, Ulivi S, Vachon CM, Vitart V, Völker U, Vollenweider P, Völzke H, Wang Q, Wareham NJ, Weinberg CR, Weir DR, Wilcox AN, van Dijk KW, Willemsen G, Wilson JF, Wolffenbuttel BHR, Wolk A, Wood AR, Zhao W, Zygmunt M, Chen Z, Li L, Franke L, Burgess S, Deelen P, Pers TH, Grøndahl ML, Andersen CY, Pujol A, Lopez-Contreras AJ, Daniel JA, Stefansson K, Chang-Claude J, van der Schouw YT, Lunetta KL, Chasman DI, Easton DF, Visser JA, Ozanne SE, Namekawa SH, Solc P, Murabito JM, Ong KK, Hoffmann ER, Murray A, Roig I, and Perry JRB

Subjects
Adult, Alleles, Animals, Bone and Bones metabolism, Checkpoint Kinase 1 genetics, Checkpoint Kinase 2 genetics, Diabetes Mellitus, Type 2, Diet, Europe ethnology, Asia, Eastern ethnology, Female, Fertility genetics, Fragile X Mental Retardation Protein genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Healthy Aging genetics, Humans, Longevity genetics, Menopause genetics, Menopause, Premature genetics, Mice, Mice, Inbred C57BL, Middle Aged, Primary Ovarian Insufficiency genetics, Uterus, Aging genetics, Ovary metabolism
Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women 1,2 , but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations 3 . The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2021
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29. Author Correction: Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.

Author

Iotchkova V, Huang J, Morris JA, Jain D, Barbieri C, Walter K, Min JL, Chen L, Astle W, Cocca M, Deelen P, Elding H, Farmaki AE, Franklin CS, Franberg M, Gaunt TR, Hofman A, Jiang T, Kleber ME, Lachance G, Luan J, Malerba G, Matchan A, Mead D, Memari Y, Ntalla I, Panoutsopoulou K, Pazoki R, Perry JRB, Rivadeneira F, Sabater-Lleal M, Sennblad B, Shin SY, Southam L, Traglia M, van Dijk F, van Leeuwen EM, Zaza G, Zhang W, Amin N, Butterworth A, Chambers JC, Dedoussis G, Dehghan A, Franco OH, Franke L, Frontini M, Gambaro G, Gasparini P, Hamsten A, Isaacs A, Kooner JS, Kooperberg C, Langenberg C, Marz W, Scott RA, Swertz MA, Toniolo D, Uitterlinden AG, van Duijn CM, Watkins H, Zeggini E, Maurano MT, Timpson NJ, Reiner AP, Auer PL, and Soranzo N

Abstract

In the version of the article published, the surname of author Aaron Isaacs is misspelled as Issacs.

Published
2018
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30. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Author

Ligthart S, Vaez A, Võsa U, Stathopoulou MG, de Vries PS, Prins BP, Van der Most PJ, Tanaka T, Naderi E, Rose LM, Wu Y, Karlsson R, Barbalic M, Lin H, Pool R, Zhu G, Macé A, Sidore C, Trompet S, Mangino M, Sabater-Lleal M, Kemp JP, Abbasi A, Kacprowski T, Verweij N, Smith AV, Huang T, Marzi C, Feitosa MF, Lohman KK, Kleber ME, Milaneschi Y, Mueller C, Huq M, Vlachopoulou E, Lyytikäinen LP, Oldmeadow C, Deelen J, Perola M, Zhao JH, Feenstra B, Amini M, Lahti J, Schraut KE, Fornage M, Suktitipat B, Chen WM, Li X, Nutile T, Malerba G, Luan J, Bak T, Schork N, Del Greco M F, Thiering E, Mahajan A, Marioni RE, Mihailov E, Eriksson J, Ozel AB, Zhang W, Nethander M, Cheng YC, Aslibekyan S, Ang W, Gandin I, Yengo L, Portas L, Kooperberg C, Hofer E, Rajan KB, Schurmann C, den Hollander W, Ahluwalia TS, Zhao J, Draisma HHM, Ford I, Timpson N, Teumer A, Huang H, Wahl S, Liu Y, Huang J, Uh HW, Geller F, Joshi PK, Yanek LR, Trabetti E, Lehne B, Vozzi D, Verbanck M, Biino G, Saba Y, Meulenbelt I, O'Connell JR, Laakso M, Giulianini F, Magnusson PKE, Ballantyne CM, Hottenga JJ, Montgomery GW, Rivadineira F, Rueedi R, Steri M, Herzig KH, Stott DJ, Menni C, Frånberg M, St Pourcain B, Felix SB, Pers TH, Bakker SJL, Kraft P, Peters A, Vaidya D, Delgado G, Smit JH, Großmann V, Sinisalo J, Seppälä I, Williams SR, Holliday EG, Moed M, Langenberg C, Räikkönen K, Ding J, Campbell H, Sale MM, Chen YI, James AL, Ruggiero D, Soranzo N, Hartman CA, Smith EN, Berenson GS, Fuchsberger C, Hernandez D, Tiesler CMT, Giedraitis V, Liewald D, Fischer K, Mellström D, Larsson A, Wang Y, Scott WR, Lorentzon M, Beilby J, Ryan KA, Pennell CE, Vuckovic D, Balkau B, Concas MP, Schmidt R, Mendes de Leon CF, Bottinger EP, Kloppenburg M, Paternoster L, Boehnke M, Musk AW, Willemsen G, Evans DM, Madden PAF, Kähönen M, Kutalik Z, Zoledziewska M, Karhunen V, Kritchevsky SB, Sattar N, Lachance G, Clarke R, Harris TB, Raitakari OT, Attia JR, van Heemst D, Kajantie E, Sorice R, Gambaro G, Scott RA, Hicks AA, Ferrucci L, Standl M, Lindgren CM, Starr JM, Karlsson M, Lind L, Li JZ, Chambers JC, Mori TA, de Geus EJCN, Heath AC, Martin NG, Auvinen J, Buckley BM, de Craen AJM, Waldenberger M, Strauch K, Meitinger T, Scott RJ, McEvoy M, Beekman M, Bombieri C, Ridker PM, Mohlke KL, Pedersen NL, Morrison AC, Boomsma DI, Whitfield JB, Strachan DP, Hofman A, Vollenweider P, Cucca F, Jarvelin MR, Jukema JW, Spector TD, Hamsten A, Zeller T, Uitterlinden AG, Nauck M, Gudnason V, Qi L, Grallert H, Borecki IB, Rotter JI, März W, Wild PS, Lokki ML, Boyle M, Salomaa V, Melbye M, Eriksson JG, Wilson JF, Penninx BWJH, Becker DM, Worrall BB, Gibson G, Krauss RM, Ciullo M, Zaza G, Wareham NJ, Oldehinkel AJ, Palmer LJ, Murray SS, Pramstaller PP, Bandinelli S, Heinrich J, Ingelsson E, Deary IJ, Mägi R, Vandenput L, van der Harst P, Desch KC, Kooner JS, Ohlsson C, Hayward C, Lehtimäki T, Shuldiner AR, Arnett DK, Beilin LJ, Robino A, Froguel P, Pirastu M, Jess T, Koenig W, Loos RJF, Evans DA, Schmidt H, Smith GD, Slagboom PE, Eiriksdottir G, Morris AP, Psaty BM, Tracy RP, Nolte IM, Boerwinkle E, Visvikis-Siest S, Reiner AP, Gross M, Bis JC, Franke L, Franco OH, Benjamin EJ, Chasman DI, Dupuis J, Snieder H, Dehghan A, and Alizadeh BZ

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers metabolism, Bipolar Disorder genetics, Bipolar Disorder metabolism, Body Mass Index, C-Reactive Protein genetics, Child, Female, Genome-Wide Association Study methods, Humans, Inflammation metabolism, Liver metabolism, Liver pathology, Male, Mendelian Randomization Analysis methods, Middle Aged, Schizophrenia genetics, Schizophrenia metabolism, Young Adult, Genetic Loci genetics, Inflammation genetics, Metabolic Networks and Pathways genetics
Abstract

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10 -8 ). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)

Published
2018
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31. Differences in genetic and environmental variation in adult BMI by sex, age, time period, and region: an individual-based pooled analysis of 40 twin cohorts.

Author

Silventoinen K, Jelenkovic A, Sund R, Yokoyama Y, Hur YM, Cozen W, Hwang AE, Mack TM, Honda C, Inui F, Iwatani Y, Watanabe M, Tomizawa R, Pietiläinen KH, Rissanen A, Siribaddana SH, Hotopf M, Sumathipala A, Rijsdijk F, Tan Q, Zhang D, Pang Z, Piirtola M, Aaltonen S, Öncel SY, Aliev F, Rebato E, Hjelmborg JB, Christensen K, Skytthe A, Kyvik KO, Silberg JL, Eaves LJ, Cutler TL, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Song YM, Yang S, Lee K, Franz CE, Kremen WS, Lyons MJ, Busjahn A, Nelson TL, Whitfield KE, Kandler C, Jang KL, Gatz M, Butler DA, Stazi MA, Fagnani C, D'Ippolito C, Duncan GE, Buchwald D, Martin NG, Medland SE, Montgomery GW, Jeong HU, Swan GE, Krasnow R, Magnusson PK, Pedersen NL, Dahl Aslan AK, McAdams TA, Eley TC, Gregory AM, Tynelius P, Baker LA, Tuvblad C, Bayasgalan G, Narandalai D, Spector TD, Mangino M, Lachance G, Burt SA, Klump KL, Harris JR, Brandt I, Nilsen TS, Krueger RF, McGue M, Pahlen S, Corley RP, Huibregtse BM, Bartels M, van Beijsterveldt CE, Willemsen G, Goldberg JH, Rasmussen F, Tarnoki AD, Tarnoki DL, Derom CA, Vlietinck RF, Loos RJ, Hopper JL, Sung J, Maes HH, Turkheimer E, Boomsma DI, Sørensen TI, and Kaprio J

Subjects
Adult, Age Factors, Aged, Aged, 80 and over, Australia, Culture, Europe, Female, Humans, Male, Middle Aged, North America, Prevalence, Sex Factors, Twins, Dizygotic genetics, Twins, Monozygotic genetics, Young Adult, Body Mass Index, Body Weight genetics, Environment, Gene-Environment Interaction, Obesity genetics, Quantitative Trait, Heritable
Abstract

Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m 2 )], but factors modifying these variance components are poorly understood. Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity. Design: We used genetic structural equation modeling to analyze BMI in twins ≥20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs). Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 20-29 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI. Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population., (© 2017 American Society for Nutrition.)

Published
2017
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32. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.

Author

Day FR, Thompson DJ, Helgason H, Chasman DI, Finucane H, Sulem P, Ruth KS, Whalen S, Sarkar AK, Albrecht E, Altmaier E, Amini M, Barbieri CM, Boutin T, Campbell A, Demerath E, Giri A, He C, Hottenga JJ, Karlsson R, Kolcic I, Loh PR, Lunetta KL, Mangino M, Marco B, McMahon G, Medland SE, Nolte IM, Noordam R, Nutile T, Paternoster L, Perjakova N, Porcu E, Rose LM, Schraut KE, Segrè AV, Smith AV, Stolk L, Teumer A, Andrulis IL, Bandinelli S, Beckmann MW, Benitez J, Bergmann S, Bochud M, Boerwinkle E, Bojesen SE, Bolla MK, Brand JS, Brauch H, Brenner H, Broer L, Brüning T, Buring JE, Campbell H, Catamo E, Chanock S, Chenevix-Trench G, Corre T, Couch FJ, Cousminer DL, Cox A, Crisponi L, Czene K, Davey Smith G, de Geus EJCN, de Mutsert R, De Vivo I, Dennis J, Devilee P, Dos-Santos-Silva I, Dunning AM, Eriksson JG, Fasching PA, Fernández-Rhodes L, Ferrucci L, Flesch-Janys D, Franke L, Gabrielson M, Gandin I, Giles GG, Grallert H, Gudbjartsson DF, Guénel P, Hall P, Hallberg E, Hamann U, Harris TB, Hartman CA, Heiss G, Hooning MJ, Hopper JL, Hu F, Hunter DJ, Ikram MA, Im HK, Järvelin MR, Joshi PK, Karasik D, Kellis M, Kutalik Z, LaChance G, Lambrechts D, Langenberg C, Launer LJ, Laven JSE, Lenarduzzi S, Li J, Lind PA, Lindstrom S, Liu Y, Luan J, Mägi R, Mannermaa A, Mbarek H, McCarthy MI, Meisinger C, Meitinger T, Menni C, Metspalu A, Michailidou K, Milani L, Milne RL, Montgomery GW, Mulligan AM, Nalls MA, Navarro P, Nevanlinna H, Nyholt DR, Oldehinkel AJ, O'Mara TA, Padmanabhan S, Palotie A, Pedersen N, Peters A, Peto J, Pharoah PDP, Pouta A, Radice P, Rahman I, Ring SM, Robino A, Rosendaal FR, Rudan I, Rueedi R, Ruggiero D, Sala CF, Schmidt MK, Scott RA, Shah M, Sorice R, Southey MC, Sovio U, Stampfer M, Steri M, Strauch K, Tanaka T, Tikkanen E, Timpson NJ, Traglia M, Truong T, Tyrer JP, Uitterlinden AG, Edwards DRV, Vitart V, Völker U, Vollenweider P, Wang Q, Widen E, van Dijk KW, Willemsen G, Winqvist R, Wolffenbuttel BHR, Zhao JH, Zoledziewska M, Zygmunt M, Alizadeh BZ, Boomsma DI, Ciullo M, Cucca F, Esko T, Franceschini N, Gieger C, Gudnason V, Hayward C, Kraft P, Lawlor DA, Magnusson PKE, Martin NG, Mook-Kanamori DO, Nohr EA, Polasek O, Porteous D, Price AL, Ridker PM, Snieder H, Spector TD, Stöckl D, Toniolo D, Ulivi S, Visser JA, Völzke H, Wareham NJ, Wilson JF, Spurdle AB, Thorsteindottir U, Pollard KS, Easton DF, Tung JY, Chang-Claude J, Hinds D, Murray A, Murabito JM, Stefansson K, Ong KK, and Perry JRB

Subjects
Adolescent, Age Factors, Body Mass Index, Calcium-Binding Proteins, Databases, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomic Imprinting, Humans, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Ubiquitin-Protein Ligases, Intercellular Signaling Peptides and Proteins genetics, Membrane Proteins genetics, Menarche genetics, Neoplasms genetics, Puberty genetics, Ribonucleoproteins genetics
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10 -8 ) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Published
2017
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33. Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994.

Author

Jelenkovic A, Hur YM, Sund R, Yokoyama Y, Siribaddana SH, Hotopf M, Sumathipala A, Rijsdijk F, Tan Q, Zhang D, Pang Z, Aaltonen S, Heikkilä K, Öncel SY, Aliev F, Rebato E, Tarnoki AD, Tarnoki DL, Christensen K, Skytthe A, Kyvik KO, Silberg JL, Eaves LJ, Maes HH, Cutler TL, Hopper JL, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Cozen W, Hwang AE, Mack TM, Sung J, Song YM, Yang S, Lee K, Franz CE, Kremen WS, Lyons MJ, Busjahn A, Nelson TL, Whitfield KE, Kandler C, Jang KL, Gatz M, Butler DA, Stazi MA, Fagnani C, D'Ippolito C, Duncan GE, Buchwald D, Derom CA, Vlietinck RF, Loos RJ, Martin NG, Medland SE, Montgomery GW, Jeong HU, Swan GE, Krasnow R, Magnusson PK, Pedersen NL, Dahl-Aslan AK, McAdams TA, Eley TC, Gregory AM, Tynelius P, Baker LA, Tuvblad C, Bayasgalan G, Narandalai D, Lichtenstein P, Spector TD, Mangino M, Lachance G, Bartels M, van Beijsterveldt TC, Willemsen G, Burt SA, Klump KL, Harris JR, Brandt I, Nilsen TS, Krueger RF, McGue M, Pahlen S, Corley RP, Hjelmborg JV, Goldberg JH, Iwatani Y, Watanabe M, Honda C, Inui F, Rasmussen F, Huibregtse BM, Boomsma DI, Sørensen TI, Kaprio J, and Silventoinen K

Subjects
Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Global Health, Humans, Male, Middle Aged, Twins, Young Adult, Body Height genetics, Environmental Exposure
Abstract

Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886-1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve., Competing Interests: The authors declare that no competing interests exist.

Published
2016
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34. Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

Author

Barban N, Jansen R, de Vlaming R, Vaez A, Mandemakers JJ, Tropf FC, Shen X, Wilson JF, Chasman DI, Nolte IM, Tragante V, van der Laan SW, Perry JR, Kong A, Ahluwalia TS, Albrecht E, Yerges-Armstrong L, Atzmon G, Auro K, Ayers K, Bakshi A, Ben-Avraham D, Berger K, Bergman A, Bertram L, Bielak LF, Bjornsdottir G, Bonder MJ, Broer L, Bui M, Barbieri C, Cavadino A, Chavarro JE, Turman C, Concas MP, Cordell HJ, Davies G, Eibich P, Eriksson N, Esko T, Eriksson J, Falahi F, Felix JF, Fontana MA, Franke L, Gandin I, Gaskins AJ, Gieger C, Gunderson EP, Guo X, Hayward C, He C, Hofer E, Huang H, Joshi PK, Kanoni S, Karlsson R, Kiechl S, Kifley A, Kluttig A, Kraft P, Lagou V, Lecoeur C, Lahti J, Li-Gao R, Lind PA, Liu T, Makalic E, Mamasoula C, Matteson L, Mbarek H, McArdle PF, McMahon G, Meddens SF, Mihailov E, Miller M, Missmer SA, Monnereau C, van der Most PJ, Myhre R, Nalls MA, Nutile T, Kalafati IP, Porcu E, Prokopenko I, Rajan KB, Rich-Edwards J, Rietveld CA, Robino A, Rose LM, Rueedi R, Ryan KA, Saba Y, Schmidt D, Smith JA, Stolk L, Streeten E, Tönjes A, Thorleifsson G, Ulivi S, Wedenoja J, Wellmann J, Willeit P, Yao J, Yengo L, Zhao JH, Zhao W, Zhernakova DV, Amin N, Andrews H, Balkau B, Barzilai N, Bergmann S, Biino G, Bisgaard H, Bønnelykke K, Boomsma DI, Buring JE, Campbell H, Cappellani S, Ciullo M, Cox SR, Cucca F, Toniolo D, Davey-Smith G, Deary IJ, Dedoussis G, Deloukas P, van Duijn CM, de Geus EJ, Eriksson JG, Evans DA, Faul JD, Sala CF, Froguel P, Gasparini P, Girotto G, Grabe HJ, Greiser KH, Groenen PJ, de Haan HG, Haerting J, Harris TB, Heath AC, Heikkilä K, Hofman A, Homuth G, Holliday EG, Hopper J, Hyppönen E, Jacobsson B, Jaddoe VW, Johannesson M, Jugessur A, Kähönen M, Kajantie E, Kardia SL, Keavney B, Kolcic I, Koponen P, Kovacs P, Kronenberg F, Kutalik Z, La Bianca M, Lachance G, Iacono WG, Lai S, Lehtimäki T, Liewald DC, Lindgren CM, Liu Y, Luben R, Lucht M, Luoto R, Magnus P, Magnusson PK, Martin NG, McGue M, McQuillan R, Medland SE, Meisinger C, Mellström D, Metspalu A, Traglia M, Milani L, Mitchell P, Montgomery GW, Mook-Kanamori D, de Mutsert R, Nohr EA, Ohlsson C, Olsen J, Ong KK, Paternoster L, Pattie A, Penninx BW, Perola M, Peyser PA, Pirastu M, Polasek O, Power C, Kaprio J, Raffel LJ, Räikkönen K, Raitakari O, Ridker PM, Ring SM, Roll K, Rudan I, Ruggiero D, Rujescu D, Salomaa V, Schlessinger D, Schmidt H, Schmidt R, Schupf N, Smit J, Sorice R, Spector TD, Starr JM, Stöckl D, Strauch K, Stumvoll M, Swertz MA, Thorsteinsdottir U, Thurik AR, Timpson NJ, Tung JY, Uitterlinden AG, Vaccargiu S, Viikari J, Vitart V, Völzke H, Vollenweider P, Vuckovic D, Waage J, Wagner GG, Wang JJ, Wareham NJ, Weir DR, Willemsen G, Willeit J, Wright AF, Zondervan KT, Stefansson K, Krueger RF, Lee JJ, Benjamin DJ, Cesarini D, Koellinger PD, den Hoed M, Snieder H, and Mills MC

Subjects
Female, Fertility genetics, Humans, Maternal Age, Phenotype, Polymorphism, Single Nucleotide genetics, Pregnancy, Birth Order, Genome-Wide Association Study, Parity genetics, Quantitative Trait Loci, Reproduction genetics, Reproductive Behavior physiology
Abstract

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

Published
2016
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35. Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.

Author

Iotchkova V, Huang J, Morris JA, Jain D, Barbieri C, Walter K, Min JL, Chen L, Astle W, Cocca M, Deelen P, Elding H, Farmaki AE, Franklin CS, Franberg M, Gaunt TR, Hofman A, Jiang T, Kleber ME, Lachance G, Luan J, Malerba G, Matchan A, Mead D, Memari Y, Ntalla I, Panoutsopoulou K, Pazoki R, Perry JRB, Rivadeneira F, Sabater-Lleal M, Sennblad B, Shin SY, Southam L, Traglia M, van Dijk F, van Leeuwen EM, Zaza G, Zhang W, Amin N, Butterworth A, Chambers JC, Dedoussis G, Dehghan A, Franco OH, Franke L, Frontini M, Gambaro G, Gasparini P, Hamsten A, Issacs A, Kooner JS, Kooperberg C, Langenberg C, Marz W, Scott RA, Swertz MA, Toniolo D, Uitterlinden AG, van Duijn CM, Watkins H, Zeggini E, Maurano MT, Timpson NJ, Reiner AP, Auer PL, and Soranzo N

Subjects
Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Quantitative Trait Loci, Sequence Analysis, DNA, Genetic Loci, Genome, Human, Genome-Wide Association Study, Heart Diseases genetics, Hematologic Diseases genetics
Abstract

Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.

Published
2016
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36. Genetic and environmental effects on body mass index from infancy to the onset of adulthood: an individual-based pooled analysis of 45 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) study.

Author

Silventoinen K, Jelenkovic A, Sund R, Hur YM, Yokoyama Y, Honda C, Hjelmborg Jv, Möller S, Ooki S, Aaltonen S, Ji F, Ning F, Pang Z, Rebato E, Busjahn A, Kandler C, Saudino KJ, Jang KL, Cozen W, Hwang AE, Mack TM, Gao W, Yu C, Li L, Corley RP, Huibregtse BM, Christensen K, Skytthe A, Kyvik KO, Derom CA, Vlietinck RF, Loos RJ, Heikkilä K, Wardle J, Llewellyn CH, Fisher A, McAdams TA, Eley TC, Gregory AM, He M, Ding X, Bjerregaard-Andersen M, Beck-Nielsen H, Sodemann M, Tarnoki AD, Tarnoki DL, Stazi MA, Fagnani C, D'Ippolito C, Knafo-Noam A, Mankuta D, Abramson L, Burt SA, Klump KL, Silberg JL, Eaves LJ, Maes HH, Krueger RF, McGue M, Pahlen S, Gatz M, Butler DA, Bartels M, van Beijsterveldt TC, Craig JM, Saffery R, Freitas DL, Maia JA, Dubois L, Boivin M, Brendgen M, Dionne G, Vitaro F, Martin NG, Medland SE, Montgomery GW, Chong Y, Swan GE, Krasnow R, Magnusson PK, Pedersen NL, Tynelius P, Lichtenstein P, Haworth CM, Plomin R, Bayasgalan G, Narandalai D, Harden KP, Tucker-Drob EM, Öncel SY, Aliev F, Spector T, Mangino M, Lachance G, Baker LA, Tuvblad C, Duncan GE, Buchwald D, Willemsen G, Rasmussen F, Goldberg JH, Sørensen TIa, Boomsma DI, and Kaprio J

Subjects
Adolescent, Adult, Age Factors, Australia, Child, Child, Preschool, Europe, Asia, Eastern, Female, Humans, Infant, Male, North America, Obesity ethnology, Obesity genetics, Sex Factors, Young Adult, Body Mass Index, Environment, Gene-Environment Interaction, Genetic Variation, Obesity etiology, Twins, Dizygotic genetics, Twins, Monozygotic genetics
Abstract

Background: Both genetic and environmental factors are known to affect body mass index (BMI), but detailed understanding of how their effects differ during childhood and adolescence is lacking., Objectives: We analyzed the genetic and environmental contributions to BMI variation from infancy to early adulthood and the ways they differ by sex and geographic regions representing high (North America and Australia), moderate (Europe), and low levels (East Asia) of obesogenic environments., Design: Data were available for 87,782 complete twin pairs from 0.5 to 19.5 y of age from 45 cohorts. Analyses were based on 383,092 BMI measurements. Variation in BMI was decomposed into genetic and environmental components through genetic structural equation modeling., Results: The variance of BMI increased from 5 y of age along with increasing mean BMI. The proportion of BMI variation explained by additive genetic factors was lowest at 4 y of age in boys (a(2) = 0.42) and girls (a(2) = 0.41) and then generally increased to 0.75 in both sexes at 19 y of age. This was because of a stronger influence of environmental factors shared by co-twins in midchildhood. After 15 y of age, the effect of shared environment was not observed. The sex-specific expression of genetic factors was seen in infancy but was most prominent at 13 y of age and older. The variance of BMI was highest in North America and Australia and lowest in East Asia, but the relative proportion of genetic variation to total variation remained roughly similar across different regions., Conclusions: Environmental factors shared by co-twins affect BMI in childhood, but little evidence for their contribution was found in late adolescence. Our results suggest that genetic factors play a major role in the variation of BMI in adolescence among populations of different ethnicities exposed to different environmental factors related to obesity., (© 2016 American Society for Nutrition.)

Published
2016
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37. Genetic and environmental influences on height from infancy to early adulthood: An individual-based pooled analysis of 45 twin cohorts.

Author

Jelenkovic A, Sund R, Hur YM, Yokoyama Y, Hjelmborg JV, Möller S, Honda C, Magnusson PK, Pedersen NL, Ooki S, Aaltonen S, Stazi MA, Fagnani C, D'Ippolito C, Freitas DL, Maia JA, Ji F, Ning F, Pang Z, Rebato E, Busjahn A, Kandler C, Saudino KJ, Jang KL, Cozen W, Hwang AE, Mack TM, Gao W, Yu C, Li L, Corley RP, Huibregtse BM, Derom CA, Vlietinck RF, Loos RJ, Heikkilä K, Wardle J, Llewellyn CH, Fisher A, McAdams TA, Eley TC, Gregory AM, He M, Ding X, Bjerregaard-Andersen M, Beck-Nielsen H, Sodemann M, Tarnoki AD, Tarnoki DL, Knafo-Noam A, Mankuta D, Abramson L, Burt SA, Klump KL, Silberg JL, Eaves LJ, Maes HH, Krueger RF, McGue M, Pahlen S, Gatz M, Butler DA, Bartels M, van Beijsterveldt TC, Craig JM, Saffery R, Dubois L, Boivin M, Brendgen M, Dionne G, Vitaro F, Martin NG, Medland SE, Montgomery GW, Swan GE, Krasnow R, Tynelius P, Lichtenstein P, Haworth CM, Plomin R, Bayasgalan G, Narandalai D, Harden KP, Tucker-Drob EM, Spector T, Mangino M, Lachance G, Baker LA, Tuvblad C, Duncan GE, Buchwald D, Willemsen G, Skytthe A, Kyvik KO, Christensen K, Öncel SY, Aliev F, Rasmussen F, Goldberg JH, Sørensen TI, Boomsma DI, Kaprio J, and Silventoinen K

Subjects
Adolescent, Australia, Child, Child, Preschool, Cohort Studies, Europe, Asia, Eastern, Female, Gene-Environment Interaction, Genetic Variation, Humans, Infant, Male, North America, Young Adult, Body Height, Environment, Twins, Dizygotic genetics, Twins, Monozygotic genetics
Abstract

Height variation is known to be determined by both genetic and environmental factors, but a systematic description of how their influences differ by sex, age and global regions is lacking. We conducted an individual-based pooled analysis of 45 twin cohorts from 20 countries, including 180,520 paired measurements at ages 1-19 years. The proportion of height variation explained by shared environmental factors was greatest in early childhood, but these effects remained present until early adulthood. Accordingly, the relative genetic contribution increased with age and was greatest in adolescence (up to 0.83 in boys and 0.76 in girls). Comparing geographic-cultural regions (Europe, North-America and Australia, and East-Asia), genetic variance was greatest in North-America and Australia and lowest in East-Asia, but the relative proportion of genetic variation was roughly similar across these regions. Our findings provide further insights into height variation during childhood and adolescence in populations representing different ethnicities and exposed to different environments.

Published
2016
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38. Zygosity Differences in Height and Body Mass Index of Twins From Infancy to Old Age: A Study of the CODATwins Project.

Author

Jelenkovic A, Yokoyama Y, Sund R, Honda C, Bogl LH, Aaltonen S, Ji F, Ning F, Pang Z, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Burt SA, Klump KL, Medland SE, Montgomery GW, Kandler C, McAdams TA, Eley TC, Gregory AM, Saudino KJ, Dubois L, Boivin M, Tarnoki AD, Tarnoki DL, Haworth CM, Plomin R, Öncel SY, Aliev F, Stazi MA, Fagnani C, D'Ippolito C, Craig JM, Saffery R, Siribaddana SH, Hotopf M, Sumathipala A, Rijsdijk F, Spector T, Mangino M, Lachance G, Gatz M, Butler DA, Bayasgalan G, Narandalai D, Freitas DL, Maia JA, Harden KP, Tucker-Drob EM, Kim B, Chong Y, Hong C, Shin HJ, Christensen K, Skytthe A, Kyvik KO, Derom CA, Vlietinck RF, Loos RJ, Cozen W, Hwang AE, Mack TM, He M, Ding X, Chang B, Silberg JL, Eaves LJ, Maes HH, Cutler TL, Hopper JL, Aujard K, Magnusson PK, Pedersen NL, Aslan AK, Song YM, Yang S, Lee K, Baker LA, Tuvblad C, Bjerregaard-Andersen M, Beck-Nielsen H, Sodemann M, Heikkilä K, Tan Q, Zhang D, Swan GE, Krasnow R, Jang KL, Knafo-Noam A, Mankuta D, Abramson L, Lichtenstein P, Krueger RF, McGue M, Pahlen S, Tynelius P, Duncan GE, Buchwald D, Corley RP, Huibregtse BM, Nelson TL, Whitfield KE, Franz CE, Kremen WS, Lyons MJ, Ooki S, Brandt I, Nilsen TS, Inui F, Watanabe M, Bartels M, van Beijsterveldt TC, Wardle J, Llewellyn CH, Fisher A, Rebato E, Martin NG, Iwatani Y, Hayakawa K, Sung J, Harris JR, Willemsen G, Busjahn A, Goldberg JH, Rasmussen F, Hur YM, Boomsma DI, Sørensen TI, Kaprio J, and Silventoinen K

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Cohort Studies, Databases, Factual, Female, Humans, Infant, Linear Models, Male, Middle Aged, Twins, Monozygotic, Young Adult, Body Height, Body Mass Index, Twins, Dizygotic
Abstract

A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.

Published
2015
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39. The CODATwins Project: The Cohort Description of Collaborative Project of Development of Anthropometrical Measures in Twins to Study Macro-Environmental Variation in Genetic and Environmental Effects on Anthropometric Traits.

Author

Silventoinen K, Jelenkovic A, Sund R, Honda C, Aaltonen S, Yokoyama Y, Tarnoki AD, Tarnoki DL, Ning F, Ji F, Pang Z, Ordoñana JR, Sánchez-Romera JF, Colodro-Conde L, Burt SA, Klump KL, Medland SE, Montgomery GW, Kandler C, McAdams TA, Eley TC, Gregory AM, Saudino KJ, Dubois L, Boivin M, Haworth CM, Plomin R, Öncel SY, Aliev F, Stazi MA, Fagnani C, D'Ippolito C, Craig JM, Saffery R, Siribaddana SH, Hotopf M, Sumathipala A, Spector T, Mangino M, Lachance G, Gatz M, Butler DA, Bayasgalan G, Narandalai D, Freitas DL, Maia JA, Harden KP, Tucker-Drob EM, Christensen K, Skytthe A, Kyvik KO, Hong C, Chong Y, Derom CA, Vlietinck RF, Loos RJ, Cozen W, Hwang AE, Mack TM, He M, Ding X, Chang B, Silberg JL, Eaves LJ, Maes HH, Cutler TL, Hopper JL, Aujard K, Magnusson PK, Pedersen NL, Aslan AK, Song YM, Yang S, Lee K, Baker LA, Tuvblad C, Bjerregaard-Andersen M, Beck-Nielsen H, Sodemann M, Heikkilä K, Tan Q, Zhang D, Swan GE, Krasnow R, Jang KL, Knafo-Noam A, Mankuta D, Abramson L, Lichtenstein P, Krueger RF, McGue M, Pahlen S, Tynelius P, Duncan GE, Buchwald D, Corley RP, Huibregtse BM, Nelson TL, Whitfield KE, Franz CE, Kremen WS, Lyons MJ, Ooki S, Brandt I, Nilsen TS, Inui F, Watanabe M, Bartels M, van Beijsterveldt TC, Wardle J, Llewellyn CH, Fisher A, Rebato E, Martin NG, Iwatani Y, Hayakawa K, Rasmussen F, Sung J, Harris JR, Willemsen G, Busjahn A, Goldberg JH, Boomsma DI, Hur YM, Sørensen TI, and Kaprio J

Subjects
Female, Humans, Male, Phenotype, Twin Studies as Topic, Anthropometry, Body Height genetics, Body Mass Index, Body Weight genetics, Gene-Environment Interaction, Twins genetics
Abstract

For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.

Published
2015
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