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1. Psychosocial factors, health behaviors and risk of cancer incidence: Testing interaction and effect modification in an individual participant data meta-analysis

Author: Basten, Maartje, Pan, Kuan-Yu, van Tuijl, Lonneke A, de Graeff, Alexander, Dekker, Joost, Hoogendoorn, Adriaan W, Lamers, Femke, Ranchor, Adelita V, Vermeulen, Roel, Portengen, Lützen, Voogd, Adri C, Abell, Jessica, Awadalla, Philip, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Frank, Philipp, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, Keats, Melanie R, Kok, Almar A L, Krokstad, Steinar, van Leeuwen, Flora E, Luik, Annemarie I, Noisel, Nolwenn, Payette, Yves, Penninx, Brenda W J H, Rissanen, Ina, Roest, Annelieke M, Rosmalen, Judith G M, Ruiter, Rikje, Schoevers, Robert A, Soave, David, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Twait, Emma L, Teyhan, Alison, Verschuren, W M Monique, van der Willik, Kimberly D, Geerlings, Mirjam I, Basten, Maartje, Pan, Kuan-Yu, van Tuijl, Lonneke A, de Graeff, Alexander, Dekker, Joost, Hoogendoorn, Adriaan W, Lamers, Femke, Ranchor, Adelita V, Vermeulen, Roel, Portengen, Lützen, Voogd, Adri C, Abell, Jessica, Awadalla, Philip, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Frank, Philipp, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, Keats, Melanie R, Kok, Almar A L, Krokstad, Steinar, van Leeuwen, Flora E, Luik, Annemarie I, Noisel, Nolwenn, Payette, Yves, Penninx, Brenda W J H, Rissanen, Ina, Roest, Annelieke M, Rosmalen, Judith G M, Ruiter, Rikje, Schoevers, Robert A, Soave, David, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Twait, Emma L, Teyhan, Alison, Verschuren, W M Monique, van der Willik, Kimberly D, and Geerlings, Mirjam I
Abstract: Depression, anxiety and other psychosocial factors are hypothesized to be involved in cancer development. We examined whether psychosocial factors interact with or modify the effects of health behaviors, such as smoking and alcohol use, in relation to cancer incidence. Two-stage individual participant data meta-analyses were performed based on 22 cohorts of the PSYchosocial factors and CAncer (PSY-CA) study. We examined nine psychosocial factors (depression diagnosis, depression symptoms, anxiety diagnosis, anxiety symptoms, perceived social support, loss events, general distress, neuroticism, relationship status), seven health behaviors/behavior-related factors (smoking, alcohol use, physical activity, body mass index, sedentary behavior, sleep quality, sleep duration) and seven cancer outcomes (overall cancer, smoking-related, alcohol-related, breast, lung, prostate, colorectal). Effects of the psychosocial factor, health behavior and their product term on cancer incidence were estimated using Cox regression. We pooled cohort-specific estimates using multivariate random-effects meta-analyses. Additive and multiplicative interaction/effect modification was examined. This study involved 437,827 participants, 36,961 incident cancer diagnoses, and 4,749,481 person years of follow-up. Out of 744 combinations of psychosocial factors, health behaviors, and cancer outcomes, we found no evidence of interaction. Effect modification was found for some combinations, but there were no clear patterns for any particular factors or outcomes involved. In this first large study to systematically examine potential interaction and effect modification, we found no evidence for psychosocial factors to interact with or modify health behaviors in relation to cancer incidence. The behavioral risk profile for cancer incidence is similar in people with and without psychosocial stress.
Published: 2024

2. Genomics Research of Lifetime Depression in the Netherlands: The BIObanks Netherlands Internet Collaboration (BIONIC) Project

Author: Cardiometabolic Health, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Huider, Floris, Milaneschi, Yuri, Hottenga, Jouke-Jan, Bot, Mariska, Rietman, M Liset, Kok, Almar A L, Galesloot, Tessel E, 't Hart, Leen M, Rutters, Femke, Blom, Marieke T, Rhebergen, Didi, Visser, Marjolein, Brouwer, Ingeborg, Feskens, Edith, Hartman, Catharina A, Oldehinkel, Albertine J, de Geus, Eco J C, Kiemeney, Lambertus A, Huisman, Martijn, Picavet, H Susan J, Verschuren, W M Monique, van Loo, Hanna M, Penninx, Brenda W J H, Boomsma, Dorret I, Cardiometabolic Health, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Huider, Floris, Milaneschi, Yuri, Hottenga, Jouke-Jan, Bot, Mariska, Rietman, M Liset, Kok, Almar A L, Galesloot, Tessel E, 't Hart, Leen M, Rutters, Femke, Blom, Marieke T, Rhebergen, Didi, Visser, Marjolein, Brouwer, Ingeborg, Feskens, Edith, Hartman, Catharina A, Oldehinkel, Albertine J, de Geus, Eco J C, Kiemeney, Lambertus A, Huisman, Martijn, Picavet, H Susan J, Verschuren, W M Monique, van Loo, Hanna M, Penninx, Brenda W J H, and Boomsma, Dorret I
Published: 2024

3. Psychosocial factors, health behaviors and risk of cancer incidence: Testing interaction and effect modification in an individual participant data meta-analysis

Author: Leerstoel Boelen, Trauma and Grief, IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, Basten, Maartje, Pan, Kuan-Yu, van Tuijl, Lonneke A, de Graeff, Alexander, Dekker, Joost, Hoogendoorn, Adriaan W, Lamers, Femke, Ranchor, Adelita V, Vermeulen, Roel, Portengen, Lützen, Voogd, Adri C, Abell, Jessica, Awadalla, Philip, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Frank, Philipp, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, Keats, Melanie R, Kok, Almar A L, Krokstad, Steinar, van Leeuwen, Flora E, Luik, Annemarie I, Noisel, Nolwenn, Payette, Yves, Penninx, Brenda W J H, Rissanen, Ina, Roest, Annelieke M, Rosmalen, Judith G M, Ruiter, Rikje, Schoevers, Robert A, Soave, David, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Twait, Emma L, Teyhan, Alison, Verschuren, W M Monique, van der Willik, Kimberly D, Geerlings, Mirjam I, Leerstoel Boelen, Trauma and Grief, IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, Basten, Maartje, Pan, Kuan-Yu, van Tuijl, Lonneke A, de Graeff, Alexander, Dekker, Joost, Hoogendoorn, Adriaan W, Lamers, Femke, Ranchor, Adelita V, Vermeulen, Roel, Portengen, Lützen, Voogd, Adri C, Abell, Jessica, Awadalla, Philip, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Frank, Philipp, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, Keats, Melanie R, Kok, Almar A L, Krokstad, Steinar, van Leeuwen, Flora E, Luik, Annemarie I, Noisel, Nolwenn, Payette, Yves, Penninx, Brenda W J H, Rissanen, Ina, Roest, Annelieke M, Rosmalen, Judith G M, Ruiter, Rikje, Schoevers, Robert A, Soave, David, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Twait, Emma L, Teyhan, Alison, Verschuren, W M Monique, van der Willik, Kimberly D, and Geerlings, Mirjam I
Published: 2024

4. The human affectome

Author: Schiller, Daniela, Yu, Alessandra N. C, Alia-Klein, Nelly, Becker, Susanne, Cromwell, Howard C., Dolcos, Florin, Eslinger, Paul J., Frewen, Paul, Kemp, Andrew H., Pace-Schott, Edward F., Raber, Jacob, Silton, Rebecca L., Stefanova, Elka, Williams, Justin H. G., Abe, Nobuhito, Aghajani, Moji, Albrecht, Franziska, Alexander, Rebecca, Anders, Silke, Aragón, Oriana R., Arias, Juan A., Arzy, Shahar, Aue, Tatjana, Baez, Sandra, Balconi, Michela, Ballarini, Tommaso, Bannister, Scott, Banta, Marlissa C., Barrett, Karen C., Belzung, Catherine, Bensafi, Moustafa, Booij, Linda, Bookwala, Jamila, Boulanger-Bertolus, Julie, Boutros, Sydney W., Bräscher, Anne-Kathrin, Bruno, Antonio, Busatto, Geraldo, Bylsma, Lauren M., Caldwell-Harris, Catherine, Chan, Raymond C. K., Cherbuin, Nicolas, Chiarella, Julian, Cipresso, Pietro, Critchley, Hugo, Croote, Denise E., Demaree, Heath A., Denson, Thomas F., Depue, Brendan, Derntl, Birgit, Dickson, Joanne M., Dolcos, Sanda, Drach-Zahavy, Anat, Dubljević, Olga, Eerola, Tuomas, Ellingsen, Dan-Mikael, Fairfield, Beth, Ferdenzi, Camille, Friedman, Bruce H., Fu, Cynthia H. Y., Gatt, Justine M., de Gelder, Beatrice, Gendolla, Guido H. E., Gilam, Gadi, Goldblatt, Hadass, Gooding, Anne E. K., Gosseries, Olivia, Hamm, Alfons O., Hanson, Jamie L., Hendler, Talma, Herbert, Cornelia, Hofmann, Stefan G., Ibanez, Agustin, Joffily, Mateus, Jovanovic, Tanja, Kahrilas, Ian J., Kangas, Maria, Katsumi, Yuta, Kensinger, Elizabeth, Kirby, Lauren A. J., Koncz, Rebecca, Koster, Ernst H. W., Kozlowska, Kasia, Krach, Sören, Kret, Mariska E., Krippl, Martin, Kusi-Mensah, Kwabena, Ladouceur, Cecile D., Laureys, Steven, Lawrence, Alistair, Li, Chiang-shan R., Liddell, Belinda J., Lidhar, Navdeep K., Lowry, Christopher A., Magee, Kelsey, Marin, Marie-France, Mariotti, Veronica, Martin, Loren J., Marusak, Hilary A., Mayer, Annalina V., Merner, Amanda R., Minnier, Jessica, Moll, Jorge, Morrison, Robert G., Moore, Matthew, Mouly, Anne-Marie, Mueller, Sven C., Mühlberger, Andreas, Murphy, Nora A., Muscatello, Maria R. A., Musser, Erica D., Newton, Tamara L., Noll-Hussong, Michael, Norrholm, Seth D., Northoff, Georg, Nusslock, Robin, Okon-Singer, Hadas, Olino, Thomas M., Ortner, Catherine, Owolabi, Mayowa, Padulo, Caterina, Palermo, Romina, Palumbo, Rocco, Palumbo, Sara, Papadelis, Christos, Pegna, Alan J., Pellegrini, Silvia, Peltonen, Kirsi, Penninx, Brenda W. J. H., Pietrini, Pietro, Pinna, Graziano, Lobo, Rosario P., Polnaszek, Kelly L., Polyakova, Maryna, Rabinak, Christine, Richter, S. Helene, Richter, Thalia, Riva, Giuseppe, Rizzo, Amelia, Robinson, Jennifer L., Rosa, Pedro, Sachdev, Perminder S., Sato, Wataru, Schroeter, Matthias L., Schweizer, Susanne, Shiban, Youssef, Siddharthan, Advaith, Siedlecka, Ewa, Smith, Robert C., Soreq, Hermona, Spangler, Derek P., Stern, Emily R., Styliadis, Charis, Sullivan, Gavin B., Swain, James E., Urben, Sébastien, Van den Stock, Jan, vander Kooij, Michael A., van Overveld, Mark, Van Rheenen, Tamsyn E., VanElzakker, Michael B., Ventura-Bort, Carlos, Verona, Edelyn, Volk, Tyler, Wang, Yi, Weingast, Leah T., Weymar, Mathias, Williams, Claire, Willis, Megan L., Yamashita, Paula, Zahn, Roland, Zupan, Barbra, Lowe, Leroy, Schiller, Daniela, Yu, Alessandra N. C, Alia-Klein, Nelly, Becker, Susanne, Cromwell, Howard C., Dolcos, Florin, Eslinger, Paul J., Frewen, Paul, Kemp, Andrew H., Pace-Schott, Edward F., Raber, Jacob, Silton, Rebecca L., Stefanova, Elka, Williams, Justin H. G., Abe, Nobuhito, Aghajani, Moji, Albrecht, Franziska, Alexander, Rebecca, Anders, Silke, Aragón, Oriana R., Arias, Juan A., Arzy, Shahar, Aue, Tatjana, Baez, Sandra, Balconi, Michela, Ballarini, Tommaso, Bannister, Scott, Banta, Marlissa C., Barrett, Karen C., Belzung, Catherine, Bensafi, Moustafa, Booij, Linda, Bookwala, Jamila, Boulanger-Bertolus, Julie, Boutros, Sydney W., Bräscher, Anne-Kathrin, Bruno, Antonio, Busatto, Geraldo, Bylsma, Lauren M., Caldwell-Harris, Catherine, Chan, Raymond C. K., Cherbuin, Nicolas, Chiarella, Julian, Cipresso, Pietro, Critchley, Hugo, Croote, Denise E., Demaree, Heath A., Denson, Thomas F., Depue, Brendan, Derntl, Birgit, Dickson, Joanne M., Dolcos, Sanda, Drach-Zahavy, Anat, Dubljević, Olga, Eerola, Tuomas, Ellingsen, Dan-Mikael, Fairfield, Beth, Ferdenzi, Camille, Friedman, Bruce H., Fu, Cynthia H. Y., Gatt, Justine M., de Gelder, Beatrice, Gendolla, Guido H. E., Gilam, Gadi, Goldblatt, Hadass, Gooding, Anne E. K., Gosseries, Olivia, Hamm, Alfons O., Hanson, Jamie L., Hendler, Talma, Herbert, Cornelia, Hofmann, Stefan G., Ibanez, Agustin, Joffily, Mateus, Jovanovic, Tanja, Kahrilas, Ian J., Kangas, Maria, Katsumi, Yuta, Kensinger, Elizabeth, Kirby, Lauren A. J., Koncz, Rebecca, Koster, Ernst H. W., Kozlowska, Kasia, Krach, Sören, Kret, Mariska E., Krippl, Martin, Kusi-Mensah, Kwabena, Ladouceur, Cecile D., Laureys, Steven, Lawrence, Alistair, Li, Chiang-shan R., Liddell, Belinda J., Lidhar, Navdeep K., Lowry, Christopher A., Magee, Kelsey, Marin, Marie-France, Mariotti, Veronica, Martin, Loren J., Marusak, Hilary A., Mayer, Annalina V., Merner, Amanda R., Minnier, Jessica, Moll, Jorge, Morrison, Robert G., Moore, Matthew, Mouly, Anne-Marie, Mueller, Sven C., Mühlberger, Andreas, Murphy, Nora A., Muscatello, Maria R. A., Musser, Erica D., Newton, Tamara L., Noll-Hussong, Michael, Norrholm, Seth D., Northoff, Georg, Nusslock, Robin, Okon-Singer, Hadas, Olino, Thomas M., Ortner, Catherine, Owolabi, Mayowa, Padulo, Caterina, Palermo, Romina, Palumbo, Rocco, Palumbo, Sara, Papadelis, Christos, Pegna, Alan J., Pellegrini, Silvia, Peltonen, Kirsi, Penninx, Brenda W. J. H., Pietrini, Pietro, Pinna, Graziano, Lobo, Rosario P., Polnaszek, Kelly L., Polyakova, Maryna, Rabinak, Christine, Richter, S. Helene, Richter, Thalia, Riva, Giuseppe, Rizzo, Amelia, Robinson, Jennifer L., Rosa, Pedro, Sachdev, Perminder S., Sato, Wataru, Schroeter, Matthias L., Schweizer, Susanne, Shiban, Youssef, Siddharthan, Advaith, Siedlecka, Ewa, Smith, Robert C., Soreq, Hermona, Spangler, Derek P., Stern, Emily R., Styliadis, Charis, Sullivan, Gavin B., Swain, James E., Urben, Sébastien, Van den Stock, Jan, vander Kooij, Michael A., van Overveld, Mark, Van Rheenen, Tamsyn E., VanElzakker, Michael B., Ventura-Bort, Carlos, Verona, Edelyn, Volk, Tyler, Wang, Yi, Weingast, Leah T., Weymar, Mathias, Williams, Claire, Willis, Megan L., Yamashita, Paula, Zahn, Roland, Zupan, Barbra, and Lowe, Leroy
Abstract: Over the last decades, theoretical perspectives in the interdisciplinary field of the affective sciences have proliferated rather than converged due to differing assumptions about what human affective phenomena are and how they work. These metaphysical and mechanistic assumptions, shaped by academic context and values, have dictated affective constructs and operationalizations. However, an assumption about the purpose of affective phenomena can guide us to a common set of metaphysical and mechanistic assumptions. In this capstone paper, we home in on a nested teleological principle for human affective phenomena in order to synthesize metaphysical and mechanistic assumptions. Under this framework, human affective phenomena can collectively be considered algorithms that either adjust based on the human comfort zone (affective concerns) or monitor those adaptive processes (affective features). This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope the Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research.
Published: 2024

5. Multi-site benchmark classification of major depressive disorder using machine learning on cortical and subcortical measures

Author: Belov, Vladimir, Erwin-Grabner, Tracy, Aghajani, Moji, Aleman, Andre, Amod, Alyssa R., Basgoze, Zeynep, Benedetti, Francesco, Besteher, Bianca, Bülow, Robin, Ching, Christopher R. K., Connolly, Colm G., Cullen, Kathryn, Davey, Christopher G., Dima, Danai, Dols, Annemiek, Evans, Jennifer W., Fu, Cynthia H. Y., Gonul, Ali Saffet, Gotlib, Ian H., Grabe, Hans J., Groenewold, Nynke, Hamilton, Paul, Harrison, Ben J., Ho, Tiffany C., Mwangi, Benson, Jaworska, Natalia, Jahanshad, Neda, Klimes-Dougan, Bonnie, Koopowitz, Sheri-Michelle, Lancaster, Thomas, Li, Meng, Linden, David E. J., MacMaster, Frank P., Mehler, David M. A., Melloni, Elisa, Mueller, Bryon A., Ojha, Amar, Oudega, Mardien L., Penninx, Brenda W. J. H., Poletti, Sara, Pomarol-Clotet, Edith, Portella, Maria J., Pozzi, Elena, Reneman, Liesbeth, Sacchet, Matthew D., Saemann, Philipp G., Schrantee, Anouk, Sim, Kang, Soares, Jair C., Stein, Dan J., Thomopoulos, Sophia I., Uyar-Demir, Aslihan, van der Wee, Nic J. A., van der Werff, Steven J. A., Voelzke, Henry, Whittle, Sarah, Wittfeld, Katharina, Wright, Margaret J., Wu, Mon-Ju, Yang, Tony T., Zarate, Carlos, Veltman, Dick J., Schmaal, Lianne, Thompson, Paul M., Goya-Maldonado, Roberto, Belov, Vladimir, Erwin-Grabner, Tracy, Aghajani, Moji, Aleman, Andre, Amod, Alyssa R., Basgoze, Zeynep, Benedetti, Francesco, Besteher, Bianca, Bülow, Robin, Ching, Christopher R. K., Connolly, Colm G., Cullen, Kathryn, Davey, Christopher G., Dima, Danai, Dols, Annemiek, Evans, Jennifer W., Fu, Cynthia H. Y., Gonul, Ali Saffet, Gotlib, Ian H., Grabe, Hans J., Groenewold, Nynke, Hamilton, Paul, Harrison, Ben J., Ho, Tiffany C., Mwangi, Benson, Jaworska, Natalia, Jahanshad, Neda, Klimes-Dougan, Bonnie, Koopowitz, Sheri-Michelle, Lancaster, Thomas, Li, Meng, Linden, David E. J., MacMaster, Frank P., Mehler, David M. A., Melloni, Elisa, Mueller, Bryon A., Ojha, Amar, Oudega, Mardien L., Penninx, Brenda W. J. H., Poletti, Sara, Pomarol-Clotet, Edith, Portella, Maria J., Pozzi, Elena, Reneman, Liesbeth, Sacchet, Matthew D., Saemann, Philipp G., Schrantee, Anouk, Sim, Kang, Soares, Jair C., Stein, Dan J., Thomopoulos, Sophia I., Uyar-Demir, Aslihan, van der Wee, Nic J. A., van der Werff, Steven J. A., Voelzke, Henry, Whittle, Sarah, Wittfeld, Katharina, Wright, Margaret J., Wu, Mon-Ju, Yang, Tony T., Zarate, Carlos, Veltman, Dick J., Schmaal, Lianne, Thompson, Paul M., and Goya-Maldonado, Roberto
Abstract: Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects., Funding Agencies|NIH [U54 EB020403, R01MH116147, MH117601, R37 MH101495]; ERA-NET PRIOMEDCHILD FP 6 (EU) [11.32050.26]; University Medical Center Gottingen (UMG Startforderung); German Federal Ministry of Education and Research (Bundesministerium fuer Bildung und Forschung) [BMBF: 01 ZX 1507]; Ministerio de Ciencia e Innovacion of the Spanish Government; Instituto de Salud Carlos III through a 'Miguel Servet' research contract [CP16-0020]; National Research Plan (Plan Estatal de I + D + I 2016-2019); European Regional Development Fund (ERDF); Medical Research Council [G 1100629]; National Center for Mental Health (NCMH) - Health Research Wales [HS/14/20]; Johnson & Johnson Innovation; Swedish Medical Research Council [2017-00875, 2013-07434, 2019-01138]; ALF Grants, Region Ostergotland; National Institutes of Health [R01 CA193522, R01 NS073939]; MD Anderson Cancer Support Grant [P30CA016672]; Canadian Institutes for Health Research; Branch Out Neurological Foundation; Alberta Children's Hospital Foundation; Medical Research Council of South Africa; Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) [ZIA-MH002857]; GGZ Rivierduinen; LUMC; Generalitat de Catalunya [2014 SGR 1573]; Instituto de Salud Carlos III [CPII16/00018, PI14/01151, PI14/01148]; Gratama Foundation, the Netherlands [2012/35]; NIMH [R01 085667]; Dunn Research Foundation; NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London; National Health and Medical Research Council of Australia (NHMRC) [1064643, 1024570]; National Institute of Mental Health [K23MH090421]; Biotechnology Research Center [P41 RR008079]; National Alliance for Research on Schizophrenia and Depression; University of Minnesota Graduate School; Minnesota Medical Foundation; Brain and Behavior Research Foundation; National Health and Medical Research Council [1125504]; Geestkracht program of the Netherla
Published: 2024
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6. The Gut Microbiome in Early Life Stress: A Systematic Review

Author: Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Lamers, Femke [0000-0003-4344-5766], Penninx, Brenda W. J. H. [0000-0001-7779-9672], Sanz Herranz, Yolanda [0000-0002-1615-1976], Agustí, Ana, Lamers, Femke, Tamayo, María, Benito, Carlos, Molina-Mendoza, Gara V., Penninx, Brenda W. J. H., Sanz Herranz, Yolanda, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Lamers, Femke [0000-0003-4344-5766], Penninx, Brenda W. J. H. [0000-0001-7779-9672], Sanz Herranz, Yolanda [0000-0002-1615-1976], Agustí, Ana, Lamers, Femke, Tamayo, María, Benito, Carlos, Molina-Mendoza, Gara V., Penninx, Brenda W. J. H., and Sanz Herranz, Yolanda
Abstract: Exposure to early life stress (ELS), prenatal or postnatal during childhood and adolescence, can significantly impact mental and physical health. The role of the intestinal microbiome in human health, and particularly mental health, is becoming increasingly evident. This systematic review aims to summarize the clinical data evaluating the effect of ELS on the human intestinal microbiome. The systematic review (CRD42022351092) was performed following PRISMA guidelines, with ELS considered as exposure to psychological stressors prenatally and during early life (childhood and adolescence). Thirteen articles met all inclusion criteria, and all studies reviewed found a link between ELS and the gut microbiome in both prenatal and postnatal periods. However, we failed to find consensus microbiome signatures associated with pre- or postnatal stress, or both. The inconsistency of results is likely attributed to various factors such as different experimental designs, ages examined, questionnaires, timing of sample collection and analysis methods, small population sizes, and the type of stressors. Additional studies using similar stressors and validated stress measures, as well as higher-resolution microbiome analytical approaches, are needed to draw definitive conclusions about the links between stress and the human gut microbiome.
Published: 2023

7. A critical study of the life of the 13th-century Tibetan monk U rgyan pa Rin chen dpal based on his biographies

Author: Li, Brenda W. L. and Ramble, Charles
Subjects: 290, Tibetan and Himalayan Studies, History of Asia & Far East, Tibetan history, Tibetan biography, U rgyan pa Rin chen dpal
Abstract: U rgyan pa Rin chen dpal (1230-1309) was a great adept of the bKa' brgyud school of Tibetan Buddhism, particularly renowned for his knowledge of the Kālacakra tantra and the unique teaching known as the Approach and Attainment of the Three Vajras (rDo rje gsum gyi bsnyen sgrub), said to have been given to him in his vision by Vajrayoginī (rDo rje rnal 'byor ma) in the Miraculous Land (sprul pa'i zhing) of U rgyan. He was the student of the 2nd Karma pa, who entrusted him with the Black Hat, which he passed to the 3rd Karma pa. He was also a great traveller who journeyed widely across and beyond Tibet. He met Qubilai Khan in the capital of Yuan China and visited sacred Buddhist sites in South India. He has been aptly described by van der Kuijp as "the great Tibetan yogi, thaumaturge, scholar, alchemist, and traveler". Thanks to the availability of a large amount of hitherto unknown materials from eleven biographies, the thesis has put considerable weight on the bibliographical comparison and analysis of the different works in an attempt to establish the possible relationship between them. This is supplemented by summaries of the biographies, to give an overview of the protagonist's life in Part One of the thesis. Part Two consists of a critical study of the different phases and aspects of U rgyan pa's life in the unique historical, political and religious context of each phase, drawing materials from the corpus of biographies and in the light of other primary and secondary sources in Tibetan, Chinese and Western languages. In Chapter I, U rgyan pa's family lineage, childhood and early studies are discussed in order to find out how his innate propensities and early studies are represented as having influenced his character. In Chapter II, the account of U rgyan pa's journey to West Tibet and U rgyan is studied. A sixteen-stanza song in his own words epitomising this journey, supplemented by route maps, will be used as a framework to illustrate and reconstruct his journey to the Land of the Ḍākinīs. In Chapter III, the teachings he received and the subsequent transformation of his character and status, are explored. In Chapter IV, his career as a tantric master, his other pilgrimages and benediction trips, and his conflicts with various religious and political authorities, are examined. The materials will be scrutinised in the hope of separating as far as possible fact from fiction.
Published: 2011

8. Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

Author: Mathieson, Iain, Day, Felix R., Barban, Nicola, Tropf, Felix C., Brazel, David M., Vaez, Ahmad, van Zuydam, Natalie, Bitarello, Bárbara D., Gardner, Eugene J., Akimova, Evelina T., Azad, Ajuna, Bergmann, Sven, Bielak, Lawrence F., Boomsma, Dorret I., Bosak, Kristina, Brumat, Marco, Buring, Julie E., Cesarini, David, Chasman, Daniel I., Chavarro, Jorge E., Cocca, Massimiliano, Concas, Maria Pina, Davey Smith, George, Davies, Gail, Deary, Ian J., Esko, Tõnu, Faul, Jessica D., Franco, Oscar, Ganna, Andrea, Gaskins, Audrey J., Gelemanovic, Andrea, de Geus, Eco J. C., Gieger, Christian, Girotto, Giorgia, Gopinath, Bamini, Grabe, Hans Jörgen, Gunderson, Erica P., Hayward, Caroline, He, Chunyan, van Heemst, Diana, Hill, W. David, Hoffmann, Eva R., Homuth, Georg, Hottenga, Jouke Jan, Huang, Hongyang, Hyppönen, Elina, Ikram, M. Arfan, Jansen, Rick, Johannesson, Magnus, Kamali, Zoha, Kardia, Sharon L. R., Kavousi, Maryam, Kifley, Annette, Kiiskinen, Tuomo, Kraft, Peter, Kuehnel, Brigitte, Langenberg, Claudia, Liew, Gerald, Lind, Penelope A., Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Mark I., McMahon, George, Medland, Sarah E., Meitinger, Thomas, Metspalu, Andres, Mihailov, Evelin, Milani, Lili, Missmer, Stacey A., Mitchell, Paul, Mollegaard, Stine, Mook-Kanamori, Dennis O., Morgan, Anna, van der Most, Peter, de Mutsert, Renee, Nauck, Matthias, Nolte, Ilja M., Noordam, Raymond, Penninx, Brenda W. J. H., Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Power, Chris, Pribisalic, Ajka, Redmond, Paul, Rich-Edwards, Janet W., Ridker, Paul M., Rietveld, Cornelius A., Ring, Susan M., Rose, Lynda M., Rueedi, Rico, Shukla, Vallari, Smith, Jennifer A., Stankovic, Stasa, Stefansson, Kari, Stöckl, Doris, Strauch, Konstantin, Swertz, Morris A., Teumer, Alexander, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Turman, Constance, Uitterlinden, André G., Waldenberger, Melanie, Wareham, Nicholas J., Weir, David R., Willemsen, Gonneke, Zhao, Jing Hau, Zhao, Wei, Zhao, Yajie, Snieder, Harold, den Hoed, Marcel, Ong, Ken K., Mills, Melinda C., Perry, John R. B., Mathieson, Iain, Day, Felix R., Barban, Nicola, Tropf, Felix C., Brazel, David M., Vaez, Ahmad, van Zuydam, Natalie, Bitarello, Bárbara D., Gardner, Eugene J., Akimova, Evelina T., Azad, Ajuna, Bergmann, Sven, Bielak, Lawrence F., Boomsma, Dorret I., Bosak, Kristina, Brumat, Marco, Buring, Julie E., Cesarini, David, Chasman, Daniel I., Chavarro, Jorge E., Cocca, Massimiliano, Concas, Maria Pina, Davey Smith, George, Davies, Gail, Deary, Ian J., Esko, Tõnu, Faul, Jessica D., Franco, Oscar, Ganna, Andrea, Gaskins, Audrey J., Gelemanovic, Andrea, de Geus, Eco J. C., Gieger, Christian, Girotto, Giorgia, Gopinath, Bamini, Grabe, Hans Jörgen, Gunderson, Erica P., Hayward, Caroline, He, Chunyan, van Heemst, Diana, Hill, W. David, Hoffmann, Eva R., Homuth, Georg, Hottenga, Jouke Jan, Huang, Hongyang, Hyppönen, Elina, Ikram, M. Arfan, Jansen, Rick, Johannesson, Magnus, Kamali, Zoha, Kardia, Sharon L. R., Kavousi, Maryam, Kifley, Annette, Kiiskinen, Tuomo, Kraft, Peter, Kuehnel, Brigitte, Langenberg, Claudia, Liew, Gerald, Lind, Penelope A., Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik K. E., Mahajan, Anubha, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Mark I., McMahon, George, Medland, Sarah E., Meitinger, Thomas, Metspalu, Andres, Mihailov, Evelin, Milani, Lili, Missmer, Stacey A., Mitchell, Paul, Mollegaard, Stine, Mook-Kanamori, Dennis O., Morgan, Anna, van der Most, Peter, de Mutsert, Renee, Nauck, Matthias, Nolte, Ilja M., Noordam, Raymond, Penninx, Brenda W. J. H., Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Power, Chris, Pribisalic, Ajka, Redmond, Paul, Rich-Edwards, Janet W., Ridker, Paul M., Rietveld, Cornelius A., Ring, Susan M., Rose, Lynda M., Rueedi, Rico, Shukla, Vallari, Smith, Jennifer A., Stankovic, Stasa, Stefansson, Kari, Stöckl, Doris, Strauch, Konstantin, Swertz, Morris A., Teumer, Alexander, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Turman, Constance, Uitterlinden, André G., Waldenberger, Melanie, Wareham, Nicholas J., Weir, David R., Willemsen, Gonneke, Zhao, Jing Hau, Zhao, Wei, Zhao, Yajie, Snieder, Harold, den Hoed, Marcel, Ong, Ken K., Mills, Melinda C., and Perry, John R. B.
Abstract: Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.
Published: 2023
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9. Depression, anxiety, and the risk of cancer: An individual participant data meta-analysis

Author: van Tuijl, Lonneke A, Basten, Maartje, Pan, Kuan-Yu, Vermeulen, Roel, Portengen, Lützen, de Graeff, Alexander, Dekker, Joost, Geerlings, Mirjam I, Hoogendoorn, Adriaan, Lamers, Femke, Voogd, Adri C, Abell, Jessica, Awadalla, Philip, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Frank, Philipp, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, de Jong, Trynke R, Keats, Melanie R, Kok, Almar A L, Krokstad, Steinar, van Leeuwen, Flora E, Luik, Annemarie I, Noisel, Nolwenn, Onland-Moret, N Charlotte, Payette, Yves, Penninx, Brenda W J H, Rissanen, Ina, Roest, Annelieke M, Ruiter, Rikje, Schoevers, Robert A, Soave, David, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Twait, Emma L, Teyhan, Alison, Verschuren, W M Monique, van der Willik, Kimberly D, Rosmalen, Judith G M, Ranchor, Adelita V, van Tuijl, Lonneke A, Basten, Maartje, Pan, Kuan-Yu, Vermeulen, Roel, Portengen, Lützen, de Graeff, Alexander, Dekker, Joost, Geerlings, Mirjam I, Hoogendoorn, Adriaan, Lamers, Femke, Voogd, Adri C, Abell, Jessica, Awadalla, Philip, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Frank, Philipp, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, de Jong, Trynke R, Keats, Melanie R, Kok, Almar A L, Krokstad, Steinar, van Leeuwen, Flora E, Luik, Annemarie I, Noisel, Nolwenn, Onland-Moret, N Charlotte, Payette, Yves, Penninx, Brenda W J H, Rissanen, Ina, Roest, Annelieke M, Ruiter, Rikje, Schoevers, Robert A, Soave, David, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Twait, Emma L, Teyhan, Alison, Verschuren, W M Monique, van der Willik, Kimberly D, Rosmalen, Judith G M, and Ranchor, Adelita V
Abstract: BACKGROUND: Depression and anxiety have long been hypothesized to be related to an increased cancer risk. Despite the great amount of research that has been conducted, findings are inconclusive. To provide a stronger basis for addressing the associations between depression, anxiety, and the incidence of various cancer types (overall, breast, lung, prostate, colorectal, alcohol-related, and smoking-related cancers), individual participant data (IPD) meta-analyses were performed within the Psychosocial Factors and Cancer Incidence (PSY-CA) consortium.METHODS: The PSY-CA consortium includes data from 18 cohorts with measures of depression or anxiety (up to N = 319,613; cancer incidences, 25,803; person-years of follow-up, 3,254,714). Both symptoms and a diagnosis of depression and anxiety were examined as predictors of future cancer risk. Two-stage IPD meta-analyses were run, first by using Cox regression models in each cohort (stage 1), and then by aggregating the results in random-effects meta-analyses (stage 2).RESULTS: No associations were found between depression or anxiety and overall, breast, prostate, colorectal, and alcohol-related cancers. Depression and anxiety (symptoms and diagnoses) were associated with the incidence of lung cancer and smoking-related cancers (hazard ratios [HRs], 1.06-1.60). However, these associations were substantially attenuated when additionally adjusting for known risk factors including smoking, alcohol use, and body mass index (HRs, 1.04-1.23).CONCLUSIONS: Depression and anxiety are not related to increased risk for most cancer outcomes, except for lung and smoking-related cancers. This study shows that key covariates are likely to explain the relationship between depression, anxiety, and lung and smoking-related cancers. PREREGISTRATION NUMBER: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=157677.
Published: 2023

10. Genetic insights into resting heart rate and its role in cardiovascular disease

Author: van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, van der Harst, Pim, van de Vegte, Yordi, Eppinga, Ruben P., van der Ende, M. Yldau, Hagemeijer, Yanick, Mahendran, Yuvaraj V., Salfati, Elias Y., Smith, Albert E., Tan, Vanessa, Arking, Dan V., Ntalla, Ioanna, Appel, Emil A., Schurmann, Claudia, Brody, Jennifer, Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian'an, Hwang, Shih-Jen, Mononen, Nina U., Auro, Kirsi F., Jackson, Anne, Bielak, Lawrence, Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Mueller-Nurasyid, Martina, Roselli, Carolina E., Zhang, Weihua, Kleber, Marcus J., Guo, Xiuqing, Lin, Henry E., Pavani, Francesca, Galesloot, Tessel, Noordam, Raymond E., Milaneschi, Yuri, Schraut, Katharina, den Hoed, Marcel, Degenhardt, Frauke E., Trompet, Stella, van den Berg, Marten, Pistis, Giorgio, Tham, Yih-Chung S., Weiss, Stefan L., Sim, Xueling J., Li, Hengtong M., van der Most, Peter, Nolte, Ilja, Lyytikaeinen, Leo-Pekka R., Said, M. Abdullah, Witte, Daniel, Iribarren, Carlos M., Launer, Lenore S., Ring, Susan, de Vries, Paul, Sever, Peter P., Linneberg, Allan, Bottinger, Erwin M., Padmanabhan, Sandosh, Psaty, Bruce, Sotoodehnia, Nona, Kolcic, Ivana, Roshandel, Delnaz D., Paterson, Andrew O., Arnar, David F., Gudbjartsson, Daniel, Holm, Hilma, Balkau, Beverley T., Silva, Claudia H., Newton-Cheh, Christopher, Nikus, Kjell, Salo, Perttu L., Mohlke, Karen A., Peyser, Patricia, Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari C., Rao, Dabeeru C., Cornelis, Marilyn D., Faul, Jessica A., Smith, Jennifer, Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie F., Sinner, Moritz, Strauch, Konstantin E., Delgado, Graciela D., Taylor, Kent, Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renee, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre W., Macfarlane, Peter V., Tarasov, Kirill, Tan, Nicholas B., Felix, Stephan, Tai, E-Shyong Q., Quek, Debra, Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia P., Morris, Andrew T., Raitakari, Olli, Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur J., Timpson, Nicholas C., Morrison, Alanna B., Munroe, Patricia P., Strachan, David, Grarup, Niels, Loos, Ruth J. F. R., Heckbert, Susan, Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif J., Wareham, Nicholas M., van Duijn, Cornelia F., Feitosa, Mary J., O'Donnell, Christopher, Kaehoenen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes J., Porteous, David G., Eriksson, Johan, Bouchard, Claude, Moebus, Susanne, Kraft, Peter R., Weir, David, Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kaeaeb, Stefan, Peters, Annette C., Chambers, John S., Kooner, Jaspal, Maerz, Winfried I., Rotter, Jerome A., Hicks, Andrew, Smith, J. Gustav, Kiemeney, Lambertus A. L. M. O., Mook-Kanamori, Dennis, Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James, Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Doerr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi J., Oldehinkel, Albertine, Riese, Harriette, Lehtimaeki, Terho, Verweij, Niek, and van der Harst, Pim
Abstract: The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Published: 2023
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11. Lifestyle-related risk factors and their cumulative associations with hippocampal and total grey matter volume across the adult lifespan:A pooled analysis in the European Lifebrain consortium

Author: Binnewies, Julia, Nawijn, Laura, Brandmaier, Andreas M., Baaré, William F. C., Boraxbekk, Carl-Johan, Demnitz, Naiara, Drevon, Christian A., Fjell, Anders M., Lindenberger, Ulman, Madsen, Kathrine Skak, Nyberg, Lars, Topiwala, Anya, Walhovd, Kristine B., Ebmeier, Klaus P., Penninx, Brenda W. J. H., Binnewies, Julia, Nawijn, Laura, Brandmaier, Andreas M., Baaré, William F. C., Boraxbekk, Carl-Johan, Demnitz, Naiara, Drevon, Christian A., Fjell, Anders M., Lindenberger, Ulman, Madsen, Kathrine Skak, Nyberg, Lars, Topiwala, Anya, Walhovd, Kristine B., Ebmeier, Klaus P., and Penninx, Brenda W. J. H.
Abstract: BACKGROUND: Lifestyle-related risk factors, such as obesity, physical inactivity, short sleep, smoking and alcohol use, have been associated with low hippocampal and total grey matter volumes (GMV). However, these risk factors have mostly been assessed as separate factors, leaving it unknown if variance explained by these factors is overlapping or additive. We investigated associations of five lifestyle-related factors separately and cumulatively with hippocampal and total GMV, pooled across eight European cohorts.METHODS: We included 3838 participants aged 18-90 years from eight cohorts of the European Lifebrain consortium. Using individual person data, we performed cross-sectional meta-analyses on associations of presence of lifestyle-related risk factors separately (overweight/obesity, physical inactivity, short sleep, smoking, high alcohol use) as well as a cumulative unhealthy lifestyle score (counting the number of present lifestyle-related risk factors) with FreeSurfer-derived hippocampal volume and total GMV. Lifestyle-related risk factors were defined according to public health guidelines.RESULTS: High alcohol use was associated with lower hippocampal volume (r = -0.10, p = 0.021), and overweight/obesity with lower total GMV (r = -0.09, p = 0.001). Other lifestyle-related risk factors were not significantly associated with hippocampal volume or GMV. The cumulative unhealthy lifestyle score was negatively associated with total GMV (r = -0.08, p = 0.001), but not hippocampal volume (r = -0.01, p = 0.625).CONCLUSIONS: This large pooled study confirmed the negative association of some lifestyle-related risk factors with hippocampal volume and GMV, although with small effect sizes. Lifestyle factors should not be seen in isolation as there is evidence that having multiple unhealthy lifestyle factors is associated with a linear reduction in overall brain volume.
Published: 2023

12. Weighing psychosocial factors in relatives for the risk of psychopathology: A study of patients with depressive and anxiety disorders and their siblings

Author: van Sprang, Eleonore D. D., Maciejewski, Dominique F. F., Milaneschi, Yuri, Kullberg, Marie-Louise J., Elzinga, Bernet M. M., van Hemert, Albert M. M., Hartman, Catharina A. A., Penninx, Brenda W. J. H., van Sprang, Eleonore D. D., Maciejewski, Dominique F. F., Milaneschi, Yuri, Kullberg, Marie-Louise J., Elzinga, Bernet M. M., van Hemert, Albert M. M., Hartman, Catharina A. A., and Penninx, Brenda W. J. H.
Abstract: Purpose Siblings of probands with depressive and anxiety disorders are at increased risk for psychopathology, but little is known about how risk factors operate within families to increase psychopathology for siblings. We examined the additional impact of psychosocial risk factors in probands-on top of or in combination with those in siblings-on depressive/anxious psychopathology in siblings. Methods The sample included 636 participants (M-age = 49.7; 62.4% female) from 256 families, each including a proband with lifetime depressive and/or anxiety disorders and their sibling(s) (N = 380 proband-sibling pairs). Sixteen psychosocial risk factors were tested. In siblings, depressive and anxiety disorders were determined with standardized psychiatric interviews; symptom severity was measured using self-report questionnaires. Analyses were performed with mixed-effects models accounting for familial structure. Results In siblings, various psychosocial risk factors (female gender, low income, childhood trauma, poor parental bonding, being single, smoking, hazardous alcohol use) were associated with higher symptomatology and likelihood of disorder. The presence of the same risk factor in probands was independently associated (low income, being single) with higher symptomatology in siblings or moderated (low education, childhood trauma, hazardous alcohol use)-by reducing its strength-the association between the risk factor and symptomatology in siblings. There was no additional impact of risk factors in probands on likelihood of disorder in siblings. Conclusion Our findings demonstrate the importance of weighing psychosocial risk factors within a family context, as it may provide relevant information on the risk of affective psychopathology for individuals.
Published: 2023

13. Depression, anxiety, and the risk of cancer: An individual participant data meta-analysis

Author: Trauma and Grief, Leerstoel Boelen, IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, van Tuijl, Lonneke A, Basten, Maartje, Pan, Kuan-Yu, Vermeulen, Roel, Portengen, Lützen, de Graeff, Alexander, Dekker, Joost, Geerlings, Mirjam I, Hoogendoorn, Adriaan, Lamers, Femke, Voogd, Adri C, Abell, Jessica, Awadalla, Philip, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Frank, Philipp, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, de Jong, Trynke R, Keats, Melanie R, Kok, Almar A L, Krokstad, Steinar, van Leeuwen, Flora E, Luik, Annemarie I, Noisel, Nolwenn, Onland-Moret, N Charlotte, Payette, Yves, Penninx, Brenda W J H, Rissanen, Ina, Roest, Annelieke M, Ruiter, Rikje, Schoevers, Robert A, Soave, David, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Twait, Emma L, Teyhan, Alison, Verschuren, W M Monique, van der Willik, Kimberly D, Rosmalen, Judith G M, Ranchor, Adelita V, Trauma and Grief, Leerstoel Boelen, IRAS OH Epidemiology Chemical Agents, IRAS – One Health Chemical, van Tuijl, Lonneke A, Basten, Maartje, Pan, Kuan-Yu, Vermeulen, Roel, Portengen, Lützen, de Graeff, Alexander, Dekker, Joost, Geerlings, Mirjam I, Hoogendoorn, Adriaan, Lamers, Femke, Voogd, Adri C, Abell, Jessica, Awadalla, Philip, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Frank, Philipp, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, de Jong, Trynke R, Keats, Melanie R, Kok, Almar A L, Krokstad, Steinar, van Leeuwen, Flora E, Luik, Annemarie I, Noisel, Nolwenn, Onland-Moret, N Charlotte, Payette, Yves, Penninx, Brenda W J H, Rissanen, Ina, Roest, Annelieke M, Ruiter, Rikje, Schoevers, Robert A, Soave, David, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Twait, Emma L, Teyhan, Alison, Verschuren, W M Monique, van der Willik, Kimberly D, Rosmalen, Judith G M, and Ranchor, Adelita V
Published: 2023

14. Deep phenotyping towards precision psychiatry of first-episode depression - the Brain Drugs-Depression cohort

Author: Jensen, Kristian Høj Reveles, Dam, Vibeke H., Ganz, Melanie, Fisher, Patrick MacDonald, Ip, Cheng-Teng, Sankar, Anjali, Marstrand-Joergensen, Maja Rou, Ozenne, Brice, Osler, Merete, Penninx, Brenda W J H, Pinborg, Lars H, Frokjaer, Vibe Gedsø, Knudsen, Gitte Moos, Jørgensen, Martin Balslev, Jensen, Kristian Høj Reveles, Dam, Vibeke H., Ganz, Melanie, Fisher, Patrick MacDonald, Ip, Cheng-Teng, Sankar, Anjali, Marstrand-Joergensen, Maja Rou, Ozenne, Brice, Osler, Merete, Penninx, Brenda W J H, Pinborg, Lars H, Frokjaer, Vibe Gedsø, Knudsen, Gitte Moos, and Jørgensen, Martin Balslev
Abstract: BACKGROUND: Major Depressive Disorder (MDD) is a heterogenous brain disorder, with potentially multiple psychosocial and biological disease mechanisms. This is also a plausible explanation for why patients do not respond equally well to treatment with first- or second-line antidepressants, i.e., one-third to one-half of patients do not remit in response to first- or second-line treatment. To map MDD heterogeneity and markers of treatment response to enable a precision medicine approach, we will acquire several possible predictive markers across several domains, e.g., psychosocial, biochemical, and neuroimaging.METHODS: All patients are examined before receiving a standardised treatment package for adults aged 18-65 with first-episode depression in six public outpatient clinics in the Capital Region of Denmark. From this population, we will recruit a cohort of 800 patients for whom we will acquire clinical, cognitive, psychometric, and biological data. A subgroup (subcohort I, n = 600) will additionally provide neuroimaging data, i.e., Magnetic Resonance Imaging, and Electroencephalogram, and a subgroup of patients from subcohort I unmedicated at inclusion (subcohort II, n = 60) will also undergo a brain Positron Emission Tomography with the [ 11C]-UCB-J tracer binding to the presynaptic glycoprotein-SV2A. Subcohort allocation is based on eligibility and willingness to participate. The treatment package typically lasts six months. Depression severity is assessed with the Quick Inventory of Depressive Symptomatology (QIDS) at baseline, and 6, 12 and 18 months after treatment initiation. The primary outcome is remission (QIDS ≤ 5) and clinical improvement (≥ 50% reduction in QIDS) after 6 months. Secondary endpoints include remission at 12 and 18 months and %-change in QIDS, 10-item Symptom Checklist, 5-item WHO Well-Being Index, and modified Disability Scale from baseline through follow-up. We also assess psychotherapy and medication side-effects. We will us
Published: 2023

15. Depression, anxiety, and the risk of cancer: An individual participant data meta-analysis

Author: Cardiovasculaire Epidemiologie, MS Medische Oncologie, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Brain, Cardiovasculaire Epi Team 3, Cardiovasculaire Epi Team 7a, Cardiometabolic Health, van Tuijl, Lonneke A, Basten, Maartje, Pan, Kuan-Yu, Vermeulen, Roel, Portengen, Lützen, de Graeff, Alexander, Dekker, Joost, Geerlings, Mirjam I, Hoogendoorn, Adriaan, Lamers, Femke, Voogd, Adri C, Abell, Jessica, Awadalla, Philip, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Frank, Philipp, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, de Jong, Trynke R, Keats, Melanie R, Kok, Almar A L, Krokstad, Steinar, van Leeuwen, Flora E, Luik, Annemarie I, Noisel, Nolwenn, Onland-Moret, N Charlotte, Payette, Yves, Penninx, Brenda W J H, Rissanen, Ina, Roest, Annelieke M, Ruiter, Rikje, Schoevers, Robert A, Soave, David, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Twait, Emma, Teyhan, Alison, Verschuren, MW, van der Willik, Kimberly D, Rosmalen, Judith G M, Ranchor, Adelita V, Cardiovasculaire Epidemiologie, MS Medische Oncologie, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Brain, Cardiovasculaire Epi Team 3, Cardiovasculaire Epi Team 7a, Cardiometabolic Health, van Tuijl, Lonneke A, Basten, Maartje, Pan, Kuan-Yu, Vermeulen, Roel, Portengen, Lützen, de Graeff, Alexander, Dekker, Joost, Geerlings, Mirjam I, Hoogendoorn, Adriaan, Lamers, Femke, Voogd, Adri C, Abell, Jessica, Awadalla, Philip, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Frank, Philipp, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, de Jong, Trynke R, Keats, Melanie R, Kok, Almar A L, Krokstad, Steinar, van Leeuwen, Flora E, Luik, Annemarie I, Noisel, Nolwenn, Onland-Moret, N Charlotte, Payette, Yves, Penninx, Brenda W J H, Rissanen, Ina, Roest, Annelieke M, Ruiter, Rikje, Schoevers, Robert A, Soave, David, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Twait, Emma, Teyhan, Alison, Verschuren, MW, van der Willik, Kimberly D, Rosmalen, Judith G M, and Ranchor, Adelita V
Published: 2023

16. DenseNet and Support Vector Machine classifications of major depressive disorder using vertex-wise cortical features

Author: Belov, Vladimir, Erwin-Grabner, Tracy, Zeng, Ling-Li, Ching, Christopher R. K., Aleman, Andre, Amod, Alyssa R., Basgoze, Zeynep, Benedetti, Francesco, Besteher, Bianca, Brosch, Katharina, Bülow, Robin, Colle, Romain, Connolly, Colm G., Corruble, Emmanuelle, Couvy-Duchesne, Baptiste, Cullen, Kathryn, Dannlowski, Udo, Davey, Christopher G., Dols, Annemiek, Ernsting, Jan, Evans, Jennifer W., Fisch, Lukas, Fuentes-Claramonte, Paola, Gonul, Ali Saffet, Gotlib, Ian H., Grabe, Hans J., Groenewold, Nynke A., Grotegerd, Dominik, Hahn, Tim, Hamilton, J. Paul, Han, Laura K. M., Harrison, Ben J, Ho, Tiffany C., Jahanshad, Neda, Jamieson, Alec J., Karuk, Andriana, Kircher, Tilo, Klimes-Dougan, Bonnie, Koopowitz, Sheri-Michelle, Lancaster, Thomas, Leenings, Ramona, Li, Meng, Linden, David E. J., MacMaster, Frank P., Mehler, David M. A., Meinert, Susanne, Melloni, Elisa, Mueller, Bryon A., Mwangi, Benson, Nenadić, Igor, Ojha, Amar, Okamoto, Yasumasa, Oudega, Mardien L., Penninx, Brenda W. J. H., Poletti, Sara, Pomarol-Clotet, Edith, Portella, Maria J., Pozzi, Elena, Radua, Joaquim, Rodríguez-Cano, Elena, Sacchet, Matthew D., Salvador, Raymond, Schrantee, Anouk, Sim, Kang, Soares, Jair C., Solanes, Aleix, Stein, Dan J., Stein, Frederike, Stolicyn, Aleks, Thomopoulos, Sophia I., Toenders, Yara J., Uyar-Demir, Aslihan, Vieta, Eduard, Vives-Gilabert, Yolanda, Völzke, Henry, Walter, Martin, Whalley, Heather C., Whittle, Sarah, Winter, Nils, Wittfeld, Katharina, Wright, Margaret J., Wu, Mon-Ju, Yang, Tony T., Zarate, Carlos, Veltman, Dick J., Schmaal, Lianne, Thompson, Paul M., Goya-Maldonado, Roberto, Belov, Vladimir, Erwin-Grabner, Tracy, Zeng, Ling-Li, Ching, Christopher R. K., Aleman, Andre, Amod, Alyssa R., Basgoze, Zeynep, Benedetti, Francesco, Besteher, Bianca, Brosch, Katharina, Bülow, Robin, Colle, Romain, Connolly, Colm G., Corruble, Emmanuelle, Couvy-Duchesne, Baptiste, Cullen, Kathryn, Dannlowski, Udo, Davey, Christopher G., Dols, Annemiek, Ernsting, Jan, Evans, Jennifer W., Fisch, Lukas, Fuentes-Claramonte, Paola, Gonul, Ali Saffet, Gotlib, Ian H., Grabe, Hans J., Groenewold, Nynke A., Grotegerd, Dominik, Hahn, Tim, Hamilton, J. Paul, Han, Laura K. M., Harrison, Ben J, Ho, Tiffany C., Jahanshad, Neda, Jamieson, Alec J., Karuk, Andriana, Kircher, Tilo, Klimes-Dougan, Bonnie, Koopowitz, Sheri-Michelle, Lancaster, Thomas, Leenings, Ramona, Li, Meng, Linden, David E. J., MacMaster, Frank P., Mehler, David M. A., Meinert, Susanne, Melloni, Elisa, Mueller, Bryon A., Mwangi, Benson, Nenadić, Igor, Ojha, Amar, Okamoto, Yasumasa, Oudega, Mardien L., Penninx, Brenda W. J. H., Poletti, Sara, Pomarol-Clotet, Edith, Portella, Maria J., Pozzi, Elena, Radua, Joaquim, Rodríguez-Cano, Elena, Sacchet, Matthew D., Salvador, Raymond, Schrantee, Anouk, Sim, Kang, Soares, Jair C., Solanes, Aleix, Stein, Dan J., Stein, Frederike, Stolicyn, Aleks, Thomopoulos, Sophia I., Toenders, Yara J., Uyar-Demir, Aslihan, Vieta, Eduard, Vives-Gilabert, Yolanda, Völzke, Henry, Walter, Martin, Whalley, Heather C., Whittle, Sarah, Winter, Nils, Wittfeld, Katharina, Wright, Margaret J., Wu, Mon-Ju, Yang, Tony T., Zarate, Carlos, Veltman, Dick J., Schmaal, Lianne, Thompson, Paul M., and Goya-Maldonado, Roberto
Abstract: Major depressive disorder (MDD) is a complex psychiatric disorder that affects the lives of hundreds of millions of individuals around the globe. Even today, researchers debate if morphological alterations in the brain are linked to MDD, likely due to the heterogeneity of this disorder. The application of deep learning tools to neuroimaging data, capable of capturing complex non-linear patterns, has the potential to provide diagnostic and predictive biomarkers for MDD. However, previous attempts to demarcate MDD patients and healthy controls (HC) based on segmented cortical features via linear machine learning approaches have reported low accuracies. In this study, we used globally representative data from the ENIGMA-MDD working group containing an extensive sample of people with MDD (N=2,772) and HC (N=4,240), which allows a comprehensive analysis with generalizable results. Based on the hypothesis that integration of vertex-wise cortical features can improve classification performance, we evaluated the classification of a DenseNet and a Support Vector Machine (SVM), with the expectation that the former would outperform the latter. As we analyzed a multi-site sample, we additionally applied the ComBat harmonization tool to remove potential nuisance effects of site. We found that both classifiers exhibited close to chance performance (balanced accuracy DenseNet: 51%; SVM: 53%), when estimated on unseen sites. Slightly higher classification performance (balanced accuracy DenseNet: 58%; SVM: 55%) was found when the cross-validation folds contained subjects from all sites, indicating site effect. In conclusion, the integration of vertex-wise morphometric features and the use of the non-linear classifier did not lead to the differentiability between MDD and HC. Our results support the notion that MDD classification on this combination of features and classifiers is unfeasible.
Published: 2023

17. Demographic, Comorbid, and Clinical Variables Associated With Pointwise Visual Field Damage in Glaucoma: Data From the AGIS and CIGTS Clinical Trials.

Author: Gillespie, Brenda W, Gillespie, Brenda W, Niziol, Leslie M, Ehrlich, Joshua R, Johnson, Chris A, Caprioli, Joseph, VanVeldhuisen, Paul C, Lichter, Paul R, Musch, David C, Gillespie, Brenda W, Gillespie, Brenda W, Niziol, Leslie M, Ehrlich, Joshua R, Johnson, Chris A, Caprioli, Joseph, VanVeldhuisen, Paul C, Lichter, Paul R, and Musch, David C
Abstract: PurposeTo investigate differences across the visual field (VF) in the rate of glaucomatous progression, the likelihood of defect in four disease severity cross-sections, and comparisons of subgroups in each of between 12 demographic, comorbid, and clinical variables.MethodsTwo long-term glaucoma clinical trials used Humphrey Field Analyzer 24-2 VFs to calculate pointwise deviations from age-matched normal controls. Slopes of glaucomatous progression over time were calculated per participant using linear mixed models. Pointwise differences between subgroups in slopes and cross-sectional categories were tested, adjusting for multiple comparisons using false discovery rate (FDR) and Q values.ResultsPointwise data were available for 1118 patients who had 15,073 VFs. On average, defects were seen at all VF points. Of the 12 variables, six had average pointwise slopes where Subgroup 1 had significantly faster progression than Subgroup 2 at all or many of the 52 VF points: participants who were older (≥65 vs. younger), 52/52; were male, 13/52; had diabetes, 29/52; had hypertension, 46/52; had a larger cup-to-disc ratio (≥0.7), 36/52; or had larger differences in absolute mean deviation (MD) between eyes (>3 dB), 52/52. Cross-sectional patterns at MD severity of -12 to -6.1 dB showed strong midline effects for gender and other patterns for hypertension, cup-to-disc ratio, absolute difference in MD between eyes, and disc notching.ConclusionsThe approach used provides new longitudinal and cross-sectional insights into variation across the VF associated with demographic, comorbid, and clinical variables.Translational relevanceThis exploration and characterization of variable effects in the setting of pointwise VF testing may enable clinicians to anticipate patterns of VF loss based on demographic, comorbid, and clinical associations.
Published: 2021

18. Impact of long-term exposure to PM2.5 on peripheral blood gene expression pathways involved in cell signaling and immune response

Author: Vlaanderen, Jelle, Vermeulen, Roel, Whitaker, Matthew, Chadeau-Hyam, Marc, Hottenga, Jouke Jan, de Geus, Eco J, Willemsen, Gonneke, Penninx, Brenda W J H, Jansen, Rick, Boomsma, Dorret I, Vlaanderen, Jelle, Vermeulen, Roel, Whitaker, Matthew, Chadeau-Hyam, Marc, Hottenga, Jouke Jan, de Geus, Eco J, Willemsen, Gonneke, Penninx, Brenda W J H, Jansen, Rick, and Boomsma, Dorret I
Abstract: Background Exposure to ambient air pollution, even at low levels, is a major environmental health risk. The peripheral blood transcriptome provides a potential avenue for the elucidation of ambient air pollution related biological perturbations. We assessed the association between long-term estimates for seven priority air pollutants and perturbations in peripheral blood transcriptomics data collected in the Dutch National Twin Register (NTR) and Netherlands Study of Depression and Anxiety (NESDA) cohorts. Methods In both the discovery (n = 2438) and replication (n = 1567) cohort, outdoor concentration of 7 air pollutants (NO2, NOx, particulate matter (PM2.5, PM2.5abs, PM10, PMcoarse), and ultrafine particles) was predicted with land use regression models. Gene expression was assessed by Affymetrix U219 arrays. Multi-variable univariate mixed-effect models were applied to test for an association between the air pollutants and the transcriptome. Functional analysis was conducted in DAVID. Results In the discovery cohort, we observed for 335 genes (374 probes with FDR < 5 %) a perturbation in peripheral blood gene expression that was associated with long-term average levels of PM2.5. For 69 genes pooled effect estimates from the NTR and NESDA cohorts were significant. Identified genes play a role in biological pathways related to cell signaling and immune response. Sixty-two out of 69 genes had a similar direction of effect in an analysis in which we regressed the probes on differential PM2.5 exposure within monozygotic twin pairs, indicating that the observed differences in gene expression were likely driven by differences in air pollution, rather than by confounding by genetic factors. Conclusion Our results indicate that PM2.5 can elicit a response in cell signaling and the immune system, both hallmarks of environmental diseases. The differential effect that we observed between air pollutants may aid in the understandin
Published: 2022

19. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Author: Winkler, Thomas W., Rasheed, Humaira, Teumer, Alexander, Gorski, Mathias, Rowan, Bryce X., Stanzick, Kira J., Thomas, Laurent F., Tin, Adrienne, Hoppmann, Anselm, Chu, Audrey Y., Tayo, Bamidele, Thio, Chris H. L., Cusi, Daniele, Chai, Jin-Fang, Sieber, Karsten B., Horn, Katrin, Li, Man, Scholz, Markus, Cocca, Massimiliano, Wuttke, Matthias, van der Most, Peter J., Yang, Qiong, Ghasemi, Sahar, Nutile, Teresa, Li, Yong, Pontali, Giulia, Guenther, Felix, Dehghan, Abbas, Correa, Adolfo, Parsa, Afshin, Feresin, Agnese, de Vries, Aiko P. J., Zonderman, Alan B., Smith, Albert, V, Oldehinkel, Albertine J., De Grandi, Alessandro, Rosenkranz, Alexander R., Franke, Andre, Teren, Andrej, Metspalu, Andres, Hicks, Andrew A., Morris, Andrew P., Toenjes, Anke, Morgan, Anna, Podgornaia, Anna, I, Peters, Annette, Koerner, Antje, Mahajan, Anubha, Campbell, Archie, Freedman, Barry, I, Spedicati, Beatrice, Ponte, Belen, Schoettker, Ben, Brumpton, Ben, Banas, Bernhard, Kraemer, Bernhard K., Jung, Bettina, Asvold, Bjorn Olav, Smith, Blair H., Ning, Boting, Penninx, Brenda W. J. H., Vanderwerff, Brett R., Psaty, Bruce M., Kammerer, Candace M., Langefeld, Carl D., Hayward, Caroline, Spracklen, Cassandra N., Robinson-Cohen, Cassianne, Hartman, Catharina A., Lindgren, Cecilia M., Wang, Chaolong, Sabanayagam, Charumathi, Heng, Chew-Kiat, Lanzani, Chiara, Khor, Chiea-Chuen, Cheng, Ching-Yu, Fuchsberger, Christian, Gieger, Christian, Shaffer, Christian M., Schulz, Christina-Alexandra, Willer, Cristen J., Chasman, Daniel, I, Gudbjartsson, Daniel F., Ruggiero, Daniela, Toniolo, Daniela, Czamara, Darina, Porteous, David J., Waterworth, Dawn M., Mascalzoni, Deborah, Mook-Kanamori, Dennis O., Reilly, Dermot F., Daw, E. Warwick, Hofer, Edith, Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Tai, E-Shyong, Catamo, Eulalia, Rizzi, Federica, Guo, Feng, Rivadeneira, Fernando, Guilianini, Franco, Sveinbjornsson, Gardar, Ehret, Georg, Waeber, Gerard, Biino, Ginevra, Girotto, Giorgia, Pistis, Giorgio, Nadkarni, Girish N., Delgado, Graciela E., Montgomery, Grant W., Snieder, Harold, Campbell, Harry, White, Harvey D., Gao, He, Stringham, Heather M., Schmidt, Helena, Li, Hengtong, Brenner, Hermann, Holm, Hilma, Kirsten, Holgen, Kramer, Holly, Rudan, Igor, Nolte, Ilja M., Tzoulaki, Ioanna, Olafsson, Isleifur, Martins, Jade, Cook, James P., Wilson, James F., Halbritter, Jan, Felix, Janine F., Divers, Jasmin, Kooner, Jaspal S., Lee, Jeannette Jen-Mai, O'Connell, Jeffrey, Rotter, Jerome, I, Liu, Jianjun, Xu, Jie, Thiery, Joachim, Ärnlöv, Johan, Kuusisto, Johanna, Jakobsdottir, Johanna, Tremblay, Johanne, Chambers, John C., Whitfield, John B., Gaziano, John M., Marten, Jonathan, Coresh, Josef, Jonas, Jost B., Mychaleckyj, Josyf C., Christensen, Kaare, Eckardt, Kai-Uwe, Mohlke, Karen L., Endlich, Karlhans, Dittrich, Katalin, Ryan, Kathleen A., Rice, Kenneth M., Taylor, Kent D., Ho, Kevin, Nikus, Kjell, Matsuda, Koichi, Strauch, Konstantin, Miliku, Kozeta, Hveem, Kristian, Lind, Lars, Wallentin, Lars, Yerges-Armstrong, Laura M., Raffield, Laura M., Phillips, Lawrence S., Launer, Lenore J., Lyytikainen, Leo-Pekka, Lange, Leslie A., Citterio, Lorena, Klaric, Lucija, Ikram, M. Arfan, Ising, Marcus, Kleber, Marcus E., Francescatto, Margherita, Concas, Maria Pina, Ciullo, Marina, Piratsu, Mario, Orho-Melander, Marju, Laakso, Markku, Loeffler, Markus, Perola, Markus, de Borst, Martin H., Gogele, Martin, La Bianca, Martina, Lukas, Mary Ann, Feitosa, Mary F., Biggs, Mary L., Wojczynski, Mary K., Kavousi, Maryam, Kanai, Masahiro, Akiyama, Masato, Yasuda, Masayuki, Nauck, Matthias, Waldenberger, Melanie, Chee, Miao-Li, Chee, Miao-Ling, Boehnke, Michael, Preuss, Michael H., Stumvoll, Michael, Province, Michael A., Evans, Michele K., O'Donoghue, Michelle L., Kubo, Michiaki, Kahonen, Mika, Kastarinen, Mika, Nalls, Mike A., Kuokkanen, Mikko, Ghanbari, Mohsen, Bochud, Murielle, Josyula, Navya Shilpa, Martin, Nicholas G., Tan, Nicholas Y. Q., Palmer, Nicholette D., Pirastu, Nicola, Schupf, Nicole, Verweij, Niek, Hutri-Kahonen, Nina, Mononen, Nina, Bansal, Nisha, Devuyst, Olivier, Melander, Olle, Raitakari, Olli T., Polasek, Ozren, Manunta, Paolo, Gasparini, Paolo, Mishra, Pashupati P., Sulem, Patrick, Magnusson, Patrik K. E., Elliott, Paul, Ridker, Paul M., Hamet, Pavel, Svensson, Per O., Joshi, Peter K., Kovacs, Peter, Pramstaller, Peter P., Rossing, Peter, Vollenweider, Peter, van der Harst, Pim, Dorajoo, Rajkumar, Sim, Ralene Z. H., Burkhardt, Ralph, Tao, Ran, Noordam, Raymond, Magi, Reedik, Schmidt, Reinhold, de Mutsert, Renee, Rueedi, Rico, van Dam, Rob M., Carroll, Robert J., Gansevoort, Ron T., Loos, Ruth J. F., Felicita, Sala Cinzia, Sedaghat, Sanaz, Padmanabhan, Sandosh, Freitag-Wolf, Sandra, Pendergrass, Sarah A., Graham, Sarah E., Gordon, Scott D., Hwang, Shih-Jen, Kerr, Shona M., Vaccargiu, Simona, Patil, Snehal B., Hallan, Stein, Bakker, Stephan J. L., Lim, Su-Chi, Lucae, Susanne, Vogelezang, Suzanne, Bergmann, Sven, Corre, Tanguy, Ahluwalia, Tarunveer S., Lehtimaki, Terho, Boutin, Thibaud S., Meitinger, Thomas, Wong, Tien-Yin, Bergler, Tobias, Rabelink, Ton J., Esko, Tonu, Haller, Toomas, Thorsteinsdottir, Unnur, Voelker, Uwe, Foo, Valencia Hui Xian, Salomaa, Veikko, Vitart, Veronique, Giedraitis, Vilmantas, Gudnason, Vilmundur, Jaddoe, Vincent W. V., Huang, Wei, Zhang, Weihua, Wei, Wen Bin, Kiess, Wieland, Marz, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Gao, Xin, Sim, Xueling, Wang, Ya Xing, Friedlander, Yechiel, Tham, Yih-Chung, Kamatani, Yoichiro, Okada, Yukinori, Milaneschi, Yuri, Yu, Zhi, Stark, Klaus J., Stefansson, Kari, Boeger, Carsten A., Hung, Adriana M., Kronenberg, Florian, Koettgen, Anna, Pattaro, Cristian, Heid, Iris M., Winkler, Thomas W., Rasheed, Humaira, Teumer, Alexander, Gorski, Mathias, Rowan, Bryce X., Stanzick, Kira J., Thomas, Laurent F., Tin, Adrienne, Hoppmann, Anselm, Chu, Audrey Y., Tayo, Bamidele, Thio, Chris H. L., Cusi, Daniele, Chai, Jin-Fang, Sieber, Karsten B., Horn, Katrin, Li, Man, Scholz, Markus, Cocca, Massimiliano, Wuttke, Matthias, van der Most, Peter J., Yang, Qiong, Ghasemi, Sahar, Nutile, Teresa, Li, Yong, Pontali, Giulia, Guenther, Felix, Dehghan, Abbas, Correa, Adolfo, Parsa, Afshin, Feresin, Agnese, de Vries, Aiko P. J., Zonderman, Alan B., Smith, Albert, V, Oldehinkel, Albertine J., De Grandi, Alessandro, Rosenkranz, Alexander R., Franke, Andre, Teren, Andrej, Metspalu, Andres, Hicks, Andrew A., Morris, Andrew P., Toenjes, Anke, Morgan, Anna, Podgornaia, Anna, I, Peters, Annette, Koerner, Antje, Mahajan, Anubha, Campbell, Archie, Freedman, Barry, I, Spedicati, Beatrice, Ponte, Belen, Schoettker, Ben, Brumpton, Ben, Banas, Bernhard, Kraemer, Bernhard K., Jung, Bettina, Asvold, Bjorn Olav, Smith, Blair H., Ning, Boting, Penninx, Brenda W. J. H., Vanderwerff, Brett R., Psaty, Bruce M., Kammerer, Candace M., Langefeld, Carl D., Hayward, Caroline, Spracklen, Cassandra N., Robinson-Cohen, Cassianne, Hartman, Catharina A., Lindgren, Cecilia M., Wang, Chaolong, Sabanayagam, Charumathi, Heng, Chew-Kiat, Lanzani, Chiara, Khor, Chiea-Chuen, Cheng, Ching-Yu, Fuchsberger, Christian, Gieger, Christian, Shaffer, Christian M., Schulz, Christina-Alexandra, Willer, Cristen J., Chasman, Daniel, I, Gudbjartsson, Daniel F., Ruggiero, Daniela, Toniolo, Daniela, Czamara, Darina, Porteous, David J., Waterworth, Dawn M., Mascalzoni, Deborah, Mook-Kanamori, Dennis O., Reilly, Dermot F., Daw, E. Warwick, Hofer, Edith, Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Tai, E-Shyong, Catamo, Eulalia, Rizzi, Federica, Guo, Feng, Rivadeneira, Fernando, Guilianini, Franco, Sveinbjornsson, Gardar, Ehret, Georg, Waeber, Gerard, Biino, Ginevra, Girotto, Giorgia, Pistis, Giorgio, Nadkarni, Girish N., Delgado, Graciela E., Montgomery, Grant W., Snieder, Harold, Campbell, Harry, White, Harvey D., Gao, He, Stringham, Heather M., Schmidt, Helena, Li, Hengtong, Brenner, Hermann, Holm, Hilma, Kirsten, Holgen, Kramer, Holly, Rudan, Igor, Nolte, Ilja M., Tzoulaki, Ioanna, Olafsson, Isleifur, Martins, Jade, Cook, James P., Wilson, James F., Halbritter, Jan, Felix, Janine F., Divers, Jasmin, Kooner, Jaspal S., Lee, Jeannette Jen-Mai, O'Connell, Jeffrey, Rotter, Jerome, I, Liu, Jianjun, Xu, Jie, Thiery, Joachim, Ärnlöv, Johan, Kuusisto, Johanna, Jakobsdottir, Johanna, Tremblay, Johanne, Chambers, John C., Whitfield, John B., Gaziano, John M., Marten, Jonathan, Coresh, Josef, Jonas, Jost B., Mychaleckyj, Josyf C., Christensen, Kaare, Eckardt, Kai-Uwe, Mohlke, Karen L., Endlich, Karlhans, Dittrich, Katalin, Ryan, Kathleen A., Rice, Kenneth M., Taylor, Kent D., Ho, Kevin, Nikus, Kjell, Matsuda, Koichi, Strauch, Konstantin, Miliku, Kozeta, Hveem, Kristian, Lind, Lars, Wallentin, Lars, Yerges-Armstrong, Laura M., Raffield, Laura M., Phillips, Lawrence S., Launer, Lenore J., Lyytikainen, Leo-Pekka, Lange, Leslie A., Citterio, Lorena, Klaric, Lucija, Ikram, M. Arfan, Ising, Marcus, Kleber, Marcus E., Francescatto, Margherita, Concas, Maria Pina, Ciullo, Marina, Piratsu, Mario, Orho-Melander, Marju, Laakso, Markku, Loeffler, Markus, Perola, Markus, de Borst, Martin H., Gogele, Martin, La Bianca, Martina, Lukas, Mary Ann, Feitosa, Mary F., Biggs, Mary L., Wojczynski, Mary K., Kavousi, Maryam, Kanai, Masahiro, Akiyama, Masato, Yasuda, Masayuki, Nauck, Matthias, Waldenberger, Melanie, Chee, Miao-Li, Chee, Miao-Ling, Boehnke, Michael, Preuss, Michael H., Stumvoll, Michael, Province, Michael A., Evans, Michele K., O'Donoghue, Michelle L., Kubo, Michiaki, Kahonen, Mika, Kastarinen, Mika, Nalls, Mike A., Kuokkanen, Mikko, Ghanbari, Mohsen, Bochud, Murielle, Josyula, Navya Shilpa, Martin, Nicholas G., Tan, Nicholas Y. Q., Palmer, Nicholette D., Pirastu, Nicola, Schupf, Nicole, Verweij, Niek, Hutri-Kahonen, Nina, Mononen, Nina, Bansal, Nisha, Devuyst, Olivier, Melander, Olle, Raitakari, Olli T., Polasek, Ozren, Manunta, Paolo, Gasparini, Paolo, Mishra, Pashupati P., Sulem, Patrick, Magnusson, Patrik K. E., Elliott, Paul, Ridker, Paul M., Hamet, Pavel, Svensson, Per O., Joshi, Peter K., Kovacs, Peter, Pramstaller, Peter P., Rossing, Peter, Vollenweider, Peter, van der Harst, Pim, Dorajoo, Rajkumar, Sim, Ralene Z. H., Burkhardt, Ralph, Tao, Ran, Noordam, Raymond, Magi, Reedik, Schmidt, Reinhold, de Mutsert, Renee, Rueedi, Rico, van Dam, Rob M., Carroll, Robert J., Gansevoort, Ron T., Loos, Ruth J. F., Felicita, Sala Cinzia, Sedaghat, Sanaz, Padmanabhan, Sandosh, Freitag-Wolf, Sandra, Pendergrass, Sarah A., Graham, Sarah E., Gordon, Scott D., Hwang, Shih-Jen, Kerr, Shona M., Vaccargiu, Simona, Patil, Snehal B., Hallan, Stein, Bakker, Stephan J. L., Lim, Su-Chi, Lucae, Susanne, Vogelezang, Suzanne, Bergmann, Sven, Corre, Tanguy, Ahluwalia, Tarunveer S., Lehtimaki, Terho, Boutin, Thibaud S., Meitinger, Thomas, Wong, Tien-Yin, Bergler, Tobias, Rabelink, Ton J., Esko, Tonu, Haller, Toomas, Thorsteinsdottir, Unnur, Voelker, Uwe, Foo, Valencia Hui Xian, Salomaa, Veikko, Vitart, Veronique, Giedraitis, Vilmantas, Gudnason, Vilmundur, Jaddoe, Vincent W. V., Huang, Wei, Zhang, Weihua, Wei, Wen Bin, Kiess, Wieland, Marz, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Gao, Xin, Sim, Xueling, Wang, Ya Xing, Friedlander, Yechiel, Tham, Yih-Chung, Kamatani, Yoichiro, Okada, Yukinori, Milaneschi, Yuri, Yu, Zhi, Stark, Klaus J., Stefansson, Kari, Boeger, Carsten A., Hung, Adriana M., Kronenberg, Florian, Koettgen, Anna, Pattaro, Cristian, and Heid, Iris M.
Abstract: A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease. Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n(DM) = 178,691, n(noDM) = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
Published: 2022
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20. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author: Mullins, Niamh, Kang, JooEun, Campos, Adrian I., Coleman, Jonathan R. I., Edwards, Alexis C., Galfalvy, Hanga, Levey, Daniel F., Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J., Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D., Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B., Bergen, Andrew W., Berrettini, Wade H., Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J., Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M., Gallinger, Steven, Glatt, Stephen J., Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A., Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Klump, Kelly L., Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J., Marshall, Christian R., Mitchell, James E., Monson, Eric T., Myers, Richard M., Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M., Treasure, Janet, Tsuang, Ming T., Witt, Stephanie H., Woodside, D. Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M., Alda, Martin, Alfredsson, Lars, Andreassen, Ole A., Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M. Helena, Bass, Nicholas, Bau, Claiton H. D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Bosch, Rosa, Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Casas, Miguel, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Craig, David, Degenhardt, Franziska, Djurovic, Srdjan, Edenberg, Howard J., Fanous, Ayman H., Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Fullerton, Janice M., Gatt, Justine M., Gejman, Pablo V., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamilton, Steven P., Hamshere, Marian L., Hartmann, Annette, Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Konte, Bettina, Krebs, Marie-Odile, Landén, Mikael, Lawrence, Jacob, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Lucae, Susanne, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Medland, Sarah E., Mehta, Divya, Melle, Ingrid, Milaneschi, Yuri, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nievergelt, Caroline, Nimgaonkar, Vishwajit, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W. J. H., Pimm, Jonathan, Pistis, Giorgio, Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Rujescu, Dan, Sánchez-Mora, Cristina, Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Shyn, Stanley I., Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J. S., Spalletta, Gianfranco, Strauss, John S., Świątkowska, Beata, Trzaskowski, Maciej, Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T. R., Shannon Weickert, Cynthia, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Ashley-Koch, Allison E., Beckham, Jean C., Hauser, Elizabeth R., Hauser, Michael A., Kimbrel, Nathan A., Lindquist, Jennifer H., McMahon, Benjamin, Oslin, David W., Qin, Xuejun, Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Erlangsen, Annette, Esko, Tõnu, Gelernter, Joel, Hougaard, David M., Kessler, Ronald C., Kranzler, Henry R., Li, Qingqin S., Martin, Nicholas G., McIntosh, Andrew M., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Ursano, Robert J., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Bulik, Cynthia M., Coon, Hilary, Demontis, Ditte, Docherty, Anna R., Kuo, Po-Hsiu, Lewis, Cathryn M., Mann, J. John, Rentería, Miguel E., Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Streit, Fabian, Willour, Virginia, Ruderfer, Douglas M., Mullins, Niamh, Kang, JooEun, Campos, Adrian I., Coleman, Jonathan R. I., Edwards, Alexis C., Galfalvy, Hanga, Levey, Daniel F., Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J., Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D., Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B., Bergen, Andrew W., Berrettini, Wade H., Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J., Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M., Gallinger, Steven, Glatt, Stephen J., Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A., Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Klump, Kelly L., Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J., Marshall, Christian R., Mitchell, James E., Monson, Eric T., Myers, Richard M., Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M., Treasure, Janet, Tsuang, Ming T., Witt, Stephanie H., Woodside, D. Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M., Alda, Martin, Alfredsson, Lars, Andreassen, Ole A., Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M. Helena, Bass, Nicholas, Bau, Claiton H. D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Bosch, Rosa, Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Casas, Miguel, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Craig, David, Degenhardt, Franziska, Djurovic, Srdjan, Edenberg, Howard J., Fanous, Ayman H., Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Fullerton, Janice M., Gatt, Justine M., Gejman, Pablo V., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamilton, Steven P., Hamshere, Marian L., Hartmann, Annette, Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Konte, Bettina, Krebs, Marie-Odile, Landén, Mikael, Lawrence, Jacob, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Lucae, Susanne, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Medland, Sarah E., Mehta, Divya, Melle, Ingrid, Milaneschi, Yuri, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nievergelt, Caroline, Nimgaonkar, Vishwajit, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W. J. H., Pimm, Jonathan, Pistis, Giorgio, Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Rujescu, Dan, Sánchez-Mora, Cristina, Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Shyn, Stanley I., Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J. S., Spalletta, Gianfranco, Strauss, John S., Świątkowska, Beata, Trzaskowski, Maciej, Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T. R., Shannon Weickert, Cynthia, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Ashley-Koch, Allison E., Beckham, Jean C., Hauser, Elizabeth R., Hauser, Michael A., Kimbrel, Nathan A., Lindquist, Jennifer H., McMahon, Benjamin, Oslin, David W., Qin, Xuejun, Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Erlangsen, Annette, Esko, Tõnu, Gelernter, Joel, Hougaard, David M., Kessler, Ronald C., Kranzler, Henry R., Li, Qingqin S., Martin, Nicholas G., McIntosh, Andrew M., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Ursano, Robert J., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Bulik, Cynthia M., Coon, Hilary, Demontis, Ditte, Docherty, Anna R., Kuo, Po-Hsiu, Lewis, Cathryn M., Mann, J. John, Rentería, Miguel E., Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Streit, Fabian, Willour, Virginia, and Ruderfer, Douglas M.
Abstract: BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
Published: 2022
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21. Impact of long-term exposure to PM2.5 on peripheral blood gene expression pathways involved in cell signaling and immune response

Author: IRAS OH Epidemiology Chemical Agents, Vlaanderen, Jelle, Vermeulen, Roel, Whitaker, Matthew, Chadeau-Hyam, Marc, Hottenga, Jouke Jan, de Geus, Eco J, Willemsen, Gonneke, Penninx, Brenda W J H, Jansen, Rick, Boomsma, Dorret I, IRAS OH Epidemiology Chemical Agents, Vlaanderen, Jelle, Vermeulen, Roel, Whitaker, Matthew, Chadeau-Hyam, Marc, Hottenga, Jouke Jan, de Geus, Eco J, Willemsen, Gonneke, Penninx, Brenda W J H, Jansen, Rick, and Boomsma, Dorret I
Published: 2022

22. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Author: Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J, Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn C, Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer S, Bartz, Traci M, Bentley, Amy R, Bielak, Lawrence F, Chong, Mike, Chu, Audrey Y, Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole D, Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary F, Gieger, Christian, Graff, Mariaelisa, Hall, Leanne M, Haller, Toomas, Hartwig, Fernando P, Hillis, David A, Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne U, Johansson, Åsa, Jørgensen, Anja Moltke, Kaakinen, Marika A, Karlsson, Robert, Kerr, Kathleen F, Kim, Boram, Koolhaas, Chantal M, Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope A, Lorentzon, Mattias, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Metzendorf, Christoph, Monroe, Kristine R, Pacolet, Alexander, Pérusse, Louis, Pool, Rene, Richmond, Rebecca C, Rivera, Natalia V, Robiou-du-Pont, Sebastien, Schraut, Katharina E, Schulz, Christina-Alexandra, Stringham, Heather M, Tanaka, Toshiko, Teumer, Alexander, Turman, Constance, van der Most, Peter J, Vanmunster, Mathias, van Rooij, Frank J A, van Vliet-Ostaptchouk, Jana V, Zhang, Xiaoshuai, Zhao, Jing-Hua, Zhao, Wei, Balkhiyarova, Zhanna, Balslev-Harder, Marie N, Baumeister, Sebastian E, Beilby, John, Blangero, John, Boomsma, Dorret I, Brage, Soren, Braund, Peter S, Brody, Jennifer A, Bruinenberg, Marcel, Ekelund, Ulf, Liu, Ching-Ti, Cole, John W, Collins, Francis S, Cupples, L Adrienne, Esko, Tõnu, Enroth, Stefan, Faul, Jessica D, Fernandez-Rhodes, Lindsay, Fohner, Alison E, Franco, Oscar H, Galesloot, Tessel E, Gordon, Scott D, Grarup, Niels, Hartman, Catharina A, Heiss, Gerardo, Hui, Jennie, Illig, Thomas, Jago, Russell, James, Alan, Joshi, Peter K, Jung, Taeyeong, Kähönen, Mika, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Kolcic, Ivana, Kraft, Peter P, Kuusisto, Johanna, Launer, Lenore J, Li, Aihua, Linneberg, Allan, Luan, Jian'an, Vidal, Pedro Marques, Medland, Sarah E, Milaneschi, Yuri, Moscati, Arden, Musk, Bill, Nelson, Christopher P, Nolte, Ilja M, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Power, Christine, Raitakari, Olli T, Reedik, Mägi, Reiner, Alex P, Ridker, Paul M, Rudan, Igor, Ryan, Kathy, Sarzynski, Mark A, Scott, Laura J, Scott, Robert A, Sidney, Stephen, Siggeirsdottir, Kristin, Smith, Albert V, Smith, Jennifer A, Sonestedt, Emily, Strøm, Marin, Tai, E Shyong, Teo, Koon K, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Uitterlinden, Andre G, Vangipurapu, Jagadish, van Schoor, Natasja, Völker, Uwe, Willemsen, Gonneke, Williams, Kayleen, Wong, Quenna, Xu, Huichun, Young, Kristin L, Yuan, Jian Min, Zillikens, M Carola, Zonderman, Alan B, Ameur, Adam, Bandinelli, Stefania, Bis, Joshua C, Boehnke, Michael, Bouchard, Claude, Chasman, Daniel I, Smith, George Davey, de Geus, Eco J C, Deldicque, Louise, Dörr, Marcus, Evans, Michele K, Ferrucci, Luigi, Fornage, Myriam, Fox, Caroline, Garland, Theodore, Gudnason, Vilmundur, Gyllensten, Ulf, Hansen, Torben, Hayward, Caroline, Horta, Bernardo L, Hyppönen, Elina, Jarvelin, Marjo-Riitta, Johnson, W Craig, Kardia, Sharon L R, Kiemeney, Lambertus A, Laakso, Markku, Langenberg, Claudia, Lehtimäki, Terho, Marchand, Loic Le, Magnusson, Patrik K E, Martin, Nicholas G, Melbye, Mads, Metspalu, Andres, Meyre, David, North, Kari E, Ohlsson, Claes, Oldehinkel, Albertine J, Orho-Melander, Marju, Pare, Guillaume, Park, Taesung, Pedersen, Oluf, Penninx, Brenda W J H, Pers, Tune H, Polasek, Ozren, Prokopenko, Inga, Rotimi, Charles N, Samani, Nilesh J, Sim, Xueling, Snieder, Harold, Sørensen, Thorkild I A, Spector, Tim D, Timpson, Nicholas J, van Dam, Rob M, van der Velde, Nathalie, van Duijn, Cornelia M, Vollenweider, Peter, Völzke, Henry, Voortman, Trudy, Waeber, Gérard, Wareham, Nicholas J, Weir, David R, Wichmann, Heinz-Erich, Wilson, James F, Hevener, Andrea L, Krook, Anna, Zierath, Juleen R, Thomis, Martine A I, Loos, Ruth J F, den Hoed, Marcel, Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J, Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn C, Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer S, Bartz, Traci M, Bentley, Amy R, Bielak, Lawrence F, Chong, Mike, Chu, Audrey Y, Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole D, Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary F, Gieger, Christian, Graff, Mariaelisa, Hall, Leanne M, Haller, Toomas, Hartwig, Fernando P, Hillis, David A, Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne U, Johansson, Åsa, Jørgensen, Anja Moltke, Kaakinen, Marika A, Karlsson, Robert, Kerr, Kathleen F, Kim, Boram, Koolhaas, Chantal M, Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope A, Lorentzon, Mattias, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Metzendorf, Christoph, Monroe, Kristine R, Pacolet, Alexander, Pérusse, Louis, Pool, Rene, Richmond, Rebecca C, Rivera, Natalia V, Robiou-du-Pont, Sebastien, Schraut, Katharina E, Schulz, Christina-Alexandra, Stringham, Heather M, Tanaka, Toshiko, Teumer, Alexander, Turman, Constance, van der Most, Peter J, Vanmunster, Mathias, van Rooij, Frank J A, van Vliet-Ostaptchouk, Jana V, Zhang, Xiaoshuai, Zhao, Jing-Hua, Zhao, Wei, Balkhiyarova, Zhanna, Balslev-Harder, Marie N, Baumeister, Sebastian E, Beilby, John, Blangero, John, Boomsma, Dorret I, Brage, Soren, Braund, Peter S, Brody, Jennifer A, Bruinenberg, Marcel, Ekelund, Ulf, Liu, Ching-Ti, Cole, John W, Collins, Francis S, Cupples, L Adrienne, Esko, Tõnu, Enroth, Stefan, Faul, Jessica D, Fernandez-Rhodes, Lindsay, Fohner, Alison E, Franco, Oscar H, Galesloot, Tessel E, Gordon, Scott D, Grarup, Niels, Hartman, Catharina A, Heiss, Gerardo, Hui, Jennie, Illig, Thomas, Jago, Russell, James, Alan, Joshi, Peter K, Jung, Taeyeong, Kähönen, Mika, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Kolcic, Ivana, Kraft, Peter P, Kuusisto, Johanna, Launer, Lenore J, Li, Aihua, Linneberg, Allan, Luan, Jian'an, Vidal, Pedro Marques, Medland, Sarah E, Milaneschi, Yuri, Moscati, Arden, Musk, Bill, Nelson, Christopher P, Nolte, Ilja M, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Power, Christine, Raitakari, Olli T, Reedik, Mägi, Reiner, Alex P, Ridker, Paul M, Rudan, Igor, Ryan, Kathy, Sarzynski, Mark A, Scott, Laura J, Scott, Robert A, Sidney, Stephen, Siggeirsdottir, Kristin, Smith, Albert V, Smith, Jennifer A, Sonestedt, Emily, Strøm, Marin, Tai, E Shyong, Teo, Koon K, Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Uitterlinden, Andre G, Vangipurapu, Jagadish, van Schoor, Natasja, Völker, Uwe, Willemsen, Gonneke, Williams, Kayleen, Wong, Quenna, Xu, Huichun, Young, Kristin L, Yuan, Jian Min, Zillikens, M Carola, Zonderman, Alan B, Ameur, Adam, Bandinelli, Stefania, Bis, Joshua C, Boehnke, Michael, Bouchard, Claude, Chasman, Daniel I, Smith, George Davey, de Geus, Eco J C, Deldicque, Louise, Dörr, Marcus, Evans, Michele K, Ferrucci, Luigi, Fornage, Myriam, Fox, Caroline, Garland, Theodore, Gudnason, Vilmundur, Gyllensten, Ulf, Hansen, Torben, Hayward, Caroline, Horta, Bernardo L, Hyppönen, Elina, Jarvelin, Marjo-Riitta, Johnson, W Craig, Kardia, Sharon L R, Kiemeney, Lambertus A, Laakso, Markku, Langenberg, Claudia, Lehtimäki, Terho, Marchand, Loic Le, Magnusson, Patrik K E, Martin, Nicholas G, Melbye, Mads, Metspalu, Andres, Meyre, David, North, Kari E, Ohlsson, Claes, Oldehinkel, Albertine J, Orho-Melander, Marju, Pare, Guillaume, Park, Taesung, Pedersen, Oluf, Penninx, Brenda W J H, Pers, Tune H, Polasek, Ozren, Prokopenko, Inga, Rotimi, Charles N, Samani, Nilesh J, Sim, Xueling, Snieder, Harold, Sørensen, Thorkild I A, Spector, Tim D, Timpson, Nicholas J, van Dam, Rob M, van der Velde, Nathalie, van Duijn, Cornelia M, Vollenweider, Peter, Völzke, Henry, Voortman, Trudy, Waeber, Gérard, Wareham, Nicholas J, Weir, David R, Wichmann, Heinz-Erich, Wilson, James F, Hevener, Andrea L, Krook, Anna, Zierath, Juleen R, Thomis, Martine A I, Loos, Ruth J F, and den Hoed, Marcel
Abstract: Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.
Published: 2022
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23. Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies

Author: Gorski, Mathias, Rasheed, Humaira, Teumer, Alexander, Thomas, Laurent F., Graham, Sarah E., Sveinbjornsson, Gardar, Winkler, Thomas W., Guenther, Felix, Stark, Klaus J., Chai, Jin-Fang, Tayo, Bamidele O., Wuttke, Matthias, Li, Yong, Tin, Adrienne, Ahluwalia, Tarunveer S., Ärnlöv, Johan, Asvold, Bjorn Olav, Bakker, Stephan J. L., Banas, Bernhard, Bansal, Nisha, Biggs, Mary L., Biino, Ginevra, Bohnke, Michael, Boerwinkle, Eric, Bottinger, Erwin P., Brenner, Hermann, Brumpton, Ben, Carroll, Robert J., Chaker, Layal, Chalmers, John, Chee, Miao-Li, Chee, Miao-Ling, Cheng, Ching-Yu, Chu, Audrey Y., Ciullo, Marina, Cocca, Massimiliano, Cook, James P., Coresh, Josef, Cusi, Daniele, de Borst, Martin H., Degenhardt, Frauke, Eckardt, Kai-Uwe, Endlich, Karlhans, Evans, Michele K., Feitosa, Mary F., Franke, Andre, Freitag-Wolf, Sandra, Fuchsberger, Christian, Gampawar, Piyush, Gansevoort, Ron T., Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Gieger, Christian, Gudbjartsson, Daniel F., Hallan, Stein, Hamet, Pavel, Hishida, Asahi, Ho, Kevin, Hofer, Edith, Holleczek, Bernd, Holm, Hilma, Hoppmann, Anselm, Horn, Katrin, Hutri-Kahonen, Nina, Hveem, Kristian, Hwang, Shih-Jen, Ikram, M. Arfan, Josyula, Navya Shilpa, Jung, Bettina, Kahonen, Mika, Karabegovic, Irma, Khor, Chiea-Chuen, Koenig, Wolfgang, Kramer, Holly, Kramer, Bernhard K., Kuehnel, Brigitte, Kuusisto, Johanna, Laakso, Markku, Lange, Leslie A., Lehtimaki, Terho, Li, Man, Lieb, Wolfgang, Lind, Lars, Lindgren, Cecilia M., Loos, Ruth J. F., Lukas, Mary Ann, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Matias-Garcia, Pamela R., Meisinger, Christa, Meitinger, Thomas, Melander, Olle, Milaneschi, Yuri, Mishra, Pashupati P., Mononen, Nina, Morris, Andrew P., Mychaleckyj, Josyf C., Nadkarni, Girish N., Naito, Mariko, Nakatochi, Masahiro, Nalls, Mike A., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M., Nutile, Teresa, O'Donoghue, Michelle L., O'Connell, Jeffrey, Olafsson, Isleifur, Orho-Melander, Marju, Parsa, Afshin, Pendergrass, Sarah A., Penninx, Brenda W. J. H., Pirastu, Mario, Preuss, Michael H., Psaty, Bruce M., Raffield, Laura M., Raitakari, Olli T., Rheinberger, Myriam, Rice, Kenneth M., Rizzi, Federica, Rosenkranz, Alexander R., Rossing, Peter, Rotter, Jerome I., Ruggiero, Daniela, Ryan, Kathleen A., Sabanayagam, Charumathi, Salvi, Erika, Schmidt, Helena, Schmidt, Reinhold, Scholz, Markus, Schoettker, Ben, Schulz, Christina-Alexandra, Sedaghat, Sanaz, Shaffer, Christian M., Sieber, Karsten B., Sim, Xueling, Sims, Mario, Snieder, Harold, Stanzick, Kira J., Thorsteinsdottir, Unnur, Stocker, Hannah, Strauch, Konstantin, Stringham, Heather M., Sulem, Patrick, Szymczak, Silke, Taylor, Kent D., Thio, Chris H. L., Tremblay, Johanne, Vaccargiu, Simona, van der Harst, Pim, van der Most, Peter J., Verweij, Niek, Volker, Uwe, Wakai, Kenji, Waldenberger, Melanie, Wallentin, Lars, Wallner, Stefan, Wang, Judy, Waterworth, Dawn M., White, Harvey D., Willer, Cristen J., Wong, Tien-Yin, Woodward, Mark, Yang, Qiong, Yerges-Armstrong, Laura M., Zimmermann, Martina, Zonderman, Alan B., Bergler, Tobias, Stefansson, Kari, Boger, Carsten A., Pattaro, Cristian, Koettgen, Anna, Kronenberg, Florian, Heid, Iris M., Gorski, Mathias, Rasheed, Humaira, Teumer, Alexander, Thomas, Laurent F., Graham, Sarah E., Sveinbjornsson, Gardar, Winkler, Thomas W., Guenther, Felix, Stark, Klaus J., Chai, Jin-Fang, Tayo, Bamidele O., Wuttke, Matthias, Li, Yong, Tin, Adrienne, Ahluwalia, Tarunveer S., Ärnlöv, Johan, Asvold, Bjorn Olav, Bakker, Stephan J. L., Banas, Bernhard, Bansal, Nisha, Biggs, Mary L., Biino, Ginevra, Bohnke, Michael, Boerwinkle, Eric, Bottinger, Erwin P., Brenner, Hermann, Brumpton, Ben, Carroll, Robert J., Chaker, Layal, Chalmers, John, Chee, Miao-Li, Chee, Miao-Ling, Cheng, Ching-Yu, Chu, Audrey Y., Ciullo, Marina, Cocca, Massimiliano, Cook, James P., Coresh, Josef, Cusi, Daniele, de Borst, Martin H., Degenhardt, Frauke, Eckardt, Kai-Uwe, Endlich, Karlhans, Evans, Michele K., Feitosa, Mary F., Franke, Andre, Freitag-Wolf, Sandra, Fuchsberger, Christian, Gampawar, Piyush, Gansevoort, Ron T., Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Gieger, Christian, Gudbjartsson, Daniel F., Hallan, Stein, Hamet, Pavel, Hishida, Asahi, Ho, Kevin, Hofer, Edith, Holleczek, Bernd, Holm, Hilma, Hoppmann, Anselm, Horn, Katrin, Hutri-Kahonen, Nina, Hveem, Kristian, Hwang, Shih-Jen, Ikram, M. Arfan, Josyula, Navya Shilpa, Jung, Bettina, Kahonen, Mika, Karabegovic, Irma, Khor, Chiea-Chuen, Koenig, Wolfgang, Kramer, Holly, Kramer, Bernhard K., Kuehnel, Brigitte, Kuusisto, Johanna, Laakso, Markku, Lange, Leslie A., Lehtimaki, Terho, Li, Man, Lieb, Wolfgang, Lind, Lars, Lindgren, Cecilia M., Loos, Ruth J. F., Lukas, Mary Ann, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Matias-Garcia, Pamela R., Meisinger, Christa, Meitinger, Thomas, Melander, Olle, Milaneschi, Yuri, Mishra, Pashupati P., Mononen, Nina, Morris, Andrew P., Mychaleckyj, Josyf C., Nadkarni, Girish N., Naito, Mariko, Nakatochi, Masahiro, Nalls, Mike A., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M., Nutile, Teresa, O'Donoghue, Michelle L., O'Connell, Jeffrey, Olafsson, Isleifur, Orho-Melander, Marju, Parsa, Afshin, Pendergrass, Sarah A., Penninx, Brenda W. J. H., Pirastu, Mario, Preuss, Michael H., Psaty, Bruce M., Raffield, Laura M., Raitakari, Olli T., Rheinberger, Myriam, Rice, Kenneth M., Rizzi, Federica, Rosenkranz, Alexander R., Rossing, Peter, Rotter, Jerome I., Ruggiero, Daniela, Ryan, Kathleen A., Sabanayagam, Charumathi, Salvi, Erika, Schmidt, Helena, Schmidt, Reinhold, Scholz, Markus, Schoettker, Ben, Schulz, Christina-Alexandra, Sedaghat, Sanaz, Shaffer, Christian M., Sieber, Karsten B., Sim, Xueling, Sims, Mario, Snieder, Harold, Stanzick, Kira J., Thorsteinsdottir, Unnur, Stocker, Hannah, Strauch, Konstantin, Stringham, Heather M., Sulem, Patrick, Szymczak, Silke, Taylor, Kent D., Thio, Chris H. L., Tremblay, Johanne, Vaccargiu, Simona, van der Harst, Pim, van der Most, Peter J., Verweij, Niek, Volker, Uwe, Wakai, Kenji, Waldenberger, Melanie, Wallentin, Lars, Wallner, Stefan, Wang, Judy, Waterworth, Dawn M., White, Harvey D., Willer, Cristen J., Wong, Tien-Yin, Woodward, Mark, Yang, Qiong, Yerges-Armstrong, Laura M., Zimmermann, Martina, Zonderman, Alan B., Bergler, Tobias, Stefansson, Kari, Boger, Carsten A., Pattaro, Cristian, Koettgen, Anna, Kronenberg, Florian, and Heid, Iris M.
Abstract: Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
Published: 2022
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24. A saturated map of common genetic variants associated with human height

Author: Yengo, Loïc, Vedantam, Sailaja, Marouli, Eirini, Sidorenko, Julia, Bartell, Eric, Sakaue, Saori, Graff, Marielisa, Eliasen, Anders U., Jiang, Yunxuan, Raghavan, Sridharan, Miao, Jenkai, Arias, Joshua D., Graham, Sarah E., Mukamel, Ronen E., Spracklen, Cassandra N., Yin, Xianyong, Chen, Shyh-Huei, Ferreira, Teresa, Highland, Heather H., Ji, Yingjie, Karaderi, Tugce, Lin, Kuang, Lüll, Kreete, Malden, Deborah E., Medina-Gomez, Carolina, Machado, Moara, Moore, Amy, Rüeger, Sina, Sim, Xueling, Vrieze, Scott, Ahluwalia, Tarunveer S., Akiyama, Masato, Allison, Matthew A., Alvarez, Marcus, Andersen, Mette K., Ani, Alireza, Appadurai, Vivek, Arbeeva, Liubov, Bhaskar, Seema, Bielak, Lawrence F., Bollepalli, Sailalitha, Bonnycastle, Lori L., Bork-Jensen, Jette, Bradfield, Jonathan P., Bradford, Yuki, Braund, Peter S., Brody, Jennifer A., Burgdorf, Kristoffer S., Cade, Brian E., Cai, Hui, Cai, Qiuyin, Campbell, Archie, Cañadas-Garre, Marisa, Catamo, Eulalia, Chai, Jin-Fang, Chai, Xiaoran, Chang, Li-Ching, Chang, Yi-Cheng, Chen, Chien-Hsiun, Chesi, Alessandra, Choi, Seung Hoan, Chung, Ren-Hua, Cocca, Massimiliano, Concas, Maria Pina, Couture, Christian, Cuellar-Partida, Gabriel, Danning, Rebecca, Daw, E. Warwick, Degenhard, Frauke, Delgado, Graciela E., Delitala, Alessandro, Demirkan, Ayse, Deng, Xuan, Devineni, Poornima, Dietl, Alexander, Dimitriou, Maria, Dimitrov, Latchezar, Dorajoo, Rajkumar, Ekici, Arif B., Engmann, Jorgen E., Fairhurst-Hunter, Zammy, Farmaki, Aliki-Eleni, Faul, Jessica D., Fernandez-Lopez, Juan-Carlos, Forer, Lukas, Francescatto, Margherita, Freitag-Wolf, Sandra, Fuchsberger, Christian, Galesloot, Tessel E., Gao, Yan, Gao, Zishan, Geller, Frank, Giannakopoulou, Olga, Giulianini, Franco, Gjesing, Anette P., Goel, Anuj, Gordon, Scott D., Gorski, Mathias, Grove, Jakob, Guo, Xiuqing, Gustafsson, Stefan, Haessler, Jeffrey, Hansen, Thomas F., Havulinna, Aki S., Haworth, Simon J., He, Jing, Heard-Costa, Nancy, Hebbar, Prashantha, Hindy, George, Ho, Yuk-Lam A., Hofer, Edith, Holliday, Elizabeth, Horn, Katrin, Hornsby, Whitney E., Hottenga, Jouke-Jan, Huang, Hongyan, Huang, Jie, Huerta-Chagoya, Alicia, Huffman, Jennifer E., Hung, Yi-Jen, Huo, Shaofeng, Hwang, Mi Yeong, Iha, Hiroyuki, Ikeda, Daisuke D., Isono, Masato, Jackson, Anne U., Jäger, Susanne, Jansen, Iris E., Johansson, Ingegerd, Jonas, Jost B., Jonsson, Anna, Jørgensen, Torben, Kalafati, Ioanna-Panagiota, Kanai, Masahiro, Kanoni, Stavroula, Kårhus, Line L., Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kawaguchi, Takahisa, Kember, Rachel L., Kentistou, Katherine A., Kim, Han-Na, Kim, Young Jin, Kleber, Marcus E., Knol, Maria J., Kurbasic, Azra, Lauzon, Marie, Le, Phuong, Lea, Rodney, Lee, Jong-Young, Leonard, Hampton L., Li, Shengchao A., Li, Xiaohui, Li, Xiaoyin, Liang, Jingjing, Lin, Honghuang, Lin, Shih-Yi, Liu, Jun, Liu, Xueping, Lo, Ken Sin, Long, Jirong, Lores-Motta, Laura, Luan, Jian’an, Lyssenko, Valeriya, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamakou, Vasiliki, Mangino, Massimo, Manichaikul, Ani, Marten, Jonathan, Mattheisen, Manuel, Mavarani, Laven, McDaid, Aaron F., Meidtner, Karina, Melendez, Tori L., Mercader, Josep M., Milaneschi, Yuri, Miller, Jason E., Millwood, Iona Y., Mishra, Pashupati P., Mitchell, Ruth E., Møllehave, Line T., Morgan, Anna, Mucha, Soeren, Munz, Matthias, Nakatochi, Masahiro, Nelson, Christopher P., Nethander, Maria, Nho, Chu Won, Nielsen, Aneta A., Nolte, Ilja M., Nongmaithem, Suraj S., Noordam, Raymond, Ntalla, Ioanna, Nutile, Teresa, Pandit, Anita, Christofidou, Paraskevi, Pärna, Katri, Pauper, Marc, Petersen, Eva R. B., Petersen, Liselotte V., Pitkänen, Niina, Polašek, Ozren, Poveda, Alaitz, Preuss, Michael H., Pyarajan, Saiju, Raffield, Laura M., Rakugi, Hiromi, Ramirez, Julia, Rasheed, Asif, Raven, Dennis, Rayner, Nigel W., Riveros, Carlos, Rohde, Rebecca, Ruggiero, Daniela, Ruotsalainen, Sanni E., Ryan, Kathleen A., Sabater-Lleal, Maria, Saxena, Richa, Scholz, Markus, Sendamarai, Anoop, Shen, Botong, Shi, Jingchunzi, Shin, Jae Hun, Sidore, Carlo, Sitlani, Colleen M., Slieker, Roderick C., Smit, Roelof A. J., Smith, Albert V., Smith, Jennifer A., Smyth, Laura J., Southam, Lorraine, Steinthorsdottir, Valgerdur, Sun, Liang, Takeuchi, Fumihiko, Tallapragada, Divya Sri Priyanka, Taylor, Kent D., Tayo, Bamidele O., Tcheandjieu, Catherine, Terzikhan, Natalie, Tesolin, Paola, Teumer, Alexander, Theusch, Elizabeth, Thompson, Deborah J., Thorleifsson, Gudmar, Timmers, Paul R. H. J., Trompet, Stella, Turman, Constance, Vaccargiu, Simona, van der Laan, Sander W., van der Most, Peter J., van Klinken, Jan B., van Setten, Jessica, Verma, Shefali S., Verweij, Niek, Veturi, Yogasudha, Wang, Carol A., Wang, Chaolong, Wang, Lihua, Wang, Zhe, Warren, Helen R., Bin Wei, Wen, Wickremasinghe, Ananda R., Wielscher, Matthias, Wiggins, Kerri L., Winsvold, Bendik S., Wong, Andrew, Wu, Yang, Wuttke, Matthias, Xia, Rui, Xie, Tian, Yamamoto, Ken, Yang, Jingyun, Yao, Jie, Young, Hannah, Yousri, Noha A., Yu, Lei, Zeng, Lingyao, Zhang, Weihua, Zhang, Xinyuan, Zhao, Jing-Hua, Zhao, Wei, Zhou, Wei, Zimmermann, Martina E., Zoledziewska, Magdalena, Adair, Linda S., Adams, Hieab H. H., Aguilar-Salinas, Carlos A., Al-Mulla, Fahd, Arnett, Donna K., Asselbergs, Folkert W., Åsvold, Bjørn Olav, Attia, John, Banas, Bernhard, Bandinelli, Stefania, Bennett, David A., Bergler, Tobias, Bharadwaj, Dwaipayan, Biino, Ginevra, Bisgaard, Hans, Boerwinkle, Eric, Böger, Carsten A., Bønnelykke, Klaus, Boomsma, Dorret I., Børglum, Anders D., Borja, Judith B., Bouchard, Claude, Bowden, Donald W., Brandslund, Ivan, Brumpton, Ben, Buring, Julie E., Caulfield, Mark J., Chambers, John C., Chandak, Giriraj R., Chanock, Stephen J., Chaturvedi, Nish, Chen, Yii-Der Ida, Chen, Zhengming, Cheng, Ching-Yu, Christophersen, Ingrid E., Ciullo, Marina, Cole, John W., Collins, Francis S., Cooper, Richard S., Cruz, Miguel, Cucca, Francesco, Cupples, L. Adrienne, Cutler, Michael J., Damrauer, Scott M., Dantoft, Thomas M., de Borst, Gert J., de Groot, Lisette C. P. G. M., De Jager, Philip L., de Kleijn, Dominique P. V., Janaka de Silva, H., Dedoussis, George V., den Hollander, Anneke I., Du, Shufa, Easton, Douglas F., Elders, Petra J. M., Eliassen, A. Heather, Ellinor, Patrick T., Elmståhl, Sölve, Erdmann, Jeanette, Evans, Michele K., Fatkin, Diane, Feenstra, Bjarke, Feitosa, Mary F., Ferrucci, Luigi, Ford, Ian, Fornage, Myriam, Franke, Andre, Franks, Paul W., Freedman, Barry I., Gasparini, Paolo, Gieger, Christian, Girotto, Giorgia, Goddard, Michael E., Golightly, Yvonne M., Gonzalez-Villalpando, Clicerio, Gordon-Larsen, Penny, Grallert, Harald, Grant, Struan F. A., Grarup, Niels, Griffiths, Lyn, Gudnason, Vilmundur, Haiman, Christopher, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayward, Caroline, Heckbert, Susan R., Heng, Chew-Kiat, Hengstenberg, Christian, Hewitt, Alex W., Hishigaki, Haretsugu, Hoyng, Carel B., Huang, Paul L., Huang, Wei, Hunt, Steven C., Hveem, Kristian, Hyppönen, Elina, Iacono, William G., Ichihara, Sahoko, Ikram, M. Arfan, Isasi, Carmen R., Jackson, Rebecca D., Jarvelin, Marjo-Riitta, Jin, Zi-Bing, Jöckel, Karl-Heinz, Joshi, Peter K., Jousilahti, Pekka, Jukema, J. Wouter, Kähönen, Mika, Kamatani, Yoichiro, Kang, Kui Dong, Kaprio, Jaakko, Kardia, Sharon L. R., Karpe, Fredrik, Kato, Norihiro, Kee, Frank, Kessler, Thorsten, Khera, Amit V., Khor, Chiea Chuen, Kiemeney, Lambertus A. L. M., Kim, Bong-Jo, Kim, Eung Kweon, Kim, Hyung-Lae, Kirchhof, Paulus, Kivimaki, Mika, Koh, Woon-Puay, Koistinen, Heikki A., Kolovou, Genovefa D., Kooner, Jaspal S., Kooperberg, Charles, Köttgen, Anna, Kovacs, Peter, Kraaijeveld, Adriaan, Kraft, Peter, Krauss, Ronald M., Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lange, Leslie A., Langenberg, Claudia, Launer, Lenore J., Le Marchand, Loic, Lee, Hyejin, Lee, Nanette R., Lehtimäki, Terho, Li, Huaixing, Li, Liming, Lieb, Wolfgang, Lin, Xu, Lind, Lars, Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Loeffler, Markus, London, Barry, Lubitz, Steven A., Lye, Stephen J., Mackey, David A., Mägi, Reedik, Magnusson, Patrik K. E., Marcus, Gregory M., Vidal, Pedro Marques, Martin, Nicholas G., März, Winfried, Matsuda, Fumihiko, McGarrah, Robert W., McGue, Matt, McKnight, Amy Jayne, Medland, Sarah E., Mellström, Dan, Metspalu, Andres, Mitchell, Braxton D., Mitchell, Paul, Mook-Kanamori, Dennis O., Morris, Andrew D., Mucci, Lorelei A., Munroe, Patricia B., Nalls, Mike A., Nazarian, Saman, Nelson, Amanda E., Neville, Matt J., Newton-Cheh, Christopher, Nielsen, Christopher S., Nöthen, Markus M., Ohlsson, Claes, Oldehinkel, Albertine J., Orozco, Lorena, Pahkala, Katja, Pajukanta, Päivi, Palmer, Colin N. A., Parra, Esteban J., Pattaro, Cristian, Pedersen, Oluf, Pennell, Craig E., Penninx, Brenda W. J. H., Perusse, Louis, Peters, Annette, Peyser, Patricia A., Porteous, David J., Posthuma, Danielle, Power, Chris, Pramstaller, Peter P., Province, Michael A., Qi, Qibin, Qu, Jia, Rader, Daniel J., Raitakari, Olli T., Ralhan, Sarju, Rallidis, Loukianos S., Rao, Dabeeru C., Redline, Susan, Reilly, Dermot F., Reiner, Alexander P., Rhee, Sang Youl, Ridker, Paul M., Rienstra, Michiel, Ripatti, Samuli, Ritchie, Marylyn D., Roden, Dan M., Rosendaal, Frits R., Rotter, Jerome I., Rudan, Igor, Rutters, Femke, Sabanayagam, Charumathi, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sanghera, Dharambir K., Sattar, Naveed, Schmidt, Börge, Schmidt, Helena, Schmidt, Reinhold, Schulze, Matthias B., Schunkert, Heribert, Scott, Laura J., Scott, Rodney J., Sever, Peter, Shiroma, Eric J., Shoemaker, M. Benjamin, Shu, Xiao-Ou, Simonsick, Eleanor M., Sims, Mario, Singh, Jai Rup, Singleton, Andrew B., Sinner, Moritz F., Smith, J. Gustav, Snieder, Harold, Spector, Tim D., Stampfer, Meir J., Stark, Klaus J., Strachan, David P., ‘t Hart, Leen M., Tabara, Yasuharu, Tang, Hua, Tardif, Jean-Claude, Thanaraj, Thangavel A., Timpson, Nicholas J., Tönjes, Anke, Tremblay, Angelo, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Tusié-Luna, Maria-Teresa, Uitterlinden, Andre G., van Dam, Rob M., van der Harst, Pim, Van der Velde, Nathalie, van Duijn, Cornelia M., van Schoor, Natasja M., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wacher-Rodarte, Niels H., Walker, Mark, Wang, Ya Xing, Wareham, Nicholas J., Watanabe, Richard M., Watkins, Hugh, Weir, David R., Werge, Thomas M., Widen, Elisabeth, Wilkens, Lynne R., Willemsen, Gonneke, Willett, Walter C., Wilson, James F., Wong, Tien-Yin, Woo, Jeong-Taek, Wright, Alan F., Wu, Jer-Yuarn, Xu, Huichun, Yajnik, Chittaranjan S., Yokota, Mitsuhiro, Yuan, Jian-Min, Zeggini, Eleftheria, Zemel, Babette S., Zheng, Wei, Zhu, Xiaofeng, Zmuda, Joseph M., Zonderman, Alan B., Zwart, John-Anker, Partida, Gabriel Cuellar, Sun, Yan, Croteau-Chonka, Damien, Vonk, Judith M., Chanock, Stephen, Chasman, Daniel I., Cho, Yoon Shin, Heid, Iris M., McCarthy, Mark I., Ng, Maggie C. Y., O’Donnell, Christopher J., Rivadeneira, Fernando, Thorsteinsdottir, Unnur, Sun, Yan V., Tai, E. Shyong, Boehnke, Michael, Deloukas, Panos, Justice, Anne E., Lindgren, Cecilia M., Loos, Ruth J. F., Mohlke, Karen L., North, Kari E., Stefansson, Kari, Walters, Robin G., Winkler, Thomas W., Young, Kristin L., Loh, Po-Ru, Yang, Jian, Esko, Tõnu, Assimes, Themistocles L., Auton, Adam, Abecasis, Goncalo R., Willer, Cristen J., Locke, Adam E., Berndt, Sonja I., Lettre, Guillaume, Frayling, Timothy M., Okada, Yukinori, Wood, Andrew R., Visscher, Peter M., Hirschhorn, Joel N., Yengo, Loïc, Vedantam, Sailaja, Marouli, Eirini, Sidorenko, Julia, Bartell, Eric, Sakaue, Saori, Graff, Marielisa, Eliasen, Anders U., Jiang, Yunxuan, Raghavan, Sridharan, Miao, Jenkai, Arias, Joshua D., Graham, Sarah E., Mukamel, Ronen E., Spracklen, Cassandra N., Yin, Xianyong, Chen, Shyh-Huei, Ferreira, Teresa, Highland, Heather H., Ji, Yingjie, Karaderi, Tugce, Lin, Kuang, Lüll, Kreete, Malden, Deborah E., Medina-Gomez, Carolina, Machado, Moara, Moore, Amy, Rüeger, Sina, Sim, Xueling, Vrieze, Scott, Ahluwalia, Tarunveer S., Akiyama, Masato, Allison, Matthew A., Alvarez, Marcus, Andersen, Mette K., Ani, Alireza, Appadurai, Vivek, Arbeeva, Liubov, Bhaskar, Seema, Bielak, Lawrence F., Bollepalli, Sailalitha, Bonnycastle, Lori L., Bork-Jensen, Jette, Bradfield, Jonathan P., Bradford, Yuki, Braund, Peter S., Brody, Jennifer A., Burgdorf, Kristoffer S., Cade, Brian E., Cai, Hui, Cai, Qiuyin, Campbell, Archie, Cañadas-Garre, Marisa, Catamo, Eulalia, Chai, Jin-Fang, Chai, Xiaoran, Chang, Li-Ching, Chang, Yi-Cheng, Chen, Chien-Hsiun, Chesi, Alessandra, Choi, Seung Hoan, Chung, Ren-Hua, Cocca, Massimiliano, Concas, Maria Pina, Couture, Christian, Cuellar-Partida, Gabriel, Danning, Rebecca, Daw, E. Warwick, Degenhard, Frauke, Delgado, Graciela E., Delitala, Alessandro, Demirkan, Ayse, Deng, Xuan, Devineni, Poornima, Dietl, Alexander, Dimitriou, Maria, Dimitrov, Latchezar, Dorajoo, Rajkumar, Ekici, Arif B., Engmann, Jorgen E., Fairhurst-Hunter, Zammy, Farmaki, Aliki-Eleni, Faul, Jessica D., Fernandez-Lopez, Juan-Carlos, Forer, Lukas, Francescatto, Margherita, Freitag-Wolf, Sandra, Fuchsberger, Christian, Galesloot, Tessel E., Gao, Yan, Gao, Zishan, Geller, Frank, Giannakopoulou, Olga, Giulianini, Franco, Gjesing, Anette P., Goel, Anuj, Gordon, Scott D., Gorski, Mathias, Grove, Jakob, Guo, Xiuqing, Gustafsson, Stefan, Haessler, Jeffrey, Hansen, Thomas F., Havulinna, Aki S., Haworth, Simon J., He, Jing, Heard-Costa, Nancy, Hebbar, Prashantha, Hindy, George, Ho, Yuk-Lam A., Hofer, Edith, Holliday, Elizabeth, Horn, Katrin, Hornsby, Whitney E., Hottenga, Jouke-Jan, Huang, Hongyan, Huang, Jie, Huerta-Chagoya, Alicia, Huffman, Jennifer E., Hung, Yi-Jen, Huo, Shaofeng, Hwang, Mi Yeong, Iha, Hiroyuki, Ikeda, Daisuke D., Isono, Masato, Jackson, Anne U., Jäger, Susanne, Jansen, Iris E., Johansson, Ingegerd, Jonas, Jost B., Jonsson, Anna, Jørgensen, Torben, Kalafati, Ioanna-Panagiota, Kanai, Masahiro, Kanoni, Stavroula, Kårhus, Line L., Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kawaguchi, Takahisa, Kember, Rachel L., Kentistou, Katherine A., Kim, Han-Na, Kim, Young Jin, Kleber, Marcus E., Knol, Maria J., Kurbasic, Azra, Lauzon, Marie, Le, Phuong, Lea, Rodney, Lee, Jong-Young, Leonard, Hampton L., Li, Shengchao A., Li, Xiaohui, Li, Xiaoyin, Liang, Jingjing, Lin, Honghuang, Lin, Shih-Yi, Liu, Jun, Liu, Xueping, Lo, Ken Sin, Long, Jirong, Lores-Motta, Laura, Luan, Jian’an, Lyssenko, Valeriya, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamakou, Vasiliki, Mangino, Massimo, Manichaikul, Ani, Marten, Jonathan, Mattheisen, Manuel, Mavarani, Laven, McDaid, Aaron F., Meidtner, Karina, Melendez, Tori L., Mercader, Josep M., Milaneschi, Yuri, Miller, Jason E., Millwood, Iona Y., Mishra, Pashupati P., Mitchell, Ruth E., Møllehave, Line T., Morgan, Anna, Mucha, Soeren, Munz, Matthias, Nakatochi, Masahiro, Nelson, Christopher P., Nethander, Maria, Nho, Chu Won, Nielsen, Aneta A., Nolte, Ilja M., Nongmaithem, Suraj S., Noordam, Raymond, Ntalla, Ioanna, Nutile, Teresa, Pandit, Anita, Christofidou, Paraskevi, Pärna, Katri, Pauper, Marc, Petersen, Eva R. B., Petersen, Liselotte V., Pitkänen, Niina, Polašek, Ozren, Poveda, Alaitz, Preuss, Michael H., Pyarajan, Saiju, Raffield, Laura M., Rakugi, Hiromi, Ramirez, Julia, Rasheed, Asif, Raven, Dennis, Rayner, Nigel W., Riveros, Carlos, Rohde, Rebecca, Ruggiero, Daniela, Ruotsalainen, Sanni E., Ryan, Kathleen A., Sabater-Lleal, Maria, Saxena, Richa, Scholz, Markus, Sendamarai, Anoop, Shen, Botong, Shi, Jingchunzi, Shin, Jae Hun, Sidore, Carlo, Sitlani, Colleen M., Slieker, Roderick C., Smit, Roelof A. J., Smith, Albert V., Smith, Jennifer A., Smyth, Laura J., Southam, Lorraine, Steinthorsdottir, Valgerdur, Sun, Liang, Takeuchi, Fumihiko, Tallapragada, Divya Sri Priyanka, Taylor, Kent D., Tayo, Bamidele O., Tcheandjieu, Catherine, Terzikhan, Natalie, Tesolin, Paola, Teumer, Alexander, Theusch, Elizabeth, Thompson, Deborah J., Thorleifsson, Gudmar, Timmers, Paul R. H. J., Trompet, Stella, Turman, Constance, Vaccargiu, Simona, van der Laan, Sander W., van der Most, Peter J., van Klinken, Jan B., van Setten, Jessica, Verma, Shefali S., Verweij, Niek, Veturi, Yogasudha, Wang, Carol A., Wang, Chaolong, Wang, Lihua, Wang, Zhe, Warren, Helen R., Bin Wei, Wen, Wickremasinghe, Ananda R., Wielscher, Matthias, Wiggins, Kerri L., Winsvold, Bendik S., Wong, Andrew, Wu, Yang, Wuttke, Matthias, Xia, Rui, Xie, Tian, Yamamoto, Ken, Yang, Jingyun, Yao, Jie, Young, Hannah, Yousri, Noha A., Yu, Lei, Zeng, Lingyao, Zhang, Weihua, Zhang, Xinyuan, Zhao, Jing-Hua, Zhao, Wei, Zhou, Wei, Zimmermann, Martina E., Zoledziewska, Magdalena, Adair, Linda S., Adams, Hieab H. H., Aguilar-Salinas, Carlos A., Al-Mulla, Fahd, Arnett, Donna K., Asselbergs, Folkert W., Åsvold, Bjørn Olav, Attia, John, Banas, Bernhard, Bandinelli, Stefania, Bennett, David A., Bergler, Tobias, Bharadwaj, Dwaipayan, Biino, Ginevra, Bisgaard, Hans, Boerwinkle, Eric, Böger, Carsten A., Bønnelykke, Klaus, Boomsma, Dorret I., Børglum, Anders D., Borja, Judith B., Bouchard, Claude, Bowden, Donald W., Brandslund, Ivan, Brumpton, Ben, Buring, Julie E., Caulfield, Mark J., Chambers, John C., Chandak, Giriraj R., Chanock, Stephen J., Chaturvedi, Nish, Chen, Yii-Der Ida, Chen, Zhengming, Cheng, Ching-Yu, Christophersen, Ingrid E., Ciullo, Marina, Cole, John W., Collins, Francis S., Cooper, Richard S., Cruz, Miguel, Cucca, Francesco, Cupples, L. Adrienne, Cutler, Michael J., Damrauer, Scott M., Dantoft, Thomas M., de Borst, Gert J., de Groot, Lisette C. P. G. M., De Jager, Philip L., de Kleijn, Dominique P. V., Janaka de Silva, H., Dedoussis, George V., den Hollander, Anneke I., Du, Shufa, Easton, Douglas F., Elders, Petra J. M., Eliassen, A. Heather, Ellinor, Patrick T., Elmståhl, Sölve, Erdmann, Jeanette, Evans, Michele K., Fatkin, Diane, Feenstra, Bjarke, Feitosa, Mary F., Ferrucci, Luigi, Ford, Ian, Fornage, Myriam, Franke, Andre, Franks, Paul W., Freedman, Barry I., Gasparini, Paolo, Gieger, Christian, Girotto, Giorgia, Goddard, Michael E., Golightly, Yvonne M., Gonzalez-Villalpando, Clicerio, Gordon-Larsen, Penny, Grallert, Harald, Grant, Struan F. A., Grarup, Niels, Griffiths, Lyn, Gudnason, Vilmundur, Haiman, Christopher, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayward, Caroline, Heckbert, Susan R., Heng, Chew-Kiat, Hengstenberg, Christian, Hewitt, Alex W., Hishigaki, Haretsugu, Hoyng, Carel B., Huang, Paul L., Huang, Wei, Hunt, Steven C., Hveem, Kristian, Hyppönen, Elina, Iacono, William G., Ichihara, Sahoko, Ikram, M. Arfan, Isasi, Carmen R., Jackson, Rebecca D., Jarvelin, Marjo-Riitta, Jin, Zi-Bing, Jöckel, Karl-Heinz, Joshi, Peter K., Jousilahti, Pekka, Jukema, J. Wouter, Kähönen, Mika, Kamatani, Yoichiro, Kang, Kui Dong, Kaprio, Jaakko, Kardia, Sharon L. R., Karpe, Fredrik, Kato, Norihiro, Kee, Frank, Kessler, Thorsten, Khera, Amit V., Khor, Chiea Chuen, Kiemeney, Lambertus A. L. M., Kim, Bong-Jo, Kim, Eung Kweon, Kim, Hyung-Lae, Kirchhof, Paulus, Kivimaki, Mika, Koh, Woon-Puay, Koistinen, Heikki A., Kolovou, Genovefa D., Kooner, Jaspal S., Kooperberg, Charles, Köttgen, Anna, Kovacs, Peter, Kraaijeveld, Adriaan, Kraft, Peter, Krauss, Ronald M., Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lange, Leslie A., Langenberg, Claudia, Launer, Lenore J., Le Marchand, Loic, Lee, Hyejin, Lee, Nanette R., Lehtimäki, Terho, Li, Huaixing, Li, Liming, Lieb, Wolfgang, Lin, Xu, Lind, Lars, Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Loeffler, Markus, London, Barry, Lubitz, Steven A., Lye, Stephen J., Mackey, David A., Mägi, Reedik, Magnusson, Patrik K. E., Marcus, Gregory M., Vidal, Pedro Marques, Martin, Nicholas G., März, Winfried, Matsuda, Fumihiko, McGarrah, Robert W., McGue, Matt, McKnight, Amy Jayne, Medland, Sarah E., Mellström, Dan, Metspalu, Andres, Mitchell, Braxton D., Mitchell, Paul, Mook-Kanamori, Dennis O., Morris, Andrew D., Mucci, Lorelei A., Munroe, Patricia B., Nalls, Mike A., Nazarian, Saman, Nelson, Amanda E., Neville, Matt J., Newton-Cheh, Christopher, Nielsen, Christopher S., Nöthen, Markus M., Ohlsson, Claes, Oldehinkel, Albertine J., Orozco, Lorena, Pahkala, Katja, Pajukanta, Päivi, Palmer, Colin N. A., Parra, Esteban J., Pattaro, Cristian, Pedersen, Oluf, Pennell, Craig E., Penninx, Brenda W. J. H., Perusse, Louis, Peters, Annette, Peyser, Patricia A., Porteous, David J., Posthuma, Danielle, Power, Chris, Pramstaller, Peter P., Province, Michael A., Qi, Qibin, Qu, Jia, Rader, Daniel J., Raitakari, Olli T., Ralhan, Sarju, Rallidis, Loukianos S., Rao, Dabeeru C., Redline, Susan, Reilly, Dermot F., Reiner, Alexander P., Rhee, Sang Youl, Ridker, Paul M., Rienstra, Michiel, Ripatti, Samuli, Ritchie, Marylyn D., Roden, Dan M., Rosendaal, Frits R., Rotter, Jerome I., Rudan, Igor, Rutters, Femke, Sabanayagam, Charumathi, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sanghera, Dharambir K., Sattar, Naveed, Schmidt, Börge, Schmidt, Helena, Schmidt, Reinhold, Schulze, Matthias B., Schunkert, Heribert, Scott, Laura J., Scott, Rodney J., Sever, Peter, Shiroma, Eric J., Shoemaker, M. Benjamin, Shu, Xiao-Ou, Simonsick, Eleanor M., Sims, Mario, Singh, Jai Rup, Singleton, Andrew B., Sinner, Moritz F., Smith, J. Gustav, Snieder, Harold, Spector, Tim D., Stampfer, Meir J., Stark, Klaus J., Strachan, David P., ‘t Hart, Leen M., Tabara, Yasuharu, Tang, Hua, Tardif, Jean-Claude, Thanaraj, Thangavel A., Timpson, Nicholas J., Tönjes, Anke, Tremblay, Angelo, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Tusié-Luna, Maria-Teresa, Uitterlinden, Andre G., van Dam, Rob M., van der Harst, Pim, Van der Velde, Nathalie, van Duijn, Cornelia M., van Schoor, Natasja M., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wacher-Rodarte, Niels H., Walker, Mark, Wang, Ya Xing, Wareham, Nicholas J., Watanabe, Richard M., Watkins, Hugh, Weir, David R., Werge, Thomas M., Widen, Elisabeth, Wilkens, Lynne R., Willemsen, Gonneke, Willett, Walter C., Wilson, James F., Wong, Tien-Yin, Woo, Jeong-Taek, Wright, Alan F., Wu, Jer-Yuarn, Xu, Huichun, Yajnik, Chittaranjan S., Yokota, Mitsuhiro, Yuan, Jian-Min, Zeggini, Eleftheria, Zemel, Babette S., Zheng, Wei, Zhu, Xiaofeng, Zmuda, Joseph M., Zonderman, Alan B., Zwart, John-Anker, Partida, Gabriel Cuellar, Sun, Yan, Croteau-Chonka, Damien, Vonk, Judith M., Chanock, Stephen, Chasman, Daniel I., Cho, Yoon Shin, Heid, Iris M., McCarthy, Mark I., Ng, Maggie C. Y., O’Donnell, Christopher J., Rivadeneira, Fernando, Thorsteinsdottir, Unnur, Sun, Yan V., Tai, E. Shyong, Boehnke, Michael, Deloukas, Panos, Justice, Anne E., Lindgren, Cecilia M., Loos, Ruth J. F., Mohlke, Karen L., North, Kari E., Stefansson, Kari, Walters, Robin G., Winkler, Thomas W., Young, Kristin L., Loh, Po-Ru, Yang, Jian, Esko, Tõnu, Assimes, Themistocles L., Auton, Adam, Abecasis, Goncalo R., Willer, Cristen J., Locke, Adam E., Berndt, Sonja I., Lettre, Guillaume, Frayling, Timothy M., Okada, Yukinori, Wood, Andrew R., Visscher, Peter M., and Hirschhorn, Joel N.
Abstract: Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
Published: 2022
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25. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Blokland, Gabriëlla A. M., Grove, Jakob, Chen, Chia-Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, St Clair, David, Lencz, Todd, Mowry, Bryan J., Periyasamy, Sathish, Cairns, Murray J., Tooney, Paul A., Wu, Jing Qin, Kelly, Brian, Kirov, George, Sullivan, Patrick F., Corvin, Aiden, Riley, Brien P., Esko, Tõnu, Milani, Lili, Jönsson, Erik G., Palotie, Aarno, Ehrenreich, Hannelore, Begemann, Martin, Steixner-Kumar, Agnes, Sham, Pak C., Iwata, Nakao, Weinberger, Daniel R., Gejman, Pablo V., Sanders, Alan R., Buxbaum, Joseph D., Rujescu, Dan, Giegling, Ina, Konte, Bettina, Hartmann, Anette M., Bramon, Elvira, Murray, Robin M., Pato, Michele T., Lee, Jimmy, Melle, Ingrid, Molden, Espen, Ophoff, Roel A., McQuillin, Andrew, Bass, Nicholas J., Adolfsson, Rolf, Malhotra, Anil K., Martin, Nicholas G., Fullerton, Janice M., Mitchell, Philip B., Schofield, Peter R., Forstner, Andreas J., Degenhardt, Franziska, Schaupp, Sabrina, Comes, Ashley L., Kogevinas, Manolis, Guzman-Parra, José, Reif, Andreas, Streit, Fabian, Sirignano, Lea, Cichon, Sven, Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Lissowska, Jolanta, Mayoral, Fermin, Müller-Myhsok, Bertram, Świątkowska, Beata, Schulze, Thomas G., Nöthen, Markus M., Rietschel, Marcella, Kelsoe, John, Leboyer, Marion, Jamain, Stéphane, Etain, Bruno, Bellivier, Frank, Vincent, John B., Alda, Martin, O'Donovan, Claire, Cervantes, Pablo, Biernacka, Joanna M., Frye, Mark, McElroy, Susan L., Scott, Laura J., Stahl, Eli A., Landén, Mikael, Hamshere, Marian L., Smeland, Olav B., Djurovic, Srdjan, Vaaler, Arne E., Andreassen, Ole A., Baune, Bernhard T., Air, Tracy, Preisig, Martin, Uher, Rudolf, Levinson, Douglas F., Weissman, Myrna M., Potash, James B., Shi, Jianxin, Knowles, James A., Perlis, Roy H., Lucae, Susanne, Boomsma, Dorret I, Penninx, Brenda W. J. H., Hottenga, Jouke-Jan, de Geus, Eco J. C., Willemsen, Gonneke, Milaneschi, Yuri, Tiemeier, Henning, Grabe, Hans J., Teumer, Alexander, Van der Auwera, Sandra, Völker, Uwe, Hamilton, Steven P., Magnusson, Patrik K. E., Viktorin, Alexander, Mehta, Divya, Mullins, Niamh, Adams, Mark J., Breen, Gerome, McIntosh, Andrew M., Lewis, Cathryn M., Hougaard, David M., Nordentoft, Merete, Mors, Ole, Mortensen, Preben B., Werge, Thomas, Als, Thomas D., Børglum, Anders D., Petryshen, Tracey L., Smoller, Jordan W., Goldstein, Jill M., Blokland, Gabriëlla A. M., Grove, Jakob, Chen, Chia-Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, St Clair, David, Lencz, Todd, Mowry, Bryan J., Periyasamy, Sathish, Cairns, Murray J., Tooney, Paul A., Wu, Jing Qin, Kelly, Brian, Kirov, George, Sullivan, Patrick F., Corvin, Aiden, Riley, Brien P., Esko, Tõnu, Milani, Lili, Jönsson, Erik G., Palotie, Aarno, Ehrenreich, Hannelore, Begemann, Martin, Steixner-Kumar, Agnes, Sham, Pak C., Iwata, Nakao, Weinberger, Daniel R., Gejman, Pablo V., Sanders, Alan R., Buxbaum, Joseph D., Rujescu, Dan, Giegling, Ina, Konte, Bettina, Hartmann, Anette M., Bramon, Elvira, Murray, Robin M., Pato, Michele T., Lee, Jimmy, Melle, Ingrid, Molden, Espen, Ophoff, Roel A., McQuillin, Andrew, Bass, Nicholas J., Adolfsson, Rolf, Malhotra, Anil K., Martin, Nicholas G., Fullerton, Janice M., Mitchell, Philip B., Schofield, Peter R., Forstner, Andreas J., Degenhardt, Franziska, Schaupp, Sabrina, Comes, Ashley L., Kogevinas, Manolis, Guzman-Parra, José, Reif, Andreas, Streit, Fabian, Sirignano, Lea, Cichon, Sven, Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Lissowska, Jolanta, Mayoral, Fermin, Müller-Myhsok, Bertram, Świątkowska, Beata, Schulze, Thomas G., Nöthen, Markus M., Rietschel, Marcella, Kelsoe, John, Leboyer, Marion, Jamain, Stéphane, Etain, Bruno, Bellivier, Frank, Vincent, John B., Alda, Martin, O'Donovan, Claire, Cervantes, Pablo, Biernacka, Joanna M., Frye, Mark, McElroy, Susan L., Scott, Laura J., Stahl, Eli A., Landén, Mikael, Hamshere, Marian L., Smeland, Olav B., Djurovic, Srdjan, Vaaler, Arne E., Andreassen, Ole A., Baune, Bernhard T., Air, Tracy, Preisig, Martin, Uher, Rudolf, Levinson, Douglas F., Weissman, Myrna M., Potash, James B., Shi, Jianxin, Knowles, James A., Perlis, Roy H., Lucae, Susanne, Boomsma, Dorret I, Penninx, Brenda W. J. H., Hottenga, Jouke-Jan, de Geus, Eco J. C., Willemsen, Gonneke, Milaneschi, Yuri, Tiemeier, Henning, Grabe, Hans J., Teumer, Alexander, Van der Auwera, Sandra, Völker, Uwe, Hamilton, Steven P., Magnusson, Patrik K. E., Viktorin, Alexander, Mehta, Divya, Mullins, Niamh, Adams, Mark J., Breen, Gerome, McIntosh, Andrew M., Lewis, Cathryn M., Hougaard, David M., Nordentoft, Merete, Mors, Ole, Mortensen, Preben B., Werge, Thomas, Als, Thomas D., Børglum, Anders D., Petryshen, Tracey L., Smoller, Jordan W., and Goldstein, Jill M.
Abstract: BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular f
Published: 2022
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26. Rare genetic variants explain missing heritability in smoking.

Author: Jang, Seon-Kyeong, Jang, Seon-Kyeong, Evans, Luke, Fialkowski, Allison, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Becker, Diane M, Bis, Joshua C, Blangero, John, Bleecker, Eugene R, Boorgula, Meher Preethi, Bowden, Donald W, Brody, Jennifer A, Cade, Brian E, Jenkins, Brenda W Campbell, Carson, April P, Chavan, Sameer, Cupples, L Adrienne, Custer, Brian, Damrauer, Scott M, David, Sean P, de Andrade, Mariza, Dinardo, Carla L, Fingerlin, Tasha E, Fornage, Myriam, Freedman, Barry I, Garrett, Melanie E, Gharib, Sina A, Glahn, David C, Haessler, Jeffrey, Heckbert, Susan R, Hokanson, John E, Hou, Lifang, Hwang, Shih-Jen, Hyman, Matthew C, Judy, Renae, Justice, Anne E, Kaplan, Robert C, Kardia, Sharon LR, Kelly, Shannon, Kim, Wonji, Kooperberg, Charles, Levy, Daniel, Lloyd-Jones, Donald M, Loos, Ruth JF, Manichaikul, Ani W, Gladwin, Mark T, Martin, Lisa Warsinger, Nouraie, Mehdi, Melander, Olle, Meyers, Deborah A, Montgomery, Courtney G, North, Kari E, Oelsner, Elizabeth C, Palmer, Nicholette D, Payton, Marinelle, Peljto, Anna L, Peyser, Patricia A, Preuss, Michael, Psaty, Bruce M, Qiao, Dandi, Rader, Daniel J, Rafaels, Nicholas, Redline, Susan, Reed, Robert M, Reiner, Alexander P, Rich, Stephen S, Rotter, Jerome I, Schwartz, David A, Shadyab, Aladdin H, Silverman, Edwin K, Smith, Nicholas L, Smith, J Gustav, Smith, Albert V, Smith, Jennifer A, Tang, Weihong, Taylor, Kent D, Telen, Marilyn J, Vasan, Ramachandran S, Gordeuk, Victor R, Wang, Zhe, Wiggins, Kerri L, Yanek, Lisa R, Yang, Ivana V, Young, Kendra A, Young, Kristin L, Zhang, Yingze, Liu, Dajiang J, Keller, Matthew C, Vrieze, Scott, Jang, Seon-Kyeong, Jang, Seon-Kyeong, Evans, Luke, Fialkowski, Allison, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Becker, Diane M, Bis, Joshua C, Blangero, John, Bleecker, Eugene R, Boorgula, Meher Preethi, Bowden, Donald W, Brody, Jennifer A, Cade, Brian E, Jenkins, Brenda W Campbell, Carson, April P, Chavan, Sameer, Cupples, L Adrienne, Custer, Brian, Damrauer, Scott M, David, Sean P, de Andrade, Mariza, Dinardo, Carla L, Fingerlin, Tasha E, Fornage, Myriam, Freedman, Barry I, Garrett, Melanie E, Gharib, Sina A, Glahn, David C, Haessler, Jeffrey, Heckbert, Susan R, Hokanson, John E, Hou, Lifang, Hwang, Shih-Jen, Hyman, Matthew C, Judy, Renae, Justice, Anne E, Kaplan, Robert C, Kardia, Sharon LR, Kelly, Shannon, Kim, Wonji, Kooperberg, Charles, Levy, Daniel, Lloyd-Jones, Donald M, Loos, Ruth JF, Manichaikul, Ani W, Gladwin, Mark T, Martin, Lisa Warsinger, Nouraie, Mehdi, Melander, Olle, Meyers, Deborah A, Montgomery, Courtney G, North, Kari E, Oelsner, Elizabeth C, Palmer, Nicholette D, Payton, Marinelle, Peljto, Anna L, Peyser, Patricia A, Preuss, Michael, Psaty, Bruce M, Qiao, Dandi, Rader, Daniel J, Rafaels, Nicholas, Redline, Susan, Reed, Robert M, Reiner, Alexander P, Rich, Stephen S, Rotter, Jerome I, Schwartz, David A, Shadyab, Aladdin H, Silverman, Edwin K, Smith, Nicholas L, Smith, J Gustav, Smith, Albert V, Smith, Jennifer A, Tang, Weihong, Taylor, Kent D, Telen, Marilyn J, Vasan, Ramachandran S, Gordeuk, Victor R, Wang, Zhe, Wiggins, Kerri L, Yanek, Lisa R, Yang, Ivana V, Young, Kendra A, Young, Kristin L, Zhang, Yingze, Liu, Dajiang J, Keller, Matthew C, and Vrieze, Scott
Abstract: Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.
Published: 2022

27. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Author: Hautakangas, H. (Heidi), Winsvold, B. S. (Bendik S.), Ruotsalainen, S. E. (Sanni E.), Bjornsdottir, G. (Gyda), Harder, A. V. (Aster V. E.), Kogelman, L. J. (Lisette J. A.), Thomas, L. F. (Laurent F.), Noordam, R. (Raymond), Benner, C. (Christian), Gormley, P. (Padhraig), Artto, V. (Ville), Banasik, K. (Karina), Bjornsdottir, A. (Anna), Boomsma, D. I. (Dorret, I), Brumpton, B. M. (Ben M.), Burgdorf, K. S. (Kristoffer Solvsten), Buring, J. E. (Julie E.), Chalmer, M. A. (Mona Ameri), de Boer, I. (Irene), Dichgans, M. (Martin), Erikstrup, C. (Christian), Färkkilä, M. (Markus), Garbrielsen, M. E. (Maiken Elvestad), Ghanbari, M. (Mohsen), Hagen, K. (Knut), Häppölä, P. (Paavo), Hottenga, J.-J. (Jouke-Jan), Hrafnsdottir, M. G. (Maria G.), Hveem, K. (Kristian), Johnsen, M. B. (Marianne Bakke), Kähönen, M. (Mika), Kristoffersen, E. S. (Espen S.), Kurth, T. (Tobias), Lehtimäki, T. (Terho), Lighart, L. (Lannie), Magnusson, S. H. (Sigurdur H.), Malik, R. (Rainer), Pedersen, O. B. (Ole Birger), Pelzer, N. (Nadine), Penninx, B. W. (Brenda W. J. H.), Ran, C. (Caroline), Ridker, P. M. (Paul M.), Rosendaal, F. R. (Frits R.), Sigurdardottir, G. R. (Gudrun R.), Skogholt, A. H. (Anne Heidi), Sveinsson, O. A. (Olafur A.), Thorgeirsson, T. E. (Thorgeir E.), Ullum, H. (Henrik), Vijfhuizen, L. S. (Lisanne S.), Widen, E. (Elisabeth), van Dijk, K. W. (Ko Willems), International Headache Genetics Consortium, HUNT All-in Headache, Danish Blood Donor Study Genomic Cohort, Aromaa, A. (Arpo), Belin, A. C. (Andrea Carmine), Freilinger, T. (Tobias), Ikram, M. A. (M. Arfan), Järvelin, M.-R. (Marjo-Riitta), Raitakari, O. T. (Olli T.), Terwindt, G. M. (Gisela M.), Kallela, M. (Mikko), Wessman, M. (Maija), Olesen, J. (Jes), Chasman, D. I. (Daniel, I), Nyholt, D. R. (Dale R.), Stefansson, H. (Hreinn), Stefansson, K. (Kari), van den Maagdenberg, A. M. (Arn M. J. M.), Hansen, T. F. (Thomas Folkmann), Ripatti, S. (Samuli), Zwart, J.-A. (John-Anker), Palotie, A. (Aarno), Pirinen, M. (Matti), Hautakangas, H. (Heidi), Winsvold, B. S. (Bendik S.), Ruotsalainen, S. E. (Sanni E.), Bjornsdottir, G. (Gyda), Harder, A. V. (Aster V. E.), Kogelman, L. J. (Lisette J. A.), Thomas, L. F. (Laurent F.), Noordam, R. (Raymond), Benner, C. (Christian), Gormley, P. (Padhraig), Artto, V. (Ville), Banasik, K. (Karina), Bjornsdottir, A. (Anna), Boomsma, D. I. (Dorret, I), Brumpton, B. M. (Ben M.), Burgdorf, K. S. (Kristoffer Solvsten), Buring, J. E. (Julie E.), Chalmer, M. A. (Mona Ameri), de Boer, I. (Irene), Dichgans, M. (Martin), Erikstrup, C. (Christian), Färkkilä, M. (Markus), Garbrielsen, M. E. (Maiken Elvestad), Ghanbari, M. (Mohsen), Hagen, K. (Knut), Häppölä, P. (Paavo), Hottenga, J.-J. (Jouke-Jan), Hrafnsdottir, M. G. (Maria G.), Hveem, K. (Kristian), Johnsen, M. B. (Marianne Bakke), Kähönen, M. (Mika), Kristoffersen, E. S. (Espen S.), Kurth, T. (Tobias), Lehtimäki, T. (Terho), Lighart, L. (Lannie), Magnusson, S. H. (Sigurdur H.), Malik, R. (Rainer), Pedersen, O. B. (Ole Birger), Pelzer, N. (Nadine), Penninx, B. W. (Brenda W. J. H.), Ran, C. (Caroline), Ridker, P. M. (Paul M.), Rosendaal, F. R. (Frits R.), Sigurdardottir, G. R. (Gudrun R.), Skogholt, A. H. (Anne Heidi), Sveinsson, O. A. (Olafur A.), Thorgeirsson, T. E. (Thorgeir E.), Ullum, H. (Henrik), Vijfhuizen, L. S. (Lisanne S.), Widen, E. (Elisabeth), van Dijk, K. W. (Ko Willems), International Headache Genetics Consortium, HUNT All-in Headache, Danish Blood Donor Study Genomic Cohort, Aromaa, A. (Arpo), Belin, A. C. (Andrea Carmine), Freilinger, T. (Tobias), Ikram, M. A. (M. Arfan), Järvelin, M.-R. (Marjo-Riitta), Raitakari, O. T. (Olli T.), Terwindt, G. M. (Gisela M.), Kallela, M. (Mikko), Wessman, M. (Maija), Olesen, J. (Jes), Chasman, D. I. (Daniel, I), Nyholt, D. R. (Dale R.), Stefansson, H. (Hreinn), Stefansson, K. (Kari), van den Maagdenberg, A. M. (Arn M. J. M.), Hansen, T. F. (Thomas Folkmann), Ripatti, S. (Samuli), Zwart, J.-A. (John-Anker), Palotie, A. (Aarno), and Pirinen, M. (Matti)
Abstract: Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.
Published: 2022

28. How COVID-19 shaped mental health:from infection to pandemic effects

Author: Penninx, Brenda W J H, Benros, Michael E, Klein, Robyn S, Vinkers, Christiaan H, Penninx, Brenda W J H, Benros, Michael E, Klein, Robyn S, and Vinkers, Christiaan H
Abstract: The Coronavirus Disease 2019 (COVID-19) pandemic has threatened global mental health, both indirectly via disruptive societal changes and directly via neuropsychiatric sequelae after SARS-CoV-2 infection. Despite a small increase in self-reported mental health problems, this has (so far) not translated into objectively measurable increased rates of mental disorders, self-harm or suicide rates at the population level. This could suggest effective resilience and adaptation, but there is substantial heterogeneity among subgroups, and time-lag effects may also exist. With regard to COVID-19 itself, both acute and post-acute neuropsychiatric sequelae have become apparent, with high prevalence of fatigue, cognitive impairments and anxiety and depressive symptoms, even months after infection. To understand how COVID-19 continues to shape mental health in the longer term, fine-grained, well-controlled longitudinal data at the (neuro)biological, individual and societal levels remain essential. For future pandemics, policymakers and clinicians should prioritize mental health from the outset to identify and protect those at risk and promote long-term resilience.
Published: 2022

29. Elucidating the relationship between migraine risk and brain structure using genetic data

Author: Mitchell, Brittany L, Ligthart, Lannie, Hottenga, Jouke-Jan, Penninx, Brenda W J H, Posthuma, Danielle, Boomsma, Dorret I, International Headache Genetics Consortium, Mitchell, Brittany L, Ligthart, Lannie, Hottenga, Jouke-Jan, Penninx, Brenda W J H, Posthuma, Danielle, Boomsma, Dorret I, and International Headache Genetics Consortium
Abstract: Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = −0.11, P = 1 × 10−3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippocampal and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in individuals with high migraine r
Published: 2022
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30. Fat metabolism is associated with telomere length in six population-based studies

Author: van der Spek, Ashley, Pool, René, Willemsen, Gonneke, Van Grootheest, Gerard, Penninx, Brenda W J H, Boomsma, Dorret I, Van Duijn, Cornelia M, BBMRI Metabolomics Consortium, van der Spek, Ashley, Pool, René, Willemsen, Gonneke, Van Grootheest, Gerard, Penninx, Brenda W J H, Boomsma, Dorret I, Van Duijn, Cornelia M, and BBMRI Metabolomics Consortium
Abstract: Telomeres are repetitive DNA sequences located at the end of chromosomes, which are associated to biological aging, cardiovascular disease, cancer and mortality. Lipid and fatty acid metabolism have been associated with telomere shortening. We have conducted an in-depth study investigating the association of metabolic biomarkers with telomere length (LTL). We performed an association analysis of 226 metabolic biomarkers with LTL using data from 11 775 individuals from six independent population-based cohorts (BBMRI-NL consortium). Metabolic biomarkers include lipoprotein lipids and subclasses, fatty acids, amino acids, glycolysis measures and ketone bodies. LTL was measured by quantitative polymerase chain reaction or FlowFISH. Linear regression analysis was performed adjusting for age, sex, lipid-lowering medication and cohort-specific covariates (model 1) and additionally for body mass index (BMI) and smoking (model 2), followed by inverse variance-weighted meta-analyses (significance threshold Pmeta = 6.5 × 10−4). We identified four metabolic biomarkers positively associated with LTL, including two cholesterol to lipid ratios in small VLDL (S-VLDL-C % and S-VLDL-CE %) and two omega-6 fatty acid ratios (FAw6/FA and LA/FA). After additionally adjusting for BMI and smoking, these metabolic biomarkers remained associated with LTL with similar effect estimates. In addition, cholesterol esters in very small VLDL (XS-VLDL-CE) became significantly associated with LTL (P = 3.6 × 10−4). We replicated the association of FAw6/FA with LTL in an independent dataset of 7845 individuals (P = 1.9 × 10−4). To conclude, we identified multiple metabolic biomarkers involved in lipid and fatty acid metabolism that may be involved in LTL biology. Longitudinal studies are needed to exclude reversed causation.
Published: 2022
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31. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

Author: Hautakangas, Heidi, Winsvold, Bendik S., Ruotsalainen, Sanni E., Bjornsdottir, Gyda, Harder, Aster V. E., Kogelman, Lisette J. A., Thomas, Laurent F., Noordam, Raymond, Benner, Christian, Gormley, Padhraig, Artto, Ville, Banasik, Karina, Bjornsdottir, Anna, Boomsma, Dorret, I, Brumpton, Ben M., Burgdorf, Kristoffer Sølvsten, Buring, Julie E., Chalmer, Mona Ameri, de Boer, Irene, Dichgans, Martin, Erikstrup, Christian, Farkkila, Markus, Garbrielsen, Maiken Elvestad, Ghanbari, Mohsen, Hagen, Knut, Happola, Paavo, Hottenga, Jouke-Jan, Hrafnsdottir, Maria G., Hveem, Kristian, Johnsen, Marianne Bakke, Kahonen, Mika, Kristoffersen, Espen S., Kurth, Tobias, Lehtimaki, Terho, Lighart, Lannie, Magnusson, Sigurdur H., Malik, Rainer, Pedersen, Ole Birger, Pelzer, Nadine, Penninx, Brenda W. J. H., Ran, Caroline, Ridker, Paul M., Rosendaal, Frits R., Sigurdardottir, Gudrun R., Skogholt, Anne Heidi, Sveinsson, Olafur A., Thorgeirsson, Thorgeir E., Ullum, Henrik, Vijfhuizen, Lisanne S., Widen, Elisabeth, van Dijk, Ko Willems, Aromaa, Arpo, Belin, Andrea Carmine, Freilinger, Tobias, Ikram, M. Arfan, Jarvelin, Marjo-Riitta, Raitakari, Olli T., Terwindt, Gisela M., Kallela, Mikko, Wessman, Maija, Olesen, Jes, Chasman, Daniel, I, Nyholt, Dale R., Stefansson, Hreinn, Stefansson, Kari, van den Maagdenberg, Arn M. J. M., Hansen, Thomas Folkmann, Ripatti, Samuli, Zwart, John-Anker, Palotie, Aarno, Pirinen, Matti, Hautakangas, Heidi, Winsvold, Bendik S., Ruotsalainen, Sanni E., Bjornsdottir, Gyda, Harder, Aster V. E., Kogelman, Lisette J. A., Thomas, Laurent F., Noordam, Raymond, Benner, Christian, Gormley, Padhraig, Artto, Ville, Banasik, Karina, Bjornsdottir, Anna, Boomsma, Dorret, I, Brumpton, Ben M., Burgdorf, Kristoffer Sølvsten, Buring, Julie E., Chalmer, Mona Ameri, de Boer, Irene, Dichgans, Martin, Erikstrup, Christian, Farkkila, Markus, Garbrielsen, Maiken Elvestad, Ghanbari, Mohsen, Hagen, Knut, Happola, Paavo, Hottenga, Jouke-Jan, Hrafnsdottir, Maria G., Hveem, Kristian, Johnsen, Marianne Bakke, Kahonen, Mika, Kristoffersen, Espen S., Kurth, Tobias, Lehtimaki, Terho, Lighart, Lannie, Magnusson, Sigurdur H., Malik, Rainer, Pedersen, Ole Birger, Pelzer, Nadine, Penninx, Brenda W. J. H., Ran, Caroline, Ridker, Paul M., Rosendaal, Frits R., Sigurdardottir, Gudrun R., Skogholt, Anne Heidi, Sveinsson, Olafur A., Thorgeirsson, Thorgeir E., Ullum, Henrik, Vijfhuizen, Lisanne S., Widen, Elisabeth, van Dijk, Ko Willems, Aromaa, Arpo, Belin, Andrea Carmine, Freilinger, Tobias, Ikram, M. Arfan, Jarvelin, Marjo-Riitta, Raitakari, Olli T., Terwindt, Gisela M., Kallela, Mikko, Wessman, Maija, Olesen, Jes, Chasman, Daniel, I, Nyholt, Dale R., Stefansson, Hreinn, Stefansson, Kari, van den Maagdenberg, Arn M. J. M., Hansen, Thomas Folkmann, Ripatti, Samuli, Zwart, John-Anker, Palotie, Aarno, and Pirinen, Matti
Abstract: Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.
Published: 2022

32. Hearing Impaired Students in Postsecondary Education, 1986 Edition.

Author: American Council on Education, Washington, DC. HEATH Resource Center., Wolfe, David, and Rawlings, Brenda W.
Abstract: Postsecondary options for hard of hearing and deaf students are identified, and practical suggestions are offered for students, faculty, and service providers. In addition to providing facts about hearing loss and the effects of age of onset of hearing loss, information is provided on communication methods, special support services, and resources. Students have three environments to consider: the two federally supported national schools (Gallaudet College and the National Technical Institute for the Deaf), a separate (special) program for hearing impaired students on the regular college campus, and a mainstreamed program in a setting with mostly hearing students. The Individual Written Rehabilitation Plan is available for students in the mainstream who are clients of the State Vocational Rehabilitation program. Special support services include: interpreters, notetakers/tutors, special communications equipment, and remedial reading and writing programs. Since social concerns are also important, suggestions are offered to both students and instructors to promote acceptance and support for hearing impaired students outside of the classroom (e.g., in the cafeteria, gym, and residence hall). An annotated resource section covers books, organizations, specific programs, and special equipment. (SW)
Published: 1986

33. Psychosocial factors and cancer incidence (PSY-CA): Protocol for individual participant data meta-analyses

Author: van Tuijl, Lonneke A, Voogd, Adri C, de Graeff, Alexander, Hoogendoorn, Adriaan W, Ranchor, Adelita V, Pan, Kuan-Yu, Basten, Maartje, Lamers, Femke, Geerlings, Mirjam I, Abell, Jessica G, Awadalla, Philip, Bakker, Marije F, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, Keats, Melanie R, Kok, Almar A L, Luik, Annemarie I, Noisel, Nolwenn, Onland-Moret, N Charlotte, Payette, Yves, Penninx, Brenda W J H, Portengen, Lützen, Rissanen, Ina, Roest, Annelieke M, Rosmalen, Judith G M, Ruiter, Rikje, Schoevers, Robert A, Soave, David M, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Teyhan, Alison, Vaartjes, Ilonca, van der Willik, Kimberly D, van Leeuwen, Flora E, van Petersen, Rutger, Verschuren, W M Monique, Visseren, Frank, Vermeulen, Roel, Dekker, Joost, van Tuijl, Lonneke A, Voogd, Adri C, de Graeff, Alexander, Hoogendoorn, Adriaan W, Ranchor, Adelita V, Pan, Kuan-Yu, Basten, Maartje, Lamers, Femke, Geerlings, Mirjam I, Abell, Jessica G, Awadalla, Philip, Bakker, Marije F, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, Keats, Melanie R, Kok, Almar A L, Luik, Annemarie I, Noisel, Nolwenn, Onland-Moret, N Charlotte, Payette, Yves, Penninx, Brenda W J H, Portengen, Lützen, Rissanen, Ina, Roest, Annelieke M, Rosmalen, Judith G M, Ruiter, Rikje, Schoevers, Robert A, Soave, David M, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Teyhan, Alison, Vaartjes, Ilonca, van der Willik, Kimberly D, van Leeuwen, Flora E, van Petersen, Rutger, Verschuren, W M Monique, Visseren, Frank, Vermeulen, Roel, and Dekker, Joost
Abstract: OBJECTIVES: Psychosocial factors have been hypothesized to increase the risk of cancer. This study aims (1) to test whether psychosocial factors (depression, anxiety, recent loss events, subjective social support, relationship status, general distress, and neuroticism) are associated with the incidence of any cancer (any, breast, lung, prostate, colorectal, smoking-related, and alcohol-related); (2) to test the interaction between psychosocial factors and factors related to cancer risk (smoking, alcohol use, weight, physical activity, sedentary behavior, sleep, age, sex, education, hormone replacement therapy, and menopausal status) with regard to the incidence of cancer; and (3) to test the mediating role of health behaviors (smoking, alcohol use, weight, physical activity, sedentary behavior, and sleep) in the relationship between psychosocial factors and the incidence of cancer.METHODS: The psychosocial factors and cancer incidence (PSY-CA) consortium was established involving experts in the field of (psycho-)oncology, methodology, and epidemiology. Using data collected in 18 cohorts (N = 617,355), a preplanned two-stage individual participant data (IPD) meta-analysis is proposed. Standardized analyses will be conducted on harmonized datasets for each cohort (stage 1), and meta-analyses will be performed on the risk estimates (stage 2).CONCLUSION: PSY-CA aims to elucidate the relationship between psychosocial factors and cancer risk by addressing several shortcomings of prior meta-analyses.
Published: 2021

34. Sleep characteristics across the lifespan in 1.1 million people from the Netherlands, United Kingdom and United States: a systematic review and meta-analysis

Author: Kocevska, Desana, Lysen, Thom S., Dotinga, Aafje, Koopman-verhoeff, M. Elisabeth, Luijk, Maartje P. C. M., Antypa, Niki, Biermasz, Nienke R., Blokstra, Anneke, Brug, Johannes, Burk, Wiliam J., Comijs, Hannie C., Corpeleijn, Eva, Dashti, Hassan S., De Bruin, Eduard J., De Graaf, Ron, Derks, Ivonne P. M., Dewald-kaufmann, Julia F., Elders, Petra J. M., Gemke, Reinoldus J. B. J., Grievink, Linda, Hale, Lauren, Hartman, Catharina A., Heijnen, Cobi J., Huisman, Martijn, Huss, Anke, Ikram, M. Arfan, Jones, Samuel E., Velderman, Mariska Klein, Koning, Maaike, Meijer, Anne Marie, Meijer, Kim, Noordam, Raymond, Oldehinkel, Albertine J., Groeniger, Joost Oude, Penninx, Brenda W. J. H., Picavet, H. Susan J., Pieters, Sara, Reijneveld, Sijmen A., Reitz, Ellen, Renders, Carry M., Rodenburg, Gerda, Rutters, Femke, Smith, Matt C., Singh, Amika S., Snijder, Marieke B., Stronks, Karien, Ten Have, Margreet, Twisk, Jos W. R., Van De Mheen, Dike, Van Der Ende, Jan, Van Der Heijden, Kristiaan B., Van Der Velden, Peter G., Van Lenthe, Frank J., Van Litsenburg, Raphaële R. L., Van Oostrom, Sandra H., Van Schalkwijk, Frank J., Sheehan, Connor M., Verheij, Robert A., Verhulst, Frank C., Vermeulen, Marije C. M., Vermeulen, Roel C. H., Verschuren, W. M. Monique, Vrijkotte, Tanja G. M., Wijga, Alet H., Willemen, Agnes M., Ter Wolbeek, Maike, Wood, Andrew R., Xerxa, Yllza, Bramer, Wichor M., Franco, Oscar H., Luik, Annemarie I., Van Someren, Eus J. W., Tiemeier, Henning, Kocevska, Desana, Lysen, Thom S., Dotinga, Aafje, Koopman-verhoeff, M. Elisabeth, Luijk, Maartje P. C. M., Antypa, Niki, Biermasz, Nienke R., Blokstra, Anneke, Brug, Johannes, Burk, Wiliam J., Comijs, Hannie C., Corpeleijn, Eva, Dashti, Hassan S., De Bruin, Eduard J., De Graaf, Ron, Derks, Ivonne P. M., Dewald-kaufmann, Julia F., Elders, Petra J. M., Gemke, Reinoldus J. B. J., Grievink, Linda, Hale, Lauren, Hartman, Catharina A., Heijnen, Cobi J., Huisman, Martijn, Huss, Anke, Ikram, M. Arfan, Jones, Samuel E., Velderman, Mariska Klein, Koning, Maaike, Meijer, Anne Marie, Meijer, Kim, Noordam, Raymond, Oldehinkel, Albertine J., Groeniger, Joost Oude, Penninx, Brenda W. J. H., Picavet, H. Susan J., Pieters, Sara, Reijneveld, Sijmen A., Reitz, Ellen, Renders, Carry M., Rodenburg, Gerda, Rutters, Femke, Smith, Matt C., Singh, Amika S., Snijder, Marieke B., Stronks, Karien, Ten Have, Margreet, Twisk, Jos W. R., Van De Mheen, Dike, Van Der Ende, Jan, Van Der Heijden, Kristiaan B., Van Der Velden, Peter G., Van Lenthe, Frank J., Van Litsenburg, Raphaële R. L., Van Oostrom, Sandra H., Van Schalkwijk, Frank J., Sheehan, Connor M., Verheij, Robert A., Verhulst, Frank C., Vermeulen, Marije C. M., Vermeulen, Roel C. H., Verschuren, W. M. Monique, Vrijkotte, Tanja G. M., Wijga, Alet H., Willemen, Agnes M., Ter Wolbeek, Maike, Wood, Andrew R., Xerxa, Yllza, Bramer, Wichor M., Franco, Oscar H., Luik, Annemarie I., Van Someren, Eus J. W., and Tiemeier, Henning
Abstract: We aimed to obtain reliable reference charts for sleep duration, estimate the prevalence of sleep complaints across the lifespan and identify risk indicators of poor sleep. Studies were identified through systematic literature search in Embase, Medline and Web of Science (9 August 2019) and through personal contacts. Eligible studies had to be published between 2000 and 2017 with data on sleep assessed with questionnaires including ≥100 participants from the general population. We assembled individual participant data from 200,358 people (aged 1–100 years, 55% female) from 36 studies from the Netherlands, 471,759 people (40–69 years, 55.5% female) from the United Kingdom and 409,617 people (≥18 years, 55.8% female) from the United States. One in four people slept less than age-specific recommendations, but only 5.8% slept outside of the ‘acceptable’ sleep duration. Among teenagers, 51.5% reported total sleep times (TST) of less than the recommended 8–10 h and 18% report daytime sleepiness. In adults (≥18 years), poor sleep quality (13.3%) and insomnia symptoms (9.6–19.4%) were more prevalent than short sleep duration (6.5% with TST < 6 h). Insomnia symptoms were most frequent in people spending ≥9 h in bed, whereas poor sleep quality was more frequent in those spending <6 h in bed. TST was similar across countries, but insomnia symptoms were 1.5–2.9 times higher in the United States. Women (≥41 years) reported sleeping shorter times or slightly less efficiently than men, whereas with actigraphy they were estimated to sleep longer and more efficiently than man. This study provides age- and sex-specific population reference charts for sleep duration and efficiency which can help guide personalized advice on sleep length and preventive practices.
Published: 2021

35. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Lagou, Vasiliki, Maegi, Reedik, Hottenga, Jouke- Jan, Grallert, Harald, Perry, John R. B., Bouatia-Naji, Nabila, Marullo, Letizia, Rybin, Denis, Jansen, Rick, Min, Josine L., Dimas, Antigone S., Ulrich, Anna, Zudina, Liudmila, Gadin, Jesper R., Jiang, Longda, Faggian, Alessia, Bonnefond, Amelie, Fadista, Joao, Stathopoulou, Maria G., Isaacs, Aaron, Willems, Sara M., Navarro, Pau, Tanaka, Toshiko, Jackson, Anne U., Montasser, May E., O'Connell, Jeff R., Bielak, Lawrence F., Webster, Rebecca J., Saxena, Richa, Stafford, Jeanette M., Pourcain, Beate St, Timpson, Nicholas J., Salo, Perttu, Shin, So-Youn, Amin, Najaf, Smith, Albert V., Li, Guo, Verweij, Niek, Goel, Anuj, Ford, Ian, Johnson, Paul C. D., Johnson, Toby, Kapur, Karen, Thorleifsson, Gudmar, Strawbridge, Rona J., Rasmussen-Torvik, Laura J., Esko, Tonu, Mihailov, Evelin, Fall, Tove, Fraser, Ross M., Mahajan, Anubha, Kanoni, Stavroula, Giedraitis, Vilmantas, Kleber, Marcus E., Silbernagel, Guenther, Meyer, Julia, Mueller-Nurasyid, Martina, Ganna, Andrea, Sarin, Antti-Pekka, Yengo, Loic, Shungin, Dmitry, Luan, Jian'an, Horikoshi, Momoko, An, Ping, Sanna, Serena, Boettcher, Yvonne, Rayner, N. William, Nolte, Ilja M., Zemunik, Tatijana, Iperen, Erik van, Kovacs, Peter, Hastie, Nicholas D., Wild, Sarah H., McLachlan, Stela, Campbell, Susan, Polasek, Ozren, Carlson, Olga, Egan, Josephine, Kiess, Wieland, Willemsen, Gonneke, Kuusisto, Johanna, Laakso, Markku, Dimitriou, Maria, Hicks, Andrew A., Rauramaa, Rainer, Bandinelli, Stefania, Thorand, Barbara, Liu, Yongmei, Miljkovic, Iva, Lind, Lars, Doney, Alex, Perola, Markus, Hingorani, Aroon, Kivimaki, Mika, Kumari, Meena, Bennett, Amanda J., Groves, Christopher J., Herder, Christian, Koistinen, Heikki A., Kinnunen, Leena, Faire, Ulf de, Bakker, Stephan J. L., Uusitupa, Matti, Palmer, Colin N. A., Jukema, J. Wouter, Sattar, Naveed, Pouta, Anneli, Snieder, Harold, Boerwinkle, Eric, Pankow, James S., Magnusson, Patrik K., Krus, Ulrika, Scapoli, Chiara, de Geus, Eco J. C. N., Blueher, Matthias, Wolffenbuttel, Bruce H. R., Province, Michael A., Abecasis, Goncalo R., Meigs, James B., Hovingh, G. Kees, Lindstroem, Jaana, Wilson, James F., Wright, Alan F., Dedoussis, George V., Bornstein, Stefan R., Schwarz, Peter E. H., Toenjes, Anke, Winkelmann, Bernhard R., Boehm, Bernhard O., Maerz, Winfried, Metspalu, Andres, Price, Jackie F., Deloukas, Panos, Koerner, Antje, Lakka, Timo A., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Bergman, Richard N., Tuomilehto, Jaakko, Wareham, Nicholas J., Langenberg, Claudia, Maennistoe, Satu, Franks, Paul W., Hayward, Caroline, Vitart, Veronique, Kaprio, Jaakko, Visvikis-Siest, Sophie, Balkau, Beverley, Altshuler, David, Rudan, Igor, Stumvoll, Michael, Campbell, Harry, van Duijn, Cornelia M., Gieger, Christian, Illig, Thomas, Ferrucci, Luigi, Pedersen, Nancy L., Pramstaller, Peter P., Boehnke, Michael, Frayling, Timothy M., Shuldiner, Alan R., Peyser, Patricia A., Kardia, Sharon L. R., Palmer, Lyle J., Penninx, Brenda W., Meneton, Pierre, Harris, Tamara B., Navis, Gerjan, Harst, Pim van der, Smith, George Davey, Forouhi, Nita G., Loos, Ruth J. F., Salomaa, Veikko, Soranzo, Nicole, Boomsma, Dorret I., Groop, Leif, Tuomi, Tiinamaija, Hofman, Albert, Munroe, Patricia B., Gudnason, Vilmundur, Siscovick, David S., Watkins, Hugh, Lecoeur, Cecile, Vollenweider, Peter, Franco-Cereceda, Anders, Eriksson, Per, Jarvelin, Marjo-Riitta, Stefansson, Kari, Hamsten, Anders, Nicholson, George, Karpe, Fredrik, Dermitzakis, Emmanouil T., Lindgren, Cecilia M., McCarthy, Mark I., Froguel, Philippe, Kaakinen, Marika A., Lyssenko, Valeriya, Watanabe, Richard M., Ingelsson, Erik, Florez, Jose C., Dupuis, Josee, Barroso, Ines, Morris, Andrew P., Prokopenko, Inga, Lagou, Vasiliki, Maegi, Reedik, Hottenga, Jouke- Jan, Grallert, Harald, Perry, John R. B., Bouatia-Naji, Nabila, Marullo, Letizia, Rybin, Denis, Jansen, Rick, Min, Josine L., Dimas, Antigone S., Ulrich, Anna, Zudina, Liudmila, Gadin, Jesper R., Jiang, Longda, Faggian, Alessia, Bonnefond, Amelie, Fadista, Joao, Stathopoulou, Maria G., Isaacs, Aaron, Willems, Sara M., Navarro, Pau, Tanaka, Toshiko, Jackson, Anne U., Montasser, May E., O'Connell, Jeff R., Bielak, Lawrence F., Webster, Rebecca J., Saxena, Richa, Stafford, Jeanette M., Pourcain, Beate St, Timpson, Nicholas J., Salo, Perttu, Shin, So-Youn, Amin, Najaf, Smith, Albert V., Li, Guo, Verweij, Niek, Goel, Anuj, Ford, Ian, Johnson, Paul C. D., Johnson, Toby, Kapur, Karen, Thorleifsson, Gudmar, Strawbridge, Rona J., Rasmussen-Torvik, Laura J., Esko, Tonu, Mihailov, Evelin, Fall, Tove, Fraser, Ross M., Mahajan, Anubha, Kanoni, Stavroula, Giedraitis, Vilmantas, Kleber, Marcus E., Silbernagel, Guenther, Meyer, Julia, Mueller-Nurasyid, Martina, Ganna, Andrea, Sarin, Antti-Pekka, Yengo, Loic, Shungin, Dmitry, Luan, Jian'an, Horikoshi, Momoko, An, Ping, Sanna, Serena, Boettcher, Yvonne, Rayner, N. William, Nolte, Ilja M., Zemunik, Tatijana, Iperen, Erik van, Kovacs, Peter, Hastie, Nicholas D., Wild, Sarah H., McLachlan, Stela, Campbell, Susan, Polasek, Ozren, Carlson, Olga, Egan, Josephine, Kiess, Wieland, Willemsen, Gonneke, Kuusisto, Johanna, Laakso, Markku, Dimitriou, Maria, Hicks, Andrew A., Rauramaa, Rainer, Bandinelli, Stefania, Thorand, Barbara, Liu, Yongmei, Miljkovic, Iva, Lind, Lars, Doney, Alex, Perola, Markus, Hingorani, Aroon, Kivimaki, Mika, Kumari, Meena, Bennett, Amanda J., Groves, Christopher J., Herder, Christian, Koistinen, Heikki A., Kinnunen, Leena, Faire, Ulf de, Bakker, Stephan J. L., Uusitupa, Matti, Palmer, Colin N. A., Jukema, J. Wouter, Sattar, Naveed, Pouta, Anneli, Snieder, Harold, Boerwinkle, Eric, Pankow, James S., Magnusson, Patrik K., Krus, Ulrika, Scapoli, Chiara, de Geus, Eco J. C. N., Blueher, Matthias, Wolffenbuttel, Bruce H. R., Province, Michael A., Abecasis, Goncalo R., Meigs, James B., Hovingh, G. Kees, Lindstroem, Jaana, Wilson, James F., Wright, Alan F., Dedoussis, George V., Bornstein, Stefan R., Schwarz, Peter E. H., Toenjes, Anke, Winkelmann, Bernhard R., Boehm, Bernhard O., Maerz, Winfried, Metspalu, Andres, Price, Jackie F., Deloukas, Panos, Koerner, Antje, Lakka, Timo A., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Bergman, Richard N., Tuomilehto, Jaakko, Wareham, Nicholas J., Langenberg, Claudia, Maennistoe, Satu, Franks, Paul W., Hayward, Caroline, Vitart, Veronique, Kaprio, Jaakko, Visvikis-Siest, Sophie, Balkau, Beverley, Altshuler, David, Rudan, Igor, Stumvoll, Michael, Campbell, Harry, van Duijn, Cornelia M., Gieger, Christian, Illig, Thomas, Ferrucci, Luigi, Pedersen, Nancy L., Pramstaller, Peter P., Boehnke, Michael, Frayling, Timothy M., Shuldiner, Alan R., Peyser, Patricia A., Kardia, Sharon L. R., Palmer, Lyle J., Penninx, Brenda W., Meneton, Pierre, Harris, Tamara B., Navis, Gerjan, Harst, Pim van der, Smith, George Davey, Forouhi, Nita G., Loos, Ruth J. F., Salomaa, Veikko, Soranzo, Nicole, Boomsma, Dorret I., Groop, Leif, Tuomi, Tiinamaija, Hofman, Albert, Munroe, Patricia B., Gudnason, Vilmundur, Siscovick, David S., Watkins, Hugh, Lecoeur, Cecile, Vollenweider, Peter, Franco-Cereceda, Anders, Eriksson, Per, Jarvelin, Marjo-Riitta, Stefansson, Kari, Hamsten, Anders, Nicholson, George, Karpe, Fredrik, Dermitzakis, Emmanouil T., Lindgren, Cecilia M., McCarthy, Mark I., Froguel, Philippe, Kaakinen, Marika A., Lyssenko, Valeriya, Watanabe, Richard M., Ingelsson, Erik, Florez, Jose C., Dupuis, Josee, Barroso, Ines, Morris, Andrew P., and Prokopenko, Inga
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
Published: 2021
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36. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author: Gorski, Mathias, Jung, Bettina, Li, Yong, Matias-Garcia, Pamela R., Wuttke, Matthias, Coassin, Stefan, Thio, Chris H. L., Kleber, Marcus E., Winkler, Thomas W., Wanner, Veronika, Chai, Jin-Fang, Chu, Audrey Y., Cocca, Massimiliano, Feitosa, Mary F., Ghasemi, Sahar, Hoppmann, Anselm, Horn, Katrin, Li, Man, Nutile, Teresa, Scholz, Markus, Sieber, Karsten B., Teumer, Alexander, Tin, Adrienne, Wang, Judy, Tayo, Bamidele O., Ahluwalia, Tarunveer S., Almgren, Peter, Bakker, Stephan J. L., Banas, Bernhard, Bansal, Nisha, Biggs, Mary L., Boerwinkle, Eric, Bottinger, Erwin P., Brenner, Hermann, Carroll, Robert J., Chalmers, John, Chee, Miao-Li, Chee, Miao-Ling, Cheng, Ching-Yu, Coresh, Josef, de Borst, Martin H., Degenhardt, Frauke, Eckardt, Kai-Uwe, Endlich, Karlhans, Franke, Andre, Freitag-Wolf, Sandra, Gampawar, Piyush, Gansevoort, Ron T., Ghanbari, Mohsen, Gieger, Christian, Hamet, Pavel, Ho, Kevin, Hofer, Edith, Holleczek, Bernd, Xian Foo, Valencia Hui, Hutri-Kähönen, Nina, Hwang, Shih-Jen, Ikram, M. Arfan, Josyula, Navya Shilpa, Kähönen, Mika, Khor, Chiea-Chuen, Koenig, Wolfgang, Kramer, Holly, Krämer, Bernhard K., Kühnel, Brigitte, Lange, Leslie A., Lehtimäki, Terho, Lieb, Wolfgang, Loos, Ruth J. F., Lukas, Mary Ann, Lyytikäinen, Leo-Pekka, Meisinger, Christa, Meitinger, Thomas, Melander, Olle, Milaneschi, Yuri, Mishra, Pashupati P., Mononen, Nina, Mychaleckyj, Josyf C., Nadkarni, Girish N., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M., O'Donoghue, Michelle L., Orho-Melander, Marju, Pendergrass, Sarah A., Penninx, Brenda W. J. H., Preuss, Michael H., Psaty, Bruce M., Raffield, Laura M., Raitakari, Olli T., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Rosenkranz, Alexander R., Rossing, Peter, Rotter, Jerome I., Sabanayagam, Charumathi, Schmidt, Helena, Schmidt, Reinhold, Schöttker, Ben, Schulz, Christina-Alexandra, Sedaghat, Sanaz, Shaffer, Christian M., Strauch, Konstantin, Szymczak, Silke, Taylor, Kent D., Tremblay, Johanne, Chaker, Layal, van der Harst, Pim, van der Most, Peter J., Verweij, Niek, Völker, Uwe, Waldenberger, Melanie, Wallentin, Lars, Waterworth, Dawn M., White, Harvey D., Wilson, James G., Wong, Tien-Yin, Woodward, Mark, Yang, Qiong, Yasuda, Masayuki, Yerges-Armstrong, Laura M., Zhang, Yan, Snieder, Harold, Wanner, Christoph, Böger, Carsten A., Köttgen, Anna, Kronenberg, Florian, Pattaro, Cristian, Heid, Iris M., Gorski, Mathias, Jung, Bettina, Li, Yong, Matias-Garcia, Pamela R., Wuttke, Matthias, Coassin, Stefan, Thio, Chris H. L., Kleber, Marcus E., Winkler, Thomas W., Wanner, Veronika, Chai, Jin-Fang, Chu, Audrey Y., Cocca, Massimiliano, Feitosa, Mary F., Ghasemi, Sahar, Hoppmann, Anselm, Horn, Katrin, Li, Man, Nutile, Teresa, Scholz, Markus, Sieber, Karsten B., Teumer, Alexander, Tin, Adrienne, Wang, Judy, Tayo, Bamidele O., Ahluwalia, Tarunveer S., Almgren, Peter, Bakker, Stephan J. L., Banas, Bernhard, Bansal, Nisha, Biggs, Mary L., Boerwinkle, Eric, Bottinger, Erwin P., Brenner, Hermann, Carroll, Robert J., Chalmers, John, Chee, Miao-Li, Chee, Miao-Ling, Cheng, Ching-Yu, Coresh, Josef, de Borst, Martin H., Degenhardt, Frauke, Eckardt, Kai-Uwe, Endlich, Karlhans, Franke, Andre, Freitag-Wolf, Sandra, Gampawar, Piyush, Gansevoort, Ron T., Ghanbari, Mohsen, Gieger, Christian, Hamet, Pavel, Ho, Kevin, Hofer, Edith, Holleczek, Bernd, Xian Foo, Valencia Hui, Hutri-Kähönen, Nina, Hwang, Shih-Jen, Ikram, M. Arfan, Josyula, Navya Shilpa, Kähönen, Mika, Khor, Chiea-Chuen, Koenig, Wolfgang, Kramer, Holly, Krämer, Bernhard K., Kühnel, Brigitte, Lange, Leslie A., Lehtimäki, Terho, Lieb, Wolfgang, Loos, Ruth J. F., Lukas, Mary Ann, Lyytikäinen, Leo-Pekka, Meisinger, Christa, Meitinger, Thomas, Melander, Olle, Milaneschi, Yuri, Mishra, Pashupati P., Mononen, Nina, Mychaleckyj, Josyf C., Nadkarni, Girish N., Nauck, Matthias, Nikus, Kjell, Ning, Boting, Nolte, Ilja M., O'Donoghue, Michelle L., Orho-Melander, Marju, Pendergrass, Sarah A., Penninx, Brenda W. J. H., Preuss, Michael H., Psaty, Bruce M., Raffield, Laura M., Raitakari, Olli T., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Rosenkranz, Alexander R., Rossing, Peter, Rotter, Jerome I., Sabanayagam, Charumathi, Schmidt, Helena, Schmidt, Reinhold, Schöttker, Ben, Schulz, Christina-Alexandra, Sedaghat, Sanaz, Shaffer, Christian M., Strauch, Konstantin, Szymczak, Silke, Taylor, Kent D., Tremblay, Johanne, Chaker, Layal, van der Harst, Pim, van der Most, Peter J., Verweij, Niek, Völker, Uwe, Waldenberger, Melanie, Wallentin, Lars, Waterworth, Dawn M., White, Harvey D., Wilson, James G., Wong, Tien-Yin, Woodward, Mark, Yang, Qiong, Yasuda, Masayuki, Yerges-Armstrong, Laura M., Zhang, Yan, Snieder, Harold, Wanner, Christoph, Böger, Carsten A., Köttgen, Anna, Kronenberg, Florian, Pattaro, Cristian, and Heid, Iris M.
Abstract: Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Published: 2021
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37. Sleep characteristics across the lifespan in 1.1 million people from the Netherlands, United Kingdom and United States: a systematic review and meta-analysis

Author: IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Leerstoel Dekovic, Development and Treatment of Psychosocial Problems, Sub KGP, Urban Accessibility and Social Inclusion, LS IRAS EEPI ME (Milieu epidemiologie), Kocevska, Desana, Lysen, Thom S., Dotinga, Aafje, Koopman-verhoeff, M. Elisabeth, Luijk, Maartje P. C. M., Antypa, Niki, Biermasz, Nienke R., Blokstra, Anneke, Brug, Johannes, Burk, Wiliam J., Comijs, Hannie C., Corpeleijn, Eva, Dashti, Hassan S., De Bruin, Eduard J., De Graaf, Ron, Derks, Ivonne P. M., Dewald-kaufmann, Julia F., Elders, Petra J. M., Gemke, Reinoldus J. B. J., Grievink, Linda, Hale, Lauren, Hartman, Catharina A., Heijnen, Cobi J., Huisman, Martijn, Huss, Anke, Ikram, M. Arfan, Jones, Samuel E., Velderman, Mariska Klein, Koning, Maaike, Meijer, Anne Marie, Meijer, Kim, Noordam, Raymond, Oldehinkel, Albertine J., Groeniger, Joost Oude, Penninx, Brenda W. J. H., Picavet, H. Susan J., Pieters, Sara, Reijneveld, Sijmen A., Reitz, Ellen, Renders, Carry M., Rodenburg, Gerda, Rutters, Femke, Smith, Matt C., Singh, Amika S., Snijder, Marieke B., Stronks, Karien, Ten Have, Margreet, Twisk, Jos W. R., Van De Mheen, Dike, Van Der Ende, Jan, Van Der Heijden, Kristiaan B., Van Der Velden, Peter G., Van Lenthe, Frank J., Van Litsenburg, Raphaële R. L., Van Oostrom, Sandra H., Van Schalkwijk, Frank J., Sheehan, Connor M., Verheij, Robert A., Verhulst, Frank C., Vermeulen, Marije C. M., Vermeulen, Roel C. H., Verschuren, W. M. Monique, Vrijkotte, Tanja G. M., Wijga, Alet H., Willemen, Agnes M., Ter Wolbeek, Maike, Wood, Andrew R., Xerxa, Yllza, Bramer, Wichor M., Franco, Oscar H., Luik, Annemarie I., Van Someren, Eus J. W., Tiemeier, Henning, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Leerstoel Dekovic, Development and Treatment of Psychosocial Problems, Sub KGP, Urban Accessibility and Social Inclusion, LS IRAS EEPI ME (Milieu epidemiologie), Kocevska, Desana, Lysen, Thom S., Dotinga, Aafje, Koopman-verhoeff, M. Elisabeth, Luijk, Maartje P. C. M., Antypa, Niki, Biermasz, Nienke R., Blokstra, Anneke, Brug, Johannes, Burk, Wiliam J., Comijs, Hannie C., Corpeleijn, Eva, Dashti, Hassan S., De Bruin, Eduard J., De Graaf, Ron, Derks, Ivonne P. M., Dewald-kaufmann, Julia F., Elders, Petra J. M., Gemke, Reinoldus J. B. J., Grievink, Linda, Hale, Lauren, Hartman, Catharina A., Heijnen, Cobi J., Huisman, Martijn, Huss, Anke, Ikram, M. Arfan, Jones, Samuel E., Velderman, Mariska Klein, Koning, Maaike, Meijer, Anne Marie, Meijer, Kim, Noordam, Raymond, Oldehinkel, Albertine J., Groeniger, Joost Oude, Penninx, Brenda W. J. H., Picavet, H. Susan J., Pieters, Sara, Reijneveld, Sijmen A., Reitz, Ellen, Renders, Carry M., Rodenburg, Gerda, Rutters, Femke, Smith, Matt C., Singh, Amika S., Snijder, Marieke B., Stronks, Karien, Ten Have, Margreet, Twisk, Jos W. R., Van De Mheen, Dike, Van Der Ende, Jan, Van Der Heijden, Kristiaan B., Van Der Velden, Peter G., Van Lenthe, Frank J., Van Litsenburg, Raphaële R. L., Van Oostrom, Sandra H., Van Schalkwijk, Frank J., Sheehan, Connor M., Verheij, Robert A., Verhulst, Frank C., Vermeulen, Marije C. M., Vermeulen, Roel C. H., Verschuren, W. M. Monique, Vrijkotte, Tanja G. M., Wijga, Alet H., Willemen, Agnes M., Ter Wolbeek, Maike, Wood, Andrew R., Xerxa, Yllza, Bramer, Wichor M., Franco, Oscar H., Luik, Annemarie I., Van Someren, Eus J. W., and Tiemeier, Henning
Published: 2021

38. Psychosocial factors and cancer incidence (PSY-CA): Protocol for individual participant data meta-analyses

Author: Leerstoel Boelen, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Trauma and Grief, van Tuijl, Lonneke A, Voogd, Adri C, de Graeff, Alexander, Hoogendoorn, Adriaan W, Ranchor, Adelita V, Pan, Kuan-Yu, Basten, Maartje, Lamers, Femke, Geerlings, Mirjam I, Abell, Jessica G, Awadalla, Philip, Bakker, Marije F, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, Keats, Melanie R, Kok, Almar A L, Luik, Annemarie I, Noisel, Nolwenn, Onland-Moret, N Charlotte, Payette, Yves, Penninx, Brenda W J H, Portengen, Lützen, Rissanen, Ina, Roest, Annelieke M, Rosmalen, Judith G M, Ruiter, Rikje, Schoevers, Robert A, Soave, David M, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Teyhan, Alison, Vaartjes, Ilonca, van der Willik, Kimberly D, van Leeuwen, Flora E, van Petersen, Rutger, Verschuren, W M Monique, Visseren, Frank, Vermeulen, Roel, Dekker, Joost, Leerstoel Boelen, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Trauma and Grief, van Tuijl, Lonneke A, Voogd, Adri C, de Graeff, Alexander, Hoogendoorn, Adriaan W, Ranchor, Adelita V, Pan, Kuan-Yu, Basten, Maartje, Lamers, Femke, Geerlings, Mirjam I, Abell, Jessica G, Awadalla, Philip, Bakker, Marije F, Beekman, Aartjan T F, Bjerkeset, Ottar, Boyd, Andy, Cui, Yunsong, Galenkamp, Henrike, Garssen, Bert, Hellingman, Sean, Huisman, Martijn, Huss, Anke, Keats, Melanie R, Kok, Almar A L, Luik, Annemarie I, Noisel, Nolwenn, Onland-Moret, N Charlotte, Payette, Yves, Penninx, Brenda W J H, Portengen, Lützen, Rissanen, Ina, Roest, Annelieke M, Rosmalen, Judith G M, Ruiter, Rikje, Schoevers, Robert A, Soave, David M, Spaan, Mandy, Steptoe, Andrew, Stronks, Karien, Sund, Erik R, Sweeney, Ellen, Teyhan, Alison, Vaartjes, Ilonca, van der Willik, Kimberly D, van Leeuwen, Flora E, van Petersen, Rutger, Verschuren, W M Monique, Visseren, Frank, Vermeulen, Roel, and Dekker, Joost
Published: 2021

39. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Author: Munn-Chernoff, Melissa A, Johnson, Emma C, Chou, Yi-Ling, Coleman, Jonathan R I, Thornton, Laura M, Walters, Raymond K, Yilmaz, Zeynep, Baker, Jessica H, Hübel, Christopher, Gordon, Scott, Medland, Sarah E, Watson, Hunna J, Gaspar, Héléna A, Bryois, Julien, Hinney, Anke, Leppä, Virpi M, Mattheisen, Manuel, Ripke, Stephan, Yao, Shuyang, Giusti-Rodríguez, Paola, Hanscombe, Ken B, Adan, Roger A H, Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole A, Berrettini, Wade H, Boehm, Ilka, Boni, Claudette, Boraska Perica, Vesna, Buehren, Katharina, Burghardt, Roland, Cassina, Matteo, Cichon, Sven, Clementi, Maurizio, Cone, Roger D, Courtet, Philippe, Crow, Scott, Crowley, James J, Danner, Unna N, Davis, Oliver S P, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E, Dick, Danielle M, Dikeos, Dimitris, Dina, Christian, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Duncan, Laramie E, Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M, Fischer, Krista, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J, Forzan, Monica, Franklin, Christopher S, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos Mayora, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske G, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Huckins, Laura M, Hudson, James I, Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J H, Kennedy, James L, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klump, Kelly L, Knudsen, Gun Peggy S, La Via, Maria C, Le Hellard, Stephanie, Levitan, Robert D, Li, Dong, Lilenfeld, Lisa, Lin, Bochao Danae, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre J, Maj, Mario, Mannik, Katrin, Marsal, Sara, Marshall, Christian R, Mattingsdal, Morten, McDevitt, Sara, McGuffin, Peter, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen, Monteleone, Alessio Maria, Monteleone, Palmiero, Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, O'Toole, Julie K, Ophoff, Roel A, Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Pinto, Dalila, Rabionet, Raquel, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W, Schmidt, Ulrike, Schork, Nicholas J, Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P Eline, Slof-Op't Landt, Margarita C T, Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Szatkiewicz, Jin P, Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A, van Furth, Eric F, Wagner, Gudrun, Walton, Esther, Widen, Elisabeth, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W, Boden, Joseph M, Brandt, Harry, Crawford, Steven, Halmi, Katherine A, Horwood, L John, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Mitchell, James, Olsen, Catherine M, Pearson, John F, Pedersen, Nancy L, Strober, Michael, Werge, Thomas, Whiteman, David C, Woodside, D Blake, Grove, Jakob, Henders, Anjali K, Larsen, Janne T, Parker, Richard, Petersen, Liselotte V, Jordan, Jennifer, Kennedy, Martin A, Birgegård, Andreas, Lichtenstein, Paul, Norring, Claes, Landén, Mikael, Mortensen, Preben Bo, Polimanti, Renato, McClintick, Jeanette N, Adkins, Amy E, Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna M, Bigdeli, Tim B, Chen, Li-Shiun, Clarke, Toni-Kim, Degenhardt, Franziska, Docherty, Anna R, Edwards, Alexis C, Foo, Jerome C, Fox, Louis, Frank, Josef, Hack, Laura M, Hartmann, Annette M, Hartz, Sarah M, Heilmann-Heimbach, Stefanie, Hodgkinson, Colin, Hoffmann, Per, Hottenga, Jouke-Jan, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion S, Mbarek, Hamdi, McIntosh, Andrew M, McQueen, Matthew B, Meyers, Jacquelyn L, Milaneschi, Yuri, Palviainen, Teemu, Peterson, Roseann E, Ryu, Euijung, Saccone, Nancy L, Salvatore, Jessica E, Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley T, Wedow, Robbee, Wetherill, Leah, Wills, Amanda G, Zhou, Hang, Boardman, Jason D, Chen, Danfeng, Choi, Doo-Sup, Copeland, William E, Culverhouse, Robert C, Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W, Frye, Mark A, Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Koller, Gabriele, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T, Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison D, Nurnberger, John I, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D, Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc A, Soyka, Michael, Treutlein, Jens, Witt, Stephanie H, Wodarz, Norbert, Zill, Peter, Adkins, Daniel E, Boomsma, Dorret I, Bierut, Laura J, Brown, Sandra A, Bucholz, Kathleen K, Costello, E Jane, de Wit, Harriet, Diazgranados, Nancy, Eriksson, Johan G, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Goate, Alison M, Goldman, David, Grucza, Richard A, Hancock, Dana B, Harris, Kathleen Mullan, Hesselbrock, Victor, Hewitt, John K, Hopfer, Christian J, Iacono, William G, Johnson, Eric O, Karpyak, Victor M, Kendler, Kenneth S, Kranzler, Henry R, Krauter, Kenneth, Lind, Penelope A, McGue, Matt, MacKillop, James, Madden, Pamela A F, Maes, Hermine H, Magnusson, Patrik K E, Nelson, Elliot C, Nöthen, Markus M, Palmer, Abraham A, Penninx, Brenda W J H, Porjesz, Bernice, Rice, John P, Rietschel, Marcella, Riley, Brien P, Rose, Richard J, Shen, Pei-Hong, Silberg, Judy, Stallings, Michael C, Tarter, Ralph E, Vanyukov, Michael M, Vrieze, Scott, Wall, Tamara L, Whitfield, John B, Zhao, Hongyu, Neale, Benjamin M, Wade, Tracey D, Heath, Andrew C, Montgomery, Grant W, Martin, Nicholas G, Sullivan, Patrick F, Kaprio, Jaakko, Breen, Gerome, Gelernter, Joel, Edenberg, Howard J, Bulik, Cynthia M, Agrawal, Arpana, Munn-Chernoff, Melissa A, Johnson, Emma C, Chou, Yi-Ling, Coleman, Jonathan R I, Thornton, Laura M, Walters, Raymond K, Yilmaz, Zeynep, Baker, Jessica H, Hübel, Christopher, Gordon, Scott, Medland, Sarah E, Watson, Hunna J, Gaspar, Héléna A, Bryois, Julien, Hinney, Anke, Leppä, Virpi M, Mattheisen, Manuel, Ripke, Stephan, Yao, Shuyang, Giusti-Rodríguez, Paola, Hanscombe, Ken B, Adan, Roger A H, Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole A, Berrettini, Wade H, Boehm, Ilka, Boni, Claudette, Boraska Perica, Vesna, Buehren, Katharina, Burghardt, Roland, Cassina, Matteo, Cichon, Sven, Clementi, Maurizio, Cone, Roger D, Courtet, Philippe, Crow, Scott, Crowley, James J, Danner, Unna N, Davis, Oliver S P, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E, Dick, Danielle M, Dikeos, Dimitris, Dina, Christian, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Duncan, Laramie E, Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M, Fischer, Krista, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J, Forzan, Monica, Franklin, Christopher S, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos Mayora, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske G, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Huckins, Laura M, Hudson, James I, Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J H, Kennedy, James L, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klump, Kelly L, Knudsen, Gun Peggy S, La Via, Maria C, Le Hellard, Stephanie, Levitan, Robert D, Li, Dong, Lilenfeld, Lisa, Lin, Bochao Danae, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre J, Maj, Mario, Mannik, Katrin, Marsal, Sara, Marshall, Christian R, Mattingsdal, Morten, McDevitt, Sara, McGuffin, Peter, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen, Monteleone, Alessio Maria, Monteleone, Palmiero, Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, O'Toole, Julie K, Ophoff, Roel A, Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Pinto, Dalila, Rabionet, Raquel, Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W, Schmidt, Ulrike, Schork, Nicholas J, Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P Eline, Slof-Op't Landt, Margarita C T, Slopien, Agnieszka, Sorbi, Sandro, Świątkowska, Beata, Szatkiewicz, Jin P, Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A, van Furth, Eric F, Wagner, Gudrun, Walton, Esther, Widen, Elisabeth, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Bergen, Andrew W, Boden, Joseph M, Brandt, Harry, Crawford, Steven, Halmi, Katherine A, Horwood, L John, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Mitchell, James, Olsen, Catherine M, Pearson, John F, Pedersen, Nancy L, Strober, Michael, Werge, Thomas, Whiteman, David C, Woodside, D Blake, Grove, Jakob, Henders, Anjali K, Larsen, Janne T, Parker, Richard, Petersen, Liselotte V, Jordan, Jennifer, Kennedy, Martin A, Birgegård, Andreas, Lichtenstein, Paul, Norring, Claes, Landén, Mikael, Mortensen, Preben Bo, Polimanti, Renato, McClintick, Jeanette N, Adkins, Amy E, Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna M, Bigdeli, Tim B, Chen, Li-Shiun, Clarke, Toni-Kim, Degenhardt, Franziska, Docherty, Anna R, Edwards, Alexis C, Foo, Jerome C, Fox, Louis, Frank, Josef, Hack, Laura M, Hartmann, Annette M, Hartz, Sarah M, Heilmann-Heimbach, Stefanie, Hodgkinson, Colin, Hoffmann, Per, Hottenga, Jouke-Jan, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion S, Mbarek, Hamdi, McIntosh, Andrew M, McQueen, Matthew B, Meyers, Jacquelyn L, Milaneschi, Yuri, Palviainen, Teemu, Peterson, Roseann E, Ryu, Euijung, Saccone, Nancy L, Salvatore, Jessica E, Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley T, Wedow, Robbee, Wetherill, Leah, Wills, Amanda G, Zhou, Hang, Boardman, Jason D, Chen, Danfeng, Choi, Doo-Sup, Copeland, William E, Culverhouse, Robert C, Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W, Frye, Mark A, Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Koller, Gabriele, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T, Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison D, Nurnberger, John I, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D, Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc A, Soyka, Michael, Treutlein, Jens, Witt, Stephanie H, Wodarz, Norbert, Zill, Peter, Adkins, Daniel E, Boomsma, Dorret I, Bierut, Laura J, Brown, Sandra A, Bucholz, Kathleen K, Costello, E Jane, de Wit, Harriet, Diazgranados, Nancy, Eriksson, Johan G, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Goate, Alison M, Goldman, David, Grucza, Richard A, Hancock, Dana B, Harris, Kathleen Mullan, Hesselbrock, Victor, Hewitt, John K, Hopfer, Christian J, Iacono, William G, Johnson, Eric O, Karpyak, Victor M, Kendler, Kenneth S, Kranzler, Henry R, Krauter, Kenneth, Lind, Penelope A, McGue, Matt, MacKillop, James, Madden, Pamela A F, Maes, Hermine H, Magnusson, Patrik K E, Nelson, Elliot C, Nöthen, Markus M, Palmer, Abraham A, Penninx, Brenda W J H, Porjesz, Bernice, Rice, John P, Rietschel, Marcella, Riley, Brien P, Rose, Richard J, Shen, Pei-Hong, Silberg, Judy, Stallings, Michael C, Tarter, Ralph E, Vanyukov, Michael M, Vrieze, Scott, Wall, Tamara L, Whitfield, John B, Zhao, Hongyu, Neale, Benjamin M, Wade, Tracey D, Heath, Andrew C, Montgomery, Grant W, Martin, Nicholas G, Sullivan, Patrick F, Kaprio, Jaakko, Breen, Gerome, Gelernter, Joel, Edenberg, Howard J, Bulik, Cynthia M, and Agrawal, Arpana
Abstract: Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-sp
Published: 2021
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40. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pane-Farre, Christiane A., Pauli, Paul, Rief, Winfried, Strohle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret, I, Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Muller-Myhsok, Bertram, Hansen, Thomas Folkmann, Borglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nothen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rueck, Christian, Ripke, Stephan, Deckert, Juergen, Schumacher, Johannes, Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pane-Farre, Christiane A., Pauli, Paul, Rief, Winfried, Strohle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret, I, Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Muller-Myhsok, Bertram, Hansen, Thomas Folkmann, Borglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nothen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rueck, Christian, Ripke, Stephan, Deckert, Juergen, and Schumacher, Johannes
Abstract: Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 x 10(-4) were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 x 10(-7)). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
Published: 2021

41. Brain aging in major depressive disorder: Results from the ENIGMA major depressive disorder working group

Author: Han, Laura K M, Dinga, Richard, Hahn, Tim, Ching, Christopher R K, Eyler, Lisa T, Aftanas, Lyubomir, Aghajani, Moji, Aleman, André, Baune, Bernhard T, Berger, Klaus, Brak, Ivan, Filho, Geraldo Busatto, Carballedo, Angela, Connolly, Colm G, Couvy-Duchesne, Baptiste, Cullen, Kathryn R, Dannlowski, Udo, Davey, Christopher G, Dima, Danai, Duran, Fabio L S, Enneking, Verena, Filimonova, Elena, Frenzel, Stefan, Frodl, Thomas, Fu, Cynthia H Y, Godlewska, Beata R, Gotlib, Ian H, Grabe, Hans J, Groenewold, Nynke A, Grotegerd, Dominik, Gruber, Oliver, Hall, Geoffrey B, Harrison, Ben J, Hatton, Sean N, Hermesdorf, Marco, Hickie, Ian B, Ho, Tiffany C, Hosten, Norbert, Jansen, Andreas, Kähler, Claas, Kircher, Tilo, Klimes-Dougan, Bonnie, Krämer, Bernd, Krug, Axel, Lagopoulos, Jim, Leenings, Ramona, MacMaster, Frank P, MacQueen, Glenda, McIntosh, Andrew, McLellan, Quinn, McMahon, Katie L, Medland, Sarah E, Mueller, Bryon A, Mwangi, Benson, Osipov, Evgeny, Portella, Maria J, Pozzi, Elena, Reneman, Liesbeth, Repple, Jonathan, Rosa, Pedro G P, Sacchet, Matthew D, Sämann, Philipp G, Schnell, Knut, Schrantee, Anouk, Simulionyte, Egle, Soares, Jair C, Sommer, Jens, Stein, Dan J, Steinsträter, Olaf, Strike, Lachlan T, Thomopoulos, Sophia I, van Tol, Marie-José, Veer, Ilya M, Vermeiren, Robert R J M, Walter, Henrik, van der Wee, Nic J A, van der Werff, Steven J A, Whalley, Heather, Winter, Nils R, Wittfeld, Katharina, Wright, Margaret J, Wu, Mon-Ju, Völzke, Henry, Yang, Tony T, Zannias, Vasileios, de Zubicaray, Greig I, Zunta-Soares, Giovana B, Abé, Christoph, Alda, Martin, Andreassen, Ole A, Bøen, Erlend, Bonnin, Caterina M, Canales-Rodriguez, Erick J, Cannon, Dara, Caseras, Xavier, Chaim-Avancini, Tiffany M, Elvsåshagen, Torbjørn, Favre, Pauline, Foley, Sonya F, Fullerton, Janice M, Goikolea, Jose M, Haarman, Bartholomeus C M, Hajek, Tomas, Henry, Chantal, Houenou, Josselin, Howells, Fleur M, Ingvar, Martin, Kuplicki, Rayus, Lafer, Beny, Landén, Mikael, Machado-Vieira, Rodrigo, Malt, Ulrik F, McDonald, Colm, Mitchell, Philip B, Nabulsi, Leila, Otaduy, Maria Concepcion Garcia, Overs, Bronwyn J, Polosan, Mircea, Pomarol-Clotet, Edith, Radua, Joaquim, Rive, Maria M, Roberts, Gloria, Ruhe, Henricus G, Salvador, Raymond, Sarró, Salvador, Satterthwaite, Theodore D, Savitz, Jonathan, Schene, Aart H, Schofield, Peter R, Serpa, Mauricio H, Sim, Kang, Soeiro-de-Souza, Marcio Gerhardt, Sutherland, Ashley N, Temmingh, Henk S, Timmons, Garrett M, Uhlmann, Anne, Vieta, Eduard, Wolf, Daniel H, Zanetti, Marcus V, Jahanshad, Neda, Thompson, Paul M, Veltman, Dick J, Penninx, Brenda W J H, Marquand, Andre F, Cole, James H, Schmaal, Lianne, Han, Laura K M, Dinga, Richard, Hahn, Tim, Ching, Christopher R K, Eyler, Lisa T, Aftanas, Lyubomir, Aghajani, Moji, Aleman, André, Baune, Bernhard T, Berger, Klaus, Brak, Ivan, Filho, Geraldo Busatto, Carballedo, Angela, Connolly, Colm G, Couvy-Duchesne, Baptiste, Cullen, Kathryn R, Dannlowski, Udo, Davey, Christopher G, Dima, Danai, Duran, Fabio L S, Enneking, Verena, Filimonova, Elena, Frenzel, Stefan, Frodl, Thomas, Fu, Cynthia H Y, Godlewska, Beata R, Gotlib, Ian H, Grabe, Hans J, Groenewold, Nynke A, Grotegerd, Dominik, Gruber, Oliver, Hall, Geoffrey B, Harrison, Ben J, Hatton, Sean N, Hermesdorf, Marco, Hickie, Ian B, Ho, Tiffany C, Hosten, Norbert, Jansen, Andreas, Kähler, Claas, Kircher, Tilo, Klimes-Dougan, Bonnie, Krämer, Bernd, Krug, Axel, Lagopoulos, Jim, Leenings, Ramona, MacMaster, Frank P, MacQueen, Glenda, McIntosh, Andrew, McLellan, Quinn, McMahon, Katie L, Medland, Sarah E, Mueller, Bryon A, Mwangi, Benson, Osipov, Evgeny, Portella, Maria J, Pozzi, Elena, Reneman, Liesbeth, Repple, Jonathan, Rosa, Pedro G P, Sacchet, Matthew D, Sämann, Philipp G, Schnell, Knut, Schrantee, Anouk, Simulionyte, Egle, Soares, Jair C, Sommer, Jens, Stein, Dan J, Steinsträter, Olaf, Strike, Lachlan T, Thomopoulos, Sophia I, van Tol, Marie-José, Veer, Ilya M, Vermeiren, Robert R J M, Walter, Henrik, van der Wee, Nic J A, van der Werff, Steven J A, Whalley, Heather, Winter, Nils R, Wittfeld, Katharina, Wright, Margaret J, Wu, Mon-Ju, Völzke, Henry, Yang, Tony T, Zannias, Vasileios, de Zubicaray, Greig I, Zunta-Soares, Giovana B, Abé, Christoph, Alda, Martin, Andreassen, Ole A, Bøen, Erlend, Bonnin, Caterina M, Canales-Rodriguez, Erick J, Cannon, Dara, Caseras, Xavier, Chaim-Avancini, Tiffany M, Elvsåshagen, Torbjørn, Favre, Pauline, Foley, Sonya F, Fullerton, Janice M, Goikolea, Jose M, Haarman, Bartholomeus C M, Hajek, Tomas, Henry, Chantal, Houenou, Josselin, Howells, Fleur M, Ingvar, Martin, Kuplicki, Rayus, Lafer, Beny, Landén, Mikael, Machado-Vieira, Rodrigo, Malt, Ulrik F, McDonald, Colm, Mitchell, Philip B, Nabulsi, Leila, Otaduy, Maria Concepcion Garcia, Overs, Bronwyn J, Polosan, Mircea, Pomarol-Clotet, Edith, Radua, Joaquim, Rive, Maria M, Roberts, Gloria, Ruhe, Henricus G, Salvador, Raymond, Sarró, Salvador, Satterthwaite, Theodore D, Savitz, Jonathan, Schene, Aart H, Schofield, Peter R, Serpa, Mauricio H, Sim, Kang, Soeiro-de-Souza, Marcio Gerhardt, Sutherland, Ashley N, Temmingh, Henk S, Timmons, Garrett M, Uhlmann, Anne, Vieta, Eduard, Wolf, Daniel H, Zanetti, Marcus V, Jahanshad, Neda, Thompson, Paul M, Veltman, Dick J, Penninx, Brenda W J H, Marquand, Andre F, Cole, James H, and Schmaal, Lianne
Abstract: Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.
Published: 2021

42. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author: Forstner, Andreas J, Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J, Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C, Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W, Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L, Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A, Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J C, Boomsma, Dorret I, Penninx, Brenda W J H, Thorgeirsson, Thorgeir E, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D, Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M, Hultman, Christina M, Sullivan, Patrick F, Nöthen, Markus M, Woldbye, David P D, Mors, Ole, Binder, Elisabeth B, Rück, Christian, Ripke, Stephan, Deckert, Jürgen, Schumacher, Johannes, Forstner, Andreas J, Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J, Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C, Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W, Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L, Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A, Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J C, Boomsma, Dorret I, Penninx, Brenda W J H, Thorgeirsson, Thorgeir E, Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D, Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M, Hultman, Christina M, Sullivan, Patrick F, Nöthen, Markus M, Woldbye, David P D, Mors, Ole, Binder, Elisabeth B, Rück, Christian, Ripke, Stephan, Deckert, Jürgen, and Schumacher, Johannes
Abstract: Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.
Published: 2021
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43. Habitual Behavior as a Mediator Between Food-Related Behavioral Activation and Change in Symptoms of Depression in the MooDFOOD Trial

Author: Owens, Matthew, Watkins, Ed, Bot, Mariska, Brouwer, Ingeborg A., Roca, Miquel, Kohls, Elisabeth, Penninx, Brenda W. J. H., van Grootheest, Gerard, Hegerl, Ulrich, Gili, Margalida, Visser, Marjolein, Owens, Matthew, Watkins, Ed, Bot, Mariska, Brouwer, Ingeborg A., Roca, Miquel, Kohls, Elisabeth, Penninx, Brenda W. J. H., van Grootheest, Gerard, Hegerl, Ulrich, Gili, Margalida, and Visser, Marjolein
Abstract: In this study, we tested potential mediators that may explain change in depressive symptoms following exposure to a food-related behavioral activation intervention (F-BA). These included behavioral activation, avoidance and rumination, eating styles, body mass index, and dietary behavior at baseline and 3-month and 12-month follow-up. The trial used a community sample of 1,025 overweight adults with elevated depressive symptoms without current major depression. Participants were randomly assigned to one of four trial arms: either daily nutritional supplements (vs. placebo) alone or in combination with F-BA (vs. no F-BA) over 12 months. Although F-BA did not significantly reduce depressive symptoms (standardized regression coefficient [b] = −0.223, SE = 0.129; p = .084), significant mediators included emotional eating (b = −0.028, SE = 0.014; p = .042) and uncontrolled eating (b = −0.039, SE = 0.016; p = .013), suggesting that learning adaptive responses to emotional and food cues may underlie effects of F-BA on depressive symptoms.
Published: 2021

44. Benzodiazepines for the long-term treatment of anxiety disorders? : Authors' Reply

Author: Penninx, Brenda W. J. H., Pine, Daniel S., Holmes, Emily A., Reif, Andreas, Penninx, Brenda W. J. H., Pine, Daniel S., Holmes, Emily A., and Reif, Andreas
Abstract: Title in Web of Science: Benzodiazepines for the long-term treatment of anxiety disorders? Reply
Published: 2021
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45. Cortical thickness and resting-state cardiac function across the lifespan : A cross-sectional pooled mega-analysis

Author: Koenig, Julian, Abler, Birgit, Agartz, Ingrid, Åkerstedt, Torbjörn, Andreassen, Ole A., Anthony, Mia, Bär, Karl-Jürgen, Bertsch, Katja, Brown, Rebecca C., Brunner, Romuald, Carnevali, Luca, Critchley, Hugo D., Cullen, Kathryn R., de Geus, Eco J. C., Dziobek, Isabel, Ferger, Marc D., Fischer, Håkan, Flor, Herta, Gaebler, Michael, Gianaros, Peter J., Giummarra, Melita J., Greening, Steven G., Guendelman, Simon, Heathers, James A. J., Herpertz, Sabine C., Hu, Mandy X., Jentschke, Sebastian, Kaess, Michael, Kaufmann, Tobias, Klimes-Dougan, Bonnie, Koelsch, Stefan, Krauch, Marlene, Kumral, Deniz, Lamers, Femke, Lee, Tae-Ho, Lekander, Mats, Lin, Feng, Lotze, Martin, Makovac, Elena, Mancini, Matteo, Mancke, Falk, Månsson, Kristoffer N.T., Manuck, Stephen B., Mather, Mara, Meeten, Frances, Min, Jungwon, Mueller, Bryon, Muench, Vera, Nees, Frauke, Nga, Lin, Nilsonne, Gustav, Ordonez Acuna, Daniela, Osnes, Berge, Ottaviani, Cristina, Penninx, Brenda W. J. H., Ponzio, Allison, Poudel, Govinda R., Reinelt, Janis, Ren, Ping, Sakaki, Michiko, Schumann, Andy, Sørensen, Lin, Specht, Karsten, Straub, Joana, Tamm, Sandra, Thai, Michelle, Thayer, Julian F., Ubani, Benjamin, van der Mee, Denise J., van Velzen, Laura S., Ventura-Bort, Carlos, Villringer, Arno, Watson, David R., Wei, Luqing, Wendt, Julia, Westlund Schreiner, Melinda, Westlye, Lars T., Weymar, Mathias, Winkelmann, Tobias, Wu, Guo-Rong, Yoo, Hyun Joo, Quintana, Daniel S., Koenig, Julian, Abler, Birgit, Agartz, Ingrid, Åkerstedt, Torbjörn, Andreassen, Ole A., Anthony, Mia, Bär, Karl-Jürgen, Bertsch, Katja, Brown, Rebecca C., Brunner, Romuald, Carnevali, Luca, Critchley, Hugo D., Cullen, Kathryn R., de Geus, Eco J. C., Dziobek, Isabel, Ferger, Marc D., Fischer, Håkan, Flor, Herta, Gaebler, Michael, Gianaros, Peter J., Giummarra, Melita J., Greening, Steven G., Guendelman, Simon, Heathers, James A. J., Herpertz, Sabine C., Hu, Mandy X., Jentschke, Sebastian, Kaess, Michael, Kaufmann, Tobias, Klimes-Dougan, Bonnie, Koelsch, Stefan, Krauch, Marlene, Kumral, Deniz, Lamers, Femke, Lee, Tae-Ho, Lekander, Mats, Lin, Feng, Lotze, Martin, Makovac, Elena, Mancini, Matteo, Mancke, Falk, Månsson, Kristoffer N.T., Manuck, Stephen B., Mather, Mara, Meeten, Frances, Min, Jungwon, Mueller, Bryon, Muench, Vera, Nees, Frauke, Nga, Lin, Nilsonne, Gustav, Ordonez Acuna, Daniela, Osnes, Berge, Ottaviani, Cristina, Penninx, Brenda W. J. H., Ponzio, Allison, Poudel, Govinda R., Reinelt, Janis, Ren, Ping, Sakaki, Michiko, Schumann, Andy, Sørensen, Lin, Specht, Karsten, Straub, Joana, Tamm, Sandra, Thai, Michelle, Thayer, Julian F., Ubani, Benjamin, van der Mee, Denise J., van Velzen, Laura S., Ventura-Bort, Carlos, Villringer, Arno, Watson, David R., Wei, Luqing, Wendt, Julia, Westlund Schreiner, Melinda, Westlye, Lars T., Weymar, Mathias, Winkelmann, Tobias, Wu, Guo-Rong, Yoo, Hyun Joo, and Quintana, Daniel S.
Abstract: Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12–87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS—or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.
Published: 2021
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46. Anxiety disorders

Author: Penninx, Brenda W. J. H., Pine, Daniel S., Holmes, Emily A., Reif, Andreas, Penninx, Brenda W. J. H., Pine, Daniel S., Holmes, Emily A., and Reif, Andreas
Abstract: Anxiety disorders form the most common group of mental disorders and generally start before or in early adulthood. Core features include excessive fear and anxiety or avoidance of perceived threats that are persistent and impairing. Anxiety disorders involve dysfunction in brain circuits that respond to danger. Risk for anxiety disorders is influenced by genetic factors, environmental factors, and their epigenetic relations. Anxiety disorders are often comorbid with one another and with other mental disorders, especially depression, as well as with somatic disorders. Such comorbidity generally signifies more severe symptoms, greater clinical burden, and greater treatment difficulty. Reducing the large burden of disease from anxiety disorders in individuals and worldwide can be best achieved by timely, accurate disease detection and adequate treatment administration, scaling up of treatments when needed. Evidence-based psychotherapy (particularly cognitive behavioural therapy) and psychoactive medications (particularly serotonergic compounds) are both effective, facilitating patients' choices in therapeutic decisions. Although promising, no enduring preventive measures are available, and, along with frequent therapy resistance, clinical needs remain unaddressed. Ongoing research efforts tackle these problems, and future efforts should seek individualised, more effective approaches for treatment with precision medicine.
Published: 2021
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47. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Author: de las Fuentes, Lisa, Sung, Yun Ju, Noordam, Raymond, Winkler, Thomas, Feitosa, Mary F., Schwander, Karen, Bentley, Amy R., Brown, Michael R., Guo, Xiuqing, Manning, Alisa, Chasman, Daniel I., Aschard, Hugues, Bartz, Traci M., Bielak, Lawrence F., Campbell, Archie, Cheng, Ching-Yu, Dorajoo, Rajkumar, Hartwig, Fernando P., Horimoto, A.R.V.R., Li, Changwei, Li-Gao, Ruifang, Liu, Yongmei, Marten, Jonathan, Musani, Solomon K., Ntalla, Ioanna, Rankinen, Tuomo, Richard, Melissa, Sim, Xueling, Smith, Albert V., Tajuddin, Salman M., Tayo, Bamidele O., Vojinovic, Dina, Warren, Helen R., Xuan, Deng, Alver, Maris, Boissel, Mathilde, Chai, Jin-Fang, Chen, Xu, Christensen, Kaare, Divers, Jasmin, Evangelou, Evangelos, Gao, Chuan, Girotto, Giorgia, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Kühnel, Brigitte, Laguzzi, Federica, Li, Xiaoyin, Lyytikäinen, Leo-Pekka, Nolte, Ilja M., Poveda, Alaitz, Rauramaa, Rainer, Riaz, Muhammad, Rueedi, Rico, Shu, Xiao-ou, Snieder, Harold, Sofer, Tamar, Takeuchi, Fumihiko, Verweij, Niek, Ware, Erin B., Weiss, Stefan, Yanek, Lisa R., Amin, Najaf, Arking, Dan E., Arnett, Donna K., Bergmann, Sven, Boerwinkle, Eric, Brody, Jennifer A., Broeckel, Ulrich, Brumat, Marco, Burke, Gregory, Cabrera, Claudia P., Canouil, Mickaël, Chee, Miao Li, Chen, Yii-Der Ida, Cocca, Massimiliano, Connell, John, de Silva, H. Janaka, de Vries, Paul S., Eiriksdottir, Gudny, Faul, Jessica D., Fisher, Virginia, Forrester, Terrence, Fox, Ervin F., Friedlander, Yechiel, Gao, He, Gigante, Bruna, Giulianini, Franco, Gu, Chi Charles, Gu, Dongfeng, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven, Ikram, M. Arfan, Irvin, Marguerite R., Kähönen, Mika, Kavousi, Maryam, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Komulainen, Pirjo, Kraja, Aldi T., Krieger, J.E., Langefeld, Carl D., Li, Yize, Liang, Jingjing, Liewald, David C. M., Liu, Ching-Ti, Liu, Jianjun, Lohman, Kurt K., Mägi, Reedik, McKenzie, Colin A., Meitinger, Thomas, Metspalu, Andres, Milaneschi, Yuri, Milani, Lili, Mook-Kanamori, Dennis O., Nalls, Mike A., Nelson, Christopher P., Norris, Jill M., O’Connell, Jeff, Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmer, Nicholette D., Pedersen, Nancy L., Perls, Thomas, Peters, Annette, Petersmann, Astrid, Peyser, Patricia A., Polasek, Ozren, Porteous, David J., Raffel, Leslie J., Rice, Treva K., Rotter, Jerome I., Rudan, Igor, Rueda-Ochoa, Oscar-Leonel, Sabanayagam, Charumathi, Salako, Babatunde L., Schreiner, Pamela J., Shikany, James M., Sidney, Stephen S., Sims, Mario, Sitlani, Colleen M., Smith, Jennifer A., Starr, John M., Strauch, Konstantin, Swertz, Morris A., Teumer, Alexander, Tham, Yih Chung, Uitterlinden, André G., Vaidya, Dhananjay, van der Ende, M. Yldau, Waldenberger, Melanie, Wang, Lihua, Wang, Ya-Xing, Wei, Wen-Bin, Weir, David R., Wen, Wanqing, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Bowden, Donald W., Deary, Ian J., Dörr, Marcus, Esko, Tõnu, Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Jonas, Jost Bruno, Kammerer, Candace M., Kato, Norihiro, Lakka, Timo A., Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K. E., Marques-Vidal, Pedro, Penninx, Brenda W. J. H., Samani, Nilesh J., van der Harst, Pim, Wagenknecht, Lynne E., Wu, Tangchun, Zheng, Wei, Zhu, Xiaofeng, Bouchard, Claude, Cooper, Richard S., Correa, Adolfo, Evans, Michele K., Gudnason, Vilmundur, Hayward, Caroline, Horta, Bernardo L., Kelly, Tanika N., Kritchevsky, Stephen B., Levy, Daniel, Palmas, Walter R., Pereira, A.C., Province, Michael M., Psaty, Bruce M., Ridker, Paul M., Rotimi, Charles N., Tai, E. Shyong, van Dam, Rob M., van Duijn, Cornelia M., Wong, Tien Yin, Rice, Kenneth, Gauderman, W. James, Morrison, Alanna C., North, Kari E., Kardia, Sharon L. R., Caulfield, Mark J., Elliott, Paul, Munroe, Patricia B., Franks, Paul W., Rao, Dabeeru C., Fornage, Myriam, de las Fuentes, Lisa, Sung, Yun Ju, Noordam, Raymond, Winkler, Thomas, Feitosa, Mary F., Schwander, Karen, Bentley, Amy R., Brown, Michael R., Guo, Xiuqing, Manning, Alisa, Chasman, Daniel I., Aschard, Hugues, Bartz, Traci M., Bielak, Lawrence F., Campbell, Archie, Cheng, Ching-Yu, Dorajoo, Rajkumar, Hartwig, Fernando P., Horimoto, A.R.V.R., Li, Changwei, Li-Gao, Ruifang, Liu, Yongmei, Marten, Jonathan, Musani, Solomon K., Ntalla, Ioanna, Rankinen, Tuomo, Richard, Melissa, Sim, Xueling, Smith, Albert V., Tajuddin, Salman M., Tayo, Bamidele O., Vojinovic, Dina, Warren, Helen R., Xuan, Deng, Alver, Maris, Boissel, Mathilde, Chai, Jin-Fang, Chen, Xu, Christensen, Kaare, Divers, Jasmin, Evangelou, Evangelos, Gao, Chuan, Girotto, Giorgia, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Kühnel, Brigitte, Laguzzi, Federica, Li, Xiaoyin, Lyytikäinen, Leo-Pekka, Nolte, Ilja M., Poveda, Alaitz, Rauramaa, Rainer, Riaz, Muhammad, Rueedi, Rico, Shu, Xiao-ou, Snieder, Harold, Sofer, Tamar, Takeuchi, Fumihiko, Verweij, Niek, Ware, Erin B., Weiss, Stefan, Yanek, Lisa R., Amin, Najaf, Arking, Dan E., Arnett, Donna K., Bergmann, Sven, Boerwinkle, Eric, Brody, Jennifer A., Broeckel, Ulrich, Brumat, Marco, Burke, Gregory, Cabrera, Claudia P., Canouil, Mickaël, Chee, Miao Li, Chen, Yii-Der Ida, Cocca, Massimiliano, Connell, John, de Silva, H. Janaka, de Vries, Paul S., Eiriksdottir, Gudny, Faul, Jessica D., Fisher, Virginia, Forrester, Terrence, Fox, Ervin F., Friedlander, Yechiel, Gao, He, Gigante, Bruna, Giulianini, Franco, Gu, Chi Charles, Gu, Dongfeng, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven, Ikram, M. Arfan, Irvin, Marguerite R., Kähönen, Mika, Kavousi, Maryam, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Komulainen, Pirjo, Kraja, Aldi T., Krieger, J.E., Langefeld, Carl D., Li, Yize, Liang, Jingjing, Liewald, David C. M., Liu, Ching-Ti, Liu, Jianjun, Lohman, Kurt K., Mägi, Reedik, McKenzie, Colin A., Meitinger, Thomas, Metspalu, Andres, Milaneschi, Yuri, Milani, Lili, Mook-Kanamori, Dennis O., Nalls, Mike A., Nelson, Christopher P., Norris, Jill M., O’Connell, Jeff, Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmer, Nicholette D., Pedersen, Nancy L., Perls, Thomas, Peters, Annette, Petersmann, Astrid, Peyser, Patricia A., Polasek, Ozren, Porteous, David J., Raffel, Leslie J., Rice, Treva K., Rotter, Jerome I., Rudan, Igor, Rueda-Ochoa, Oscar-Leonel, Sabanayagam, Charumathi, Salako, Babatunde L., Schreiner, Pamela J., Shikany, James M., Sidney, Stephen S., Sims, Mario, Sitlani, Colleen M., Smith, Jennifer A., Starr, John M., Strauch, Konstantin, Swertz, Morris A., Teumer, Alexander, Tham, Yih Chung, Uitterlinden, André G., Vaidya, Dhananjay, van der Ende, M. Yldau, Waldenberger, Melanie, Wang, Lihua, Wang, Ya-Xing, Wei, Wen-Bin, Weir, David R., Wen, Wanqing, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Bowden, Donald W., Deary, Ian J., Dörr, Marcus, Esko, Tõnu, Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Jonas, Jost Bruno, Kammerer, Candace M., Kato, Norihiro, Lakka, Timo A., Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K. E., Marques-Vidal, Pedro, Penninx, Brenda W. J. H., Samani, Nilesh J., van der Harst, Pim, Wagenknecht, Lynne E., Wu, Tangchun, Zheng, Wei, Zhu, Xiaofeng, Bouchard, Claude, Cooper, Richard S., Correa, Adolfo, Evans, Michele K., Gudnason, Vilmundur, Hayward, Caroline, Horta, Bernardo L., Kelly, Tanika N., Kritchevsky, Stephen B., Levy, Daniel, Palmas, Walter R., Pereira, A.C., Province, Michael M., Psaty, Bruce M., Ridker, Paul M., Rotimi, Charles N., Tai, E. Shyong, van Dam, Rob M., van Duijn, Cornelia M., Wong, Tien Yin, Rice, Kenneth, Gauderman, W. James, Morrison, Alanna C., North, Kari E., Kardia, Sharon L. R., Caulfield, Mark J., Elliott, Paul, Munroe, Patricia B., Franks, Paul W., Rao, Dabeeru C., and Fornage, Myriam
Abstract: Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
Published: 2021
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48. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Author: Vosa, U. (Urmo), Claringbould, A. (Annique), Westra, H.-J. (Harm-Jan), Bonder, M. J. (Marc Jan), Deelen, P. (Patrick), Zeng, B. (Biao), Kirsten, H. (Holger), Saha, A. (Ashis), Kreuzhuber, R. (Roman), Yazar, S. (Seyhan), Brugge, H. (Harm), Oelen, R. (Roy), de Vries, D. H. (Dylan H.), van der Wijst, M. G. (Monique G. P.), Kasela, S. (Silva), Pervjakova, N. (Natalia), Alves, I. (Isabel), Fave, M.-J. (Marie-Julie), Agbessi, M. (Mawusse), Christiansen, M. W. (Mark W.), Jansen, R. (Rick), Seppala, I. (Ilkka), Tong, L. (Lin), Teumer, A. (Alexander), Schramm, K. (Katharina), Hemani, G. (Gibran), Verlouw, J. (Joost), Yaghootkar, H. (Hanieh), Flitman, R. S. (Reyhan Sonmez), Brown, A. (Andrew), Kukushkina, V. (Viktorija), Kalnapenkis, A. (Anette), Rueger, S. (Sina), Porcu, E. (Eleonora), Kronberg, J. (Jaanika), Kettunen, J. (Johannes), Lee, B. (Bernett), Zhang, F. (Futao), Qi, T. (Ting), Hernandez, J. A. (Jose Alquicira), Arindrarto, W. (Wibowo), Beutner, F. (Frank), Dmitrieva, J. (Julia), Elansary, M. (Mahmoud), Fairfax, B. P. (Benjamin P.), Georges, M. (Michel), Heijmans, B. T. (Bastiaan T.), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Kim, Y. (Yungil), Knight, J. C. (Julian C.), Kovacs, P. (Peter), Krohn, K. (Knut), Li, S. (Shuang), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Momozawa, Y. (Yukihide), Mueller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. G. (Michel G.), Penninx, B. W. (Brenda W. J. H.), Pritchard, J. K. (Jonathan K.), Raitakari, O. T. (Olli T.), Rotzschke, O. (Olaf), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Thiery, J. (Joachim), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), Veldink, J. H. (Jan H.), Voelker, U. (Uwe), Warmerdam, R. (Robert), Wijmenga, C. (Cisca), Swertz, M. (Morris), Andiappan, A. (Anand), Montgomery, G. W. (Grant W.), Ripatti, S. (Samuli), Perola, M. (Markus), Kutalik, Z. (Zoltan), Dermitzakis, E. (Emmanouil), Bergmann, S. (Sven), Frayling, T. (Timothy), van Meurs, J. (Joyce), Prokisch, H. (Holger), Ahsan, H. (Habibul), Pierce, B. L. (Brandon L.), Lehtimaki, T. (Terho), Boomsma, D. I. (Dorret, I), Psaty, B. M. (Bruce M.), Gharib, S. A. (Sina A.), Awadalla, P. (Philip), Milani, L. (Lili), Ouwehand, W. H. (Willem H.), Downes, K. (Kate), Stegle, O. (Oliver), Battle, A. (Alexis), Visscher, P. M. (Peter M.), Yang, J. (Jian), Scholz, M. (Markus), Powell, J. (Joseph), Gibson, G. (Greg), Esko, T. (Tonu), Franke, L. (Lude), Vosa, U. (Urmo), Claringbould, A. (Annique), Westra, H.-J. (Harm-Jan), Bonder, M. J. (Marc Jan), Deelen, P. (Patrick), Zeng, B. (Biao), Kirsten, H. (Holger), Saha, A. (Ashis), Kreuzhuber, R. (Roman), Yazar, S. (Seyhan), Brugge, H. (Harm), Oelen, R. (Roy), de Vries, D. H. (Dylan H.), van der Wijst, M. G. (Monique G. P.), Kasela, S. (Silva), Pervjakova, N. (Natalia), Alves, I. (Isabel), Fave, M.-J. (Marie-Julie), Agbessi, M. (Mawusse), Christiansen, M. W. (Mark W.), Jansen, R. (Rick), Seppala, I. (Ilkka), Tong, L. (Lin), Teumer, A. (Alexander), Schramm, K. (Katharina), Hemani, G. (Gibran), Verlouw, J. (Joost), Yaghootkar, H. (Hanieh), Flitman, R. S. (Reyhan Sonmez), Brown, A. (Andrew), Kukushkina, V. (Viktorija), Kalnapenkis, A. (Anette), Rueger, S. (Sina), Porcu, E. (Eleonora), Kronberg, J. (Jaanika), Kettunen, J. (Johannes), Lee, B. (Bernett), Zhang, F. (Futao), Qi, T. (Ting), Hernandez, J. A. (Jose Alquicira), Arindrarto, W. (Wibowo), Beutner, F. (Frank), Dmitrieva, J. (Julia), Elansary, M. (Mahmoud), Fairfax, B. P. (Benjamin P.), Georges, M. (Michel), Heijmans, B. T. (Bastiaan T.), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Kim, Y. (Yungil), Knight, J. C. (Julian C.), Kovacs, P. (Peter), Krohn, K. (Knut), Li, S. (Shuang), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Momozawa, Y. (Yukihide), Mueller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. G. (Michel G.), Penninx, B. W. (Brenda W. J. H.), Pritchard, J. K. (Jonathan K.), Raitakari, O. T. (Olli T.), Rotzschke, O. (Olaf), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Thiery, J. (Joachim), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), Veldink, J. H. (Jan H.), Voelker, U. (Uwe), Warmerdam, R. (Robert), Wijmenga, C. (Cisca), Swertz, M. (Morris), Andiappan, A. (Anand), Montgomery, G. W. (Grant W.), Ripatti, S. (Samuli), Perola, M. (Markus), Kutalik, Z. (Zoltan), Dermitzakis, E. (Emmanouil), Bergmann, S. (Sven), Frayling, T. (Timothy), van Meurs, J. (Joyce), Prokisch, H. (Holger), Ahsan, H. (Habibul), Pierce, B. L. (Brandon L.), Lehtimaki, T. (Terho), Boomsma, D. I. (Dorret, I), Psaty, B. M. (Bruce M.), Gharib, S. A. (Sina A.), Awadalla, P. (Philip), Milani, L. (Lili), Ouwehand, W. H. (Willem H.), Downes, K. (Kate), Stegle, O. (Oliver), Battle, A. (Alexis), Visscher, P. M. (Peter M.), Yang, J. (Jian), Scholz, M. (Markus), Powell, J. (Joseph), Gibson, G. (Greg), Esko, T. (Tonu), and Franke, L. (Lude)
Abstract: Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
Published: 2021

49. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Lagou, V. (Vasiliki), Maegi, R. (Reedik), Hottenga, J. J. (Jouke- Jan), Grallert, H. (Harald), Perry, J. R. (John R. B.), Bouatia-Naji, N. (Nabila), Marullo, L. (Letizia), Rybin, D. (Denis), Jansen, R. (Rick), Min, J. L. (Josine L.), Dimas, A. S. (Antigone S.), Ulrich, A. (Anna), Zudina, L. (Liudmila), Gadin, J. R. (Jesper R.), Jiang, L. (Longda), Faggian, A. (Alessia), Bonnefond, A. (Amelie), Fadista, J. (Joao), Stathopoulou, M. G. (Maria G.), Isaacs, A. (Aaron), Willems, S. M. (Sara M.), Navarro, P. (Pau), Tanaka, T. (Toshiko), Jackson, A. U. (Anne U.), Montasser, M. E. (May E.), O'Connell, J. R. (Jeff R.), Bielak, L. F. (Lawrence F.), Webster, R. J. (Rebecca J.), Saxena, R. (Richa), Stafford, J. M. (Jeanette M.), Pourcain, B. S. (Beate St), Timpson, N. J. (Nicholas J.), Salo, P. (Perttu), Shin, S.-Y. (So-Youn), Amin, N. (Najaf), Smith, A. V. (Albert V.), Li, G. (Guo), Verweij, N. (Niek), Goel, A. (Anuj), Ford, I. (Ian), Johnson, P. C. (Paul C. D.), Johnson, T. (Toby), Kapur, K. (Karen), Thorleifsson, G. (Gudmar), Strawbridge, R. J. (Rona J.), Rasmussen-Torvik, L. J. (Laura J.), Esko, T. (Tonu), Mihailov, E. (Evelin), Fall, T. (Tove), Fraser, R. M. (Ross M.), Mahajan, A. (Anubha), Kanoni, S. (Stavroula), Giedraitis, V. (Vilmantas), Kleber, M. E. (Marcus E.), Silbernagel, G. (Guenther), Meyer, J. (Julia), Mueller-Nurasyid, M. (Martina), Ganna, A. (Andrea), Sarin, A.-P. (Antti-Pekka), Yengo, L. (Loic), Shungin, D. (Dmitry), Luan, J. (Jian'an), Horikoshi, M. (Momoko), An, P. (Ping), Sanna, S. (Serena), Boettcher, Y. (Yvonne), Rayner, N. W. (N. William), Nolte, I. M. (Ilja M.), Zemunik, T. (Tatijana), Iperen, E. v. (Erik van), Kovacs, P. (Peter), Hastie, N. D. (Nicholas D.), Wild, S. H. (Sarah H.), McLachlan, S. (Stela), Campbell, S. (Susan), Polasek, O. (Ozren), Carlson, O. (Olga), Egan, J. (Josephine), Kiess, W. (Wieland), Willemsen, G. (Gonneke), Kuusisto, J. (Johanna), Laakso, M. (Markku), Dimitriou, M. (Maria), Hicks, A. A. (Andrew A.), Rauramaa, R. (Rainer), Bandinelli, S. (Stefania), Thorand, B. (Barbara), Liu, Y. (Yongmei), Miljkovic, I. (Iva), Lind, L. (Lars), Doney, A. (Alex), Perola, M. (Markus), Hingorani, A. (Aroon), Kivimaki, M. (Mika), Kumari, M. (Meena), Bennett, A. J. (Amanda J.), Groves, C. J. (Christopher J.), Herder, C. (Christian), Koistinen, H. A. (Heikki A.), Kinnunen, L. (Leena), Faire, U. d. (Ulf de), Bakker, S. J. (Stephan J. L.), Uusitupa, M. (Matti), Palmer, C. N. (Colin N. A.), Jukema, J. W. (J. Wouter), Sattar, N. (Naveed), Pouta, A. (Anneli), Snieder, H. (Harold), Boerwinkle, E. (Eric), Pankow, J. S. (James S.), Magnusson, P. K. (Patrik K.), Krus, U. (Ulrika), Scapoli, C. (Chiara), de Geus, E. J. (Eco J. C. N.), Blueher, M. (Matthias), Wolffenbuttel, B. H. (Bruce H. R.), Province, M. A. (Michael A.), Abecasis, G. R. (Goncalo R.), Meigs, J. B. (James B.), Hovingh, G. K. (G. Kees), Lindstroem, J. (Jaana), Wilson, J. F. (James F.), Wright, A. F. (Alan F.), Dedoussis, G. V. (George V.), Bornstein, S. R. (Stefan R.), Schwarz, P. E. (Peter E. H.), Toenjes, A. (Anke), Winkelmann, B. R. (Bernhard R.), Boehm, B. O. (Bernhard O.), Maerz, W. (Winfried), Metspalu, A. (Andres), Price, J. F. (Jackie F.), Deloukas, P. (Panos), Koerner, A. (Antje), Lakka, T. A. (Timo A.), Keinanen-Kiukaanniemi, S. M. (Sirkka M.), Saaristo, T. E. (Timo E.), Bergman, R. N. (Richard N.), Tuomilehto, J. (Jaakko), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Maennistoe, S. (Satu), Franks, P. W. (Paul W.), Hayward, C. (Caroline), Vitart, V. (Veronique), Kaprio, J. (Jaakko), Visvikis-Siest, S. (Sophie), Balkau, B. (Beverley), Altshuler, D. (David), Rudan, I. (Igor), Stumvoll, M. (Michael), Campbell, H. (Harry), van Duijn, C. M. (Cornelia M.), Gieger, C. (Christian), Illig, T. (Thomas), Ferrucci, L. (Luigi), Pedersen, N. L. (Nancy L.), Pramstaller, P. P. (Peter P.), Boehnke, M. (Michael), Frayling, T. M. (Timothy M.), Shuldiner, A. R. (Alan R.), Peyser, P. A. (Patricia A.), Kardia, S. L. (Sharon L. R.), Palmer, L. J. (Lyle J.), Penninx, B. W. (Brenda W.), Meneton, P. (Pierre), Harris, T. B. (Tamara B.), Navis, G. (Gerjan), Harst, P. v. (Pim van der), Smith, G. D. (George Davey), Forouhi, N. G. (Nita G.), Loos, R. J. (Ruth J. F.), Salomaa, V. (Veikko), Soranzo, N. (Nicole), Boomsma, D. I. (Dorret I.), Groop, L. (Leif), Tuomi, T. (Tiinamaija), Hofman, A. (Albert), Munroe, P. B. (Patricia B.), Gudnason, V. (Vilmundur), Siscovick, D. S. (David S.), Watkins, H. (Hugh), Lecoeur, C. (Cecile), Vollenweider, P. (Peter), Franco-Cereceda, A. (Anders), Eriksson, P. (Per), Jarvelin, M.-R. (Marjo-Riitta), Stefansson, K. (Kari), Hamsten, A. (Anders), Nicholson, G. (George), Karpe, F. (Fredrik), Dermitzakis, E. T. (Emmanouil T.), Lindgren, C. M. (Cecilia M.), McCarthy, M. I. (Mark I.), Froguel, P. (Philippe), Kaakinen, M. A. (Marika A.), Lyssenko, V. (Valeriya), Watanabe, R. M. (Richard M.), Ingelsson, E. (Erik), Florez, J. C. (Jose C.), Dupuis, J. (Josee), Barroso, I. (Ines), Morris, A. P. (Andrew P.), Prokopenko, I. (Inga), Lagou, V. (Vasiliki), Maegi, R. (Reedik), Hottenga, J. J. (Jouke- Jan), Grallert, H. (Harald), Perry, J. R. (John R. B.), Bouatia-Naji, N. (Nabila), Marullo, L. (Letizia), Rybin, D. (Denis), Jansen, R. (Rick), Min, J. L. (Josine L.), Dimas, A. S. (Antigone S.), Ulrich, A. (Anna), Zudina, L. (Liudmila), Gadin, J. R. (Jesper R.), Jiang, L. (Longda), Faggian, A. (Alessia), Bonnefond, A. (Amelie), Fadista, J. (Joao), Stathopoulou, M. G. (Maria G.), Isaacs, A. (Aaron), Willems, S. M. (Sara M.), Navarro, P. (Pau), Tanaka, T. (Toshiko), Jackson, A. U. (Anne U.), Montasser, M. E. (May E.), O'Connell, J. R. (Jeff R.), Bielak, L. F. (Lawrence F.), Webster, R. J. (Rebecca J.), Saxena, R. (Richa), Stafford, J. M. (Jeanette M.), Pourcain, B. S. (Beate St), Timpson, N. J. (Nicholas J.), Salo, P. (Perttu), Shin, S.-Y. (So-Youn), Amin, N. (Najaf), Smith, A. V. (Albert V.), Li, G. (Guo), Verweij, N. (Niek), Goel, A. (Anuj), Ford, I. (Ian), Johnson, P. C. (Paul C. D.), Johnson, T. (Toby), Kapur, K. (Karen), Thorleifsson, G. (Gudmar), Strawbridge, R. J. (Rona J.), Rasmussen-Torvik, L. J. (Laura J.), Esko, T. (Tonu), Mihailov, E. (Evelin), Fall, T. (Tove), Fraser, R. M. (Ross M.), Mahajan, A. (Anubha), Kanoni, S. (Stavroula), Giedraitis, V. (Vilmantas), Kleber, M. E. (Marcus E.), Silbernagel, G. (Guenther), Meyer, J. (Julia), Mueller-Nurasyid, M. (Martina), Ganna, A. (Andrea), Sarin, A.-P. (Antti-Pekka), Yengo, L. (Loic), Shungin, D. (Dmitry), Luan, J. (Jian'an), Horikoshi, M. (Momoko), An, P. (Ping), Sanna, S. (Serena), Boettcher, Y. (Yvonne), Rayner, N. W. (N. William), Nolte, I. M. (Ilja M.), Zemunik, T. (Tatijana), Iperen, E. v. (Erik van), Kovacs, P. (Peter), Hastie, N. D. (Nicholas D.), Wild, S. H. (Sarah H.), McLachlan, S. (Stela), Campbell, S. (Susan), Polasek, O. (Ozren), Carlson, O. (Olga), Egan, J. (Josephine), Kiess, W. (Wieland), Willemsen, G. (Gonneke), Kuusisto, J. (Johanna), Laakso, M. (Markku), Dimitriou, M. (Maria), Hicks, A. A. (Andrew A.), Rauramaa, R. (Rainer), Bandinelli, S. (Stefania), Thorand, B. (Barbara), Liu, Y. (Yongmei), Miljkovic, I. (Iva), Lind, L. (Lars), Doney, A. (Alex), Perola, M. (Markus), Hingorani, A. (Aroon), Kivimaki, M. (Mika), Kumari, M. (Meena), Bennett, A. J. (Amanda J.), Groves, C. J. (Christopher J.), Herder, C. (Christian), Koistinen, H. A. (Heikki A.), Kinnunen, L. (Leena), Faire, U. d. (Ulf de), Bakker, S. J. (Stephan J. L.), Uusitupa, M. (Matti), Palmer, C. N. (Colin N. A.), Jukema, J. W. (J. Wouter), Sattar, N. (Naveed), Pouta, A. (Anneli), Snieder, H. (Harold), Boerwinkle, E. (Eric), Pankow, J. S. (James S.), Magnusson, P. K. (Patrik K.), Krus, U. (Ulrika), Scapoli, C. (Chiara), de Geus, E. J. (Eco J. C. N.), Blueher, M. (Matthias), Wolffenbuttel, B. H. (Bruce H. R.), Province, M. A. (Michael A.), Abecasis, G. R. (Goncalo R.), Meigs, J. B. (James B.), Hovingh, G. K. (G. Kees), Lindstroem, J. (Jaana), Wilson, J. F. (James F.), Wright, A. F. (Alan F.), Dedoussis, G. V. (George V.), Bornstein, S. R. (Stefan R.), Schwarz, P. E. (Peter E. H.), Toenjes, A. (Anke), Winkelmann, B. R. (Bernhard R.), Boehm, B. O. (Bernhard O.), Maerz, W. (Winfried), Metspalu, A. (Andres), Price, J. F. (Jackie F.), Deloukas, P. (Panos), Koerner, A. (Antje), Lakka, T. A. (Timo A.), Keinanen-Kiukaanniemi, S. M. (Sirkka M.), Saaristo, T. E. (Timo E.), Bergman, R. N. (Richard N.), Tuomilehto, J. (Jaakko), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Maennistoe, S. (Satu), Franks, P. W. (Paul W.), Hayward, C. (Caroline), Vitart, V. (Veronique), Kaprio, J. (Jaakko), Visvikis-Siest, S. (Sophie), Balkau, B. (Beverley), Altshuler, D. (David), Rudan, I. (Igor), Stumvoll, M. (Michael), Campbell, H. (Harry), van Duijn, C. M. (Cornelia M.), Gieger, C. (Christian), Illig, T. (Thomas), Ferrucci, L. (Luigi), Pedersen, N. L. (Nancy L.), Pramstaller, P. P. (Peter P.), Boehnke, M. (Michael), Frayling, T. M. (Timothy M.), Shuldiner, A. R. (Alan R.), Peyser, P. A. (Patricia A.), Kardia, S. L. (Sharon L. R.), Palmer, L. J. (Lyle J.), Penninx, B. W. (Brenda W.), Meneton, P. (Pierre), Harris, T. B. (Tamara B.), Navis, G. (Gerjan), Harst, P. v. (Pim van der), Smith, G. D. (George Davey), Forouhi, N. G. (Nita G.), Loos, R. J. (Ruth J. F.), Salomaa, V. (Veikko), Soranzo, N. (Nicole), Boomsma, D. I. (Dorret I.), Groop, L. (Leif), Tuomi, T. (Tiinamaija), Hofman, A. (Albert), Munroe, P. B. (Patricia B.), Gudnason, V. (Vilmundur), Siscovick, D. S. (David S.), Watkins, H. (Hugh), Lecoeur, C. (Cecile), Vollenweider, P. (Peter), Franco-Cereceda, A. (Anders), Eriksson, P. (Per), Jarvelin, M.-R. (Marjo-Riitta), Stefansson, K. (Kari), Hamsten, A. (Anders), Nicholson, G. (George), Karpe, F. (Fredrik), Dermitzakis, E. T. (Emmanouil T.), Lindgren, C. M. (Cecilia M.), McCarthy, M. I. (Mark I.), Froguel, P. (Philippe), Kaakinen, M. A. (Marika A.), Lyssenko, V. (Valeriya), Watanabe, R. M. (Richard M.), Ingelsson, E. (Erik), Florez, J. C. (Jose C.), Dupuis, J. (Josee), Barroso, I. (Ines), Morris, A. P. (Andrew P.), and Prokopenko, I. (Inga)
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
Published: 2021

50. Identifying causative mechanisms linking early-life stress to psycho-cardio-metabolic multi-morbidity:the EarlyCause project

Author: Mariani, N. (Nicole), Borsini, A. (Alessandra), Cecil, C. A. (Charlotte A. M.), Felix, J. F. (Janine F.), Sebert, S. (Sylvain), Cattaneo, A. (Annamaria), Walton, E. (Esther), Milaneschi, Y. (Yuri), Cochrane, G. (Guy), Amid, C. (Clara), Rajan, J. (Jeena), Giacobbe, J. (Juliette), Sanz, Y. (Yolanda), Agusti, A. (Ana), Sorg, T. (Tania), Herault, Y. (Yann), Miettunen, J. (Jouko), Parmar, P. (Priyanka), Cattane, N. (Nadia), Jaddoe, V. (Vincent), Lotjonen, J. (Jyrki), Buisan, C. (Carme), Gonzalez Ballester, M. A. (Miguel A.), Piella, G. (Gemma), Gelpi, J. L. (Josep L.), Lamers, F. (Femke), Penninx, B. W. (Brenda W. J. H.), Tiemeier, H. (Henning), von Tottleben, M. (Malte), Thiel, R. (Rainer), Heil, K. F. (Katharina F.), Jarvelin, M.-R. (Marjo-Riitta), Pariante, C. (Carmine), Mansuy, I. M. (Isabelle M.), Lekadir, K. (Karim), Mariani, N. (Nicole), Borsini, A. (Alessandra), Cecil, C. A. (Charlotte A. M.), Felix, J. F. (Janine F.), Sebert, S. (Sylvain), Cattaneo, A. (Annamaria), Walton, E. (Esther), Milaneschi, Y. (Yuri), Cochrane, G. (Guy), Amid, C. (Clara), Rajan, J. (Jeena), Giacobbe, J. (Juliette), Sanz, Y. (Yolanda), Agusti, A. (Ana), Sorg, T. (Tania), Herault, Y. (Yann), Miettunen, J. (Jouko), Parmar, P. (Priyanka), Cattane, N. (Nadia), Jaddoe, V. (Vincent), Lotjonen, J. (Jyrki), Buisan, C. (Carme), Gonzalez Ballester, M. A. (Miguel A.), Piella, G. (Gemma), Gelpi, J. L. (Josep L.), Lamers, F. (Femke), Penninx, B. W. (Brenda W. J. H.), Tiemeier, H. (Henning), von Tottleben, M. (Malte), Thiel, R. (Rainer), Heil, K. F. (Katharina F.), Jarvelin, M.-R. (Marjo-Riitta), Pariante, C. (Carmine), Mansuy, I. M. (Isabelle M.), and Lekadir, K. (Karim)
Abstract: Introduction: Depression, cardiovascular diseases and diabetes are among the major non-communicable diseases, leading to significant disability and mortality worldwide. These diseases may share environmental and genetic determinants associated with multimorbid patterns. Stressful early-life events are among the primary factors associated with the development of mental and physical diseases. However, possible causative mechanisms linking early life stress (ELS) with psycho-cardio-metabolic (PCM) multi-morbidity are not well understood. This prevents a full understanding of causal pathways towards the shared risk of these diseases and the development of coordinated preventive and therapeutic interventions. Methods and analysis: This paper describes the study protocol for EarlyCause, a large-scale and inter-disciplinary research project funded by the European Union’s Horizon 2020 research and innovation programme. The project takes advantage of human longitudinal birth cohort data, animal studies and cellular models to test the hypothesis of shared mechanisms and molecular pathways by which ELS shapes an individual’s physical and mental health in adulthood. The study will research in detail how ELS converts into biological signals embedded simultaneously or sequentially in the brain, the cardiovascular and metabolic systems. The research will mainly focus on four biological processes including possible alterations of the epigenome, neuroendocrine system, inflammatome, and the gut microbiome. Life-course models will integrate the role of modifying factors as sex, socioeconomics, and lifestyle with the goal to better identify groups at risk as well as inform promising strategies to reverse the possible mechanisms and/or reduce the impact of ELS on multi-morbidity development in high-risk individuals. These strategies will help better manage the impact of multi-morbidity on human health and the associated risk.
Published: 2021

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