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2. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Author

Jia, Xiaoming, Goes, Fernando S, Locke, Adam E, Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U, Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M, Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Gonçalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Juréus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z, Levy, Shawn E, Monson, Eric T, Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zöllner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M, Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A, Richard McCombie, W, McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M, O'Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B, Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F, Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A, Zandi, Peter P, and Scott, Laura J

Subjects
Humans, Genetic Predisposition to Disease, Bipolar Disorder, Schizophrenia, Polymorphism, Single Nucleotide, Genetic Variation, Genome-Wide Association Study, Exome, Brain Disorders, Prevention, Clinical Research, Human Genome, Serious Mental Illness, Genetics, Mental Health, 2.1 Biological and endogenous factors, Mental health, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

Published
2021

3. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Marshall, Christian R., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wang, Zhouzhi, Scherer, Stephen W., Howrigan, Daniel P, Ripke, Stephan, Bulik-Sullivan, Brendan, Farh, Kai-How, Fromer, Menachem, Goldstein, Jacqueline I., Huang, Hailiang, Lee, Phil, Daly, Mark J., Neale, Benjamin M., Belliveau, Richard A., Jr., Bergen, Sarah E., Bevilacqua, Elizabeth, Chambert, Kimberley D., O'Dushlaine, Colm, Scolnick, Edward M., Smoller, Jordan W., Moran, Jennifer L., Palotie, Aarno, Petryshen, Tracey L., Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Fuentes Fajarado, Karin V., Maile, Michelle S., Holmans, Peter A., Carrera, Noa, Craddock, Nick, Escott-Price, Valentina, Georgieva, Lyudmila, Hamshere, Marian L., Kavanagh, David, Legge, Sophie E., Pocklington, Andrew J., Richards, Alexander L., Ruderfer, Douglas M., Williams, Nigel M., Kirov, George, Owen, Michael J., Pinto, Dalila, Cai, Guiqing, Davis, Kenneth L., Drapeau, Elodie, Friedman, Joseph I, Haroutunian, Vahram, Parkhomenko, Elena, Reichenberg, Abraham, Silverman, Jeremy M., Buxbaum, Joseph D., Domenici, Enrico, Agartz, Ingrid, Djurovic, Srdjan, Mattingsdal, Morten, Melle, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Söderman, Erik, Albus, Margot, Alexander, Madeline, Laurent, Claudine, Levinson, Douglas F., Amin, Farooq, Atkins, Joshua, Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Wu, Jing Qin, Bacanu, Silviu A., Bigdeli, Tim B., Reimers, Mark A., Webb, Bradley T., Wolen, Aaron R., Wormley, Brandon K., Kendler, Kenneth S., Riley, Brien P., Kähler, Anna K., Magnusson, Patrik K.E., Hultman, Christina M., Bertalan, Marcelo, Hansen, Thomas, Olsen, Line, Rasmussen, Henrik B., Werge, Thomas, Mattheisen, Manuel, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Roffman, Joshua L., Byerley, William, Cahn, Wiepke, Kahn, René S, Strengman, Eric, Ophoff, Roel A., Carr, Vaughan J., Catts, Stanley V., Henskens, Frans A., Loughland, Carmel M., Michie, Patricia T., Pantelis, Christos, Schall, Ulrich, Jablensky, Assen V., Kelly, Brian J., Campion, Dominique, Cantor, Rita M., Cheng, Wei, Cloninger, C. Robert, Svrakic, Dragan M, Cohen, David, Cormican, Paul, Donohoe, Gary, Morris, Derek W., Corvin, Aiden, Gill, Michael, Crespo-Facorro, Benedicto, Crowley, James J., Farrell, Martilias S., Giusti-Rodríguez, Paola, Kim, Yunjung, Szatkiewicz, Jin P., Williams, Stephanie, Curtis, David, Pimm, Jonathan, Gurling, Hugh, McQuillin, Andrew, Davidson, Michael, Weiser, Mark, Degenhardt, Franziska, Forstner, Andreas J., Herms, Stefan, Hoffmann, Per, Hofman, Andrea, Cichon, Sven, Nöthen, Markus M., Del Favero, Jurgen, DeLisi, Lynn E., McCarley, Robert W., Levy, Deborah L., Mesholam-Gately, Raquelle I., Seidman, Larry J., Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Duan, Jubao, Sanders, Alan R., Gejman, Pablo V., Gershon, Elliot S., Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Salomaa, Veikko, Essioux, Laurent, Fanous, Ayman H., Knowles, James A., Pato, Michele T., Pato, Carlos N., Frank, Josef, Meier, Sandra, Schulze, Thomas G., Strohmaier, Jana, Witt, Stephanie H., Rietschel, Marcella, Franke, Lude, Karjalainen, Juha, Freedman, Robert, Olincy, Ann, Freimer, Nelson B., Purcell, Shaun M., Roussos, Panos, Stahl, Eli A., Sklar, Pamela, Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Godard, Stephanie, Hirschhorn, Joel N., Pers, Tune H., Price, Alkes, Esko, Tõnu, Gratten, Jacob, Lee, S. Hong, Visscher, Peter M., Wray, Naomi R., Mowry, Bryan J., de Haan, Lieuwe, Meijer, Carin J., Hansen, Mark, Ikeda, Masashi, Iwata, Nakao, Joa, Inge, Kalaydjieva, Luba, Keller, Matthew C., Kennedy, James L., Zai, Clement C., Knight, Jo, Lerer, Bernard, Liang, Kung-Yee, Lieberman, Jeffrey, Stroup, T. Scott, Lönnqvist, Jouko, Suvisaari, Jaana, Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, McDonald, Colm, McIntosh, Andrew M., Blackwood, Douglas H.R., Metspalu, Andres, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Collier, David A., Müller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Powell, John, Myin-Germeys, Inez, Van Os, Jim, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Pulver, Ann E., Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, Adolfsson, Rolf, O'Callaghan, Eadbhard, Oh, Sang-Yun, O'Neill, F. Anthony, Paunio, Tiina, Pietiläinen, Olli, Perkins, Diana O., Quested, Digby, Savitz, Adam, Li, Qingqin S., Schwab, Sibylle G., Shi, Jianxin, Spencer, Chris C.A., Thirumalai, Srinivas, Veijola, Juha, Waddington, John, Walsh, Dermot, Wildenauer, Dieter B., Bramon, Elvira, Darvasi, Ariel, Posthuma, Danielle, St. Clair, David, Shanta, Omar, Klein, Marieke, Park, Peter J., Weinberger, Daniel, Moran, John V., Gage, Fred H., Vaccarino, Flora M., Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Bizzotto, Sara, Coulter, Michael, Dias, Caroline, D'Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lodato, Michael, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Abyzov, Alexej, Bae, Taejeong, Jang, Yeongjun, Wang, Yifan, Gage, Fred, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Pattni, Reenal, Amero, Aitor Serres, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Moruno, Manuel Solis, Perez, Raquel Garcia, Povolotskaya, Inna, Soriano, Eduardo, Averbuj, Dan, Ball, Laurel, Breuss, Martin, Yang, Xiaoxu, Chung, Changuk, Emery, Sarah B., Flasch, Diane A., Kidd, Jeffrey M., Kopera, Huira C., Kwan, Kenneth Y., Mills, Ryan E., Moldovan, John B., Sun, Chen, Zhao, Xuefang, Zhou, Weichen, Frisbie, Trenton J., Cherskov, Adriana, Fasching, Liana, Jourdon, Alexandre, Pochareddy, Sirisha, Scuderi, Soraya, Sestan, Nenad, Maury, Eduardo A., Sherman, Maxwell A., Genovese, Giulio, Gilgenast, Thomas G., Kamath, Tushar, Burris, S.J., Rajarajan, Prashanth, Flaherty, Erin, Akbarian, Schahram, Chess, Andrew, McCarroll, Steven A., Loh, Po-Ru, Phillips-Cremins, Jennifer E., Brennand, Kristen J., Macosko, Evan Z., Walters, James T.R., O’Donovan, Michael, Sullivan, Patrick, Sebat, Jonathan, Lee, Eunjung A., and Walsh, Christopher A.

Published
2023
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5. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Author

Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T.R., Farh, Kai-How, Holmans, Peter A., Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A., Jr., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberley D., Chan, Raymond C.K., Chan, Ronald Y.L., Chen, Eric Y.H., Cheng, Wei, Cheung, Eric FC., Chong, Siow Ann, Cloninger, C. Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kahn, René S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Lee, Jimmy, Lee, S. Hong, Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Magnusson, Patrik K.E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon-Cheong, Spencer, Chris C.A., Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wong, Emily H.M., Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H.R., Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jönsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Nöthen, Markus M., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P., Rujescu, Dan, Sham, Pak C., Sklar, Pamela, St Clair, David, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., Sullivan, Patrick F., O'Donovan, Michael C., Qin, Shengying, Sawa, Akira, Kahn, Rene, Hong, Kyung Sue, Shi, Wenzhao, Tsuang, Ming, Itokawa, Masanari, Feng, Gang, Glatt, Stephen J., Ma, Xiancang, Tang, Jinsong, Ruan, Yunfeng, Liu, Ruize, Zhu, Feng, Horiuchi, Yasue, Lee, Byung Dae, Joo, Eun-Jeong, Myung, Woojae, Ha, Kyooseob, Won, Hong-Hee, Baek, Ji Hyung, Chung, Young Chul, Kim, Sung-Wan, Kusumawardhani, Agung, Chen, Wei J., Hwu, Hai-Gwo, Hishimoto, Akitoyo, Otsuka, Ikuo, Sora, Ichiro, Toyota, Tomoko, Yoshikawa, Takeo, Kunugi, Hiroshi, Hattori, Kotaro, Ishiwata, Sayuri, Numata, Shusuke, Ohmori, Tetsuro, Arai, Makoto, Ozeki, Yuji, Fujii, Kumiko, Kim, Se Joo, Lee, Heon-Jeong, Ahn, Yong Min, Kim, Se Hyun, Akiyama, Kazufumi, Shimoda, Kazutaka, Kinoshita, Makoto, Hsu, Yu-Han H., Pintacuda, Greta, Nacu, Eugeniu, Kim, April, Tsafou, Kalliopi, Petrossian, Natalie, Crotty, William, Suh, Jung Min, Riseman, Jackson, Martin, Jacqueline M., Biagini, Julia C., Mena, Daya, Ching, Joshua K.T., Malolepsza, Edyta, Li, Taibo, Singh, Tarjinder, Ge, Tian, Egri, Shawn B., Tanenbaum, Benjamin, Stanclift, Caroline R., Apffel, Annie M., Carr, Steven A., Schenone, Monica, Jaffe, Jake, Fornelos, Nadine, Eggan, Kevin C., and Lage, Kasper

Published
2023
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6. Convergent coexpression of autism-associated genes suggests some novel risk genes may not be detectable in large-scale genetic studies

Author

Liao, Calwing, Moyses-Oliveira, Mariana, De Esch, Celine E.F., Bhavsar, Riya, Nuttle, Xander, Li, Aiqun, Yu, Alex, Burt, Nicholas D., Erdin, Serkan, Fu, Jack M., Wang, Minghui, Morley, Theodore, Han, Lide, Dion, Patrick A., Rouleau, Guy A., Zhang, Bin, Brennand, Kristen J., Talkowski, Michael E., and Ruderfer, Douglas M.

Published
2023
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7. Genetic variants and functional pathways associated with resilience to Alzheimer’s disease

Author

Dumitrescu, Logan, Mahoney, Emily R, Mukherjee, Shubhabrata, Lee, Michael L, Bush, William S, Engelman, Corinne D, Lu, Qiongshi, Fardo, David W, Trittschuh, Emily H, Mez, Jesse, Kaczorowski, Catherine, Saucedo, Hector Hernandez, Widaman, Keith F, Buckley, Rachel, Properzi, Michael, Mormino, Elizabeth, Yang, Hyun-Sik, Harrison, Tessa, Hedden, Trey, Nho, Kwangsik, Andrews, Shea J, Tommet, Doug, Hadad, Niran, Sanders, R Elizabeth, Ruderfer, Douglas M, Gifford, Katherine A, Moore, Annah M, Cambronero, Francis, Zhong, Xiaoyuan, Raghavan, Neha S, Vardarajan, Badri, Initiative, The Alzheimer’s Disease Neuroimaging, Consortium, A4 Study Team Alzheimer’s Disease Genetics, Pericak-Vance, Margaret A, Farrer, Lindsay A, Wang, Li-San, Cruchaga, Carlos, Schellenberg, Gerard, Cox, Nancy J, Haines, Jonathan L, Keene, C Dirk, Saykin, Andrew J, Larson, Eric B, Sperling, Reisa A, Mayeux, Richard, Bennett, David A, Schneider, Julie A, Crane, Paul K, Jefferson, Angela L, and Hohman, Timothy J

Subjects
Biological Psychology, Health Sciences, Psychology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Clinical Trials and Supportive Activities, Genetics, Dementia, Aging, Acquired Cognitive Impairment, Behavioral and Social Science, Brain Disorders, Clinical Research, Neurodegenerative, Human Genome, Alzheimer's Disease, Prevention, 2.1 Biological and endogenous factors, Aetiology, Neurological, Good Health and Well Being, Aged, 80 and over, Alzheimer Disease, Brain, Chromosomes, Human, Pair 18, Cognitive Dysfunction, Cognitive Reserve, Female, Genome-Wide Association Study, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Alzheimer's disease, amyloid, resilience, GWAS, reserve, Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Genetics Consortium (ADGC), A4 Study Team, Alzheimer’s disease, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.

Published
2020

8. Genome-Wide Association Study of Treatment-Resistant Depression: Shared Biology With Metabolic Traits

Author

Kang, JooEun, primary, Castro, Victor M., additional, Ripperger, Michael, additional, Venkatesh, Sanan, additional, Burstein, David, additional, Linnér, Richard Karlsson, additional, Rocha, Daniel B., additional, Hu, Yirui, additional, Wilimitis, Drew, additional, Morley, Theodore, additional, Han, Lide, additional, Kim, Rachel Youngjung, additional, Feng, Yen-Chen Anne, additional, Ge, Tian, additional, Heckers, Stephan, additional, Voloudakis, Georgios, additional, Chabris, Christopher, additional, Roussos, Panos, additional, McCoy, Thomas H, additional, Walsh, Colin G., additional, Perlis, Roy H., additional, and Ruderfer, Douglas M., additional

Published
2024
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9. Interoperability of phenome-wide multimorbidity patterns: a comparative study of two large-scale EHR systems

Author

Strayer, Nick, primary, Vessels, Tess J., additional, Choi, Karmel W, additional, Zhang, Siwei, additional, Li, Yajing, additional, Sharber, Brian, additional, Hsi, Ryan S, additional, Bejan, Cosmin A, additional, Bick, Alexander G, additional, Balko, Justin M, additional, Johnson, Douglas B, additional, Wheless, Lee E, additional, Wells, Quinn S, additional, Shah, Ravi V, additional, Phillips, Elizabeth J, additional, Self, Wesley H., additional, Pulley, Jill M, additional, Wilkins, Consuelo H, additional, Chen, Qingxia, additional, Hartert, Tina, additional, Savona, Michael R, additional, Shyr, Yu, additional, Roden, Dan M, additional, Smoller, Jordan W, additional, Ruderfer, Douglas M, additional, and Xu, Yaomin, additional

Published
2024
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12. A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci

Author

Kimbrel, Nathan A., Ashley-Koch, Allison E., Qin, Xue J., Lindquist, Jennifer H., Garrett, Melanie E., Dennis, Michelle F., Hair, Lauren P., Huffman, Jennifer E., Jacobson, Daniel A., Madduri, Ravi K., Trafton, Jodie A., Coon, Hilary, Docherty, Anna R., Kang, Jooeun, Mullins, Niamh, Ruderfer, Douglas M., Harvey, Philip D., McMahon, Benjamin H., Oslin, David W., Hauser, Elizabeth R., Hauser, Michael A., and Beckham, Jean C.

Published
2022
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13. Publisher Correction: Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

Author

Pardiñas, Antonio F, Holmans, Peter, Pocklington, Andrew J, Escott-Price, Valentina, Ripke, Stephan, Carrera, Noa, Legge, Sophie E, Bishop, Sophie, Cameron, Darren, Hamshere, Marian L, Han, Jun, Hubbard, Leon, Lynham, Amy, Mantripragada, Kiran, Rees, Elliott, MacCabe, James H, McCarroll, Steven A, Baune, Bernhard T, Breen, Gerome, Byrne, Enda M, Dannlowski, Udo, Eley, Thalia C, Hayward, Caroline, Martin, Nicholas G, McIntosh, Andrew M, Plomin, Robert, Porteous, David J, Wray, Naomi R, Caballero, Armando, Geschwind, Daniel H, Huckins, Laura M, Ruderfer, Douglas M, Santiago, Enrique, Sklar, Pamela, Stahl, Eli A, Won, Hyejung, Agerbo, Esben, Als, Thomas D, Andreassen, Ole A, Bækvad-Hansen, Marie, Mortensen, Preben Bo, Pedersen, Carsten Bøcker, Børglum, Anders D, Bybjerg-Grauholm, Jonas, Djurovic, Srdjan, Durmishi, Naser, Pedersen, Marianne Giørtz, Golimbet, Vera, Grove, Jakob, Hougaard, David M, Mattheisen, Manuel, Molden, Espen, Mors, Ole, Nordentoft, Merete, Pejovic-Milovancevic, Milica, Sigurdsson, Engilbert, Silagadze, Teimuraz, Hansen, Christine Søholm, Stefansson, Kari, Stefansson, Hreinn, Steinberg, Stacy, Tosato, Sarah, Werge, Thomas, Collier, David A, Rujescu, Dan, Kirov, George, Owen, Michael J, O’Donovan, Michael C, and Walters, James TR

Subjects
GERAD1 Consortium, CRESTAR Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

14. Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases

Author

Charney, Alexander W, Stahl, Eli A, Green, Elaine K, Chen, Chia-Yen, Moran, Jennifer L, Chambert, Kimberly, Belliveau, Richard A, Forty, Liz, Gordon-Smith, Katherine, Lee, Phil H, Bromet, Evelyn J, Buckley, Peter F, Escamilla, Michael A, Fanous, Ayman H, Fochtmann, Laura J, Lehrer, Douglas S, Malaspina, Dolores, Marder, Stephen R, Morley, Christopher P, Nicolini, Humberto, Perkins, Diana O, Rakofsky, Jeffrey J, Rapaport, Mark H, Medeiros, Helena, Sobell, Janet L, Backlund, Lena, Bergen, Sarah E, Juréus, Anders, Schalling, Martin, Lichtenstein, Paul, Knowles, James A, Burdick, Katherine E, Jones, Ian, Jones, Lisa A, Hultman, Christina M, Perlis, Roy, Purcell, Shaun M, McCarroll, Steven A, Pato, Carlos N, Pato, Michele T, Di Florio, Ariana, Craddock, Nick, Landén, Mikael, Smoller, Jordan W, Ruderfer, Douglas M, and Sklar, Pamela

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Genetics, Serious Mental Illness, Bipolar Disorder, Mental Health, Prevention, Brain Disorders, Schizophrenia, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Case-Control Studies, Cohort Studies, DNA Copy Number Variations, Gene Duplication, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Psychotic Disorders, Bipolar disorder, Copy number variant, Polygenic risk score, Rare variant burden, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

BackgroundGenetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood.MethodsRare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis.ResultsCNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden.ConclusionsCNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

Published
2019

15. Publisher Correction: Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Author

Huckins, Laura M, Dobbyn, Amanda, Ruderfer, Douglas M, Hoffman, Gabriel, Wang, Weiqing, Pardiñas, Antonio F, Rajagopal, Veera M, Als, Thomas D, T. Nguyen, Hoang, Girdhar, Kiran, Boocock, James, Roussos, Panos, Fromer, Menachem, Kramer, Robin, Domenici, Enrico, Gamazon, Eric R, Purcell, Shaun, Demontis, Ditte, Børglum, Anders D, Walters, James TR, O’Donovan, Michael C, Sullivan, Patrick, Owen, Michael J, Devlin, Bernie, Sieberts, Solveig K, Cox, Nancy J, Im, Hae Kyung, Sklar, Pamela, and Stahl, Eli A

Subjects
Genetics, Neurosciences, Human Genome, Serious Mental Illness, Schizophrenia, Brain Disorders, Mental Health, Biotechnology, Mental health, CommonMind Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, iPSYCH-GEMS Schizophrenia Working Group, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

In the HTML version of the article originally published, the author group 'The Schizophrenia Working Group of the Psychiatric Genomics Consortium' was displayed incorrectly. The error has been corrected in the HTML version of the article.

Published
2019

16. Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Author

Huckins, Laura M, Dobbyn, Amanda, Ruderfer, Douglas M, Hoffman, Gabriel, Wang, Weiqing, Pardiñas, Antonio F, Rajagopal, Veera M, Als, Thomas D, T. Nguyen, Hoang, Girdhar, Kiran, Boocock, James, Roussos, Panos, Fromer, Menachem, Kramer, Robin, Domenici, Enrico, Gamazon, Eric R, Purcell, Shaun, Demontis, Ditte, Børglum, Anders D, Walters, James TR, O’Donovan, Michael C, Sullivan, Patrick, Owen, Michael J, Devlin, Bernie, Sieberts, Solveig K, Cox, Nancy J, Im, Hae Kyung, Sklar, Pamela, and Stahl, Eli A

Subjects
Biological Sciences, Genetics, Mental Health, Brain Disorders, Human Genome, Schizophrenia, 2.1 Biological and endogenous factors, Aetiology, Mental health, Brain, Case-Control Studies, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Transcriptome, CommonMind Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, iPSYCH-GEMS Schizophrenia Working Group, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.

Published
2019

17. Distinct genetic liability profiles define clinically relevant patient strata across common diseases.

Author

Trastulla, Lucia, Dolgalev, Georgii, Moser, Sylvain, Jiménez-Barrón, Laura T., Andlauer, Till F. M., von Scheidt, Moritz, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Ruderfer, Douglas M., Ripke, Stephan, McQuillin, Andrew, Stahl, Eli A., Domenici, Enrico, Adolfsson, Rolf, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., and Begemann, Martin

Subjects
CORONARY artery disease, GENE expression profiling, INDIVIDUALIZED medicine, OLANZAPINE
Abstract

Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms. Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient 'biotypes' characterized by partially distinct disease mechanisms. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Author

Consortium, Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics, Ruderfer, Douglas M, Ripke, Stephan, McQuillin, Andrew, Boocock, James, Stahl, Eli A, Pavlides, Jennifer M Whitehead, Mullins, Niamh, Charney, Alexander W, Ori, Anil PS, Loohuis, Loes M Olde, Domenici, Enrico, Di Florio, Arianna, Papiol, Sergi, Kalman, Janos L, Trubetskoy, Vassily, Adolfsson, Rolf, Agartz, Ingrid, Agerbo, Esben, Akil, Huda, Albani, Diego, Albus, Margot, Alda, Martin, Alexander, Madeline, Alliey-Rodriguez, Ney, Als, Thomas D, Amin, Farooq, Anjorin, Adebayo, Arranz, Maria J, Awasthi, Swapnil, Bacanu, Silviu A, Badner, Judith A, Baekvad-Hansen, Marie, Bakker, Steven, Band, Gavin, Barchas, Jack D, Barroso, Ines, Bass, Nicholas, Bauer, Michael, Baune, Bernhard T, Begemann, Martin, Bellenguez, Celine, Belliveau, Richard A, Bellivier, Frank, Bender, Stephan, Bene, Judit, Bergen, Sarah E, Berrettini, Wade H, Bevilacqua, Elizabeth, Biernacka, Joanna M, Bigdeli, Tim B, Black, Donald W, Blackburn, Hannah, Blackwell, Jenefer M, Blackwood, Douglas HR, Pedersen, Carsten Bocker, Boehnke, Michael, Boks, Marco, Borglum, Anders D, Bramon, Elvira, Breen, Gerome, Brown, Matthew A, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Budde, Monika, Bulik-Sullivan, Brendan, Bumpstead, Suzannah J, Bunney, William, Burmeister, Margit, Buxbaum, Joseph D, Bybjerg-Grauholm, Jonas, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Casas, Juan P, Casas, Miquel, Catts, Stanley V, Cervantes, Pablo, Chambert, Kimberley D, Chan, Raymond CK, Chen, Eric YH, Chen, Ronald YL, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Clarke, Toni-Kim, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Coleman, Jonathan RI, Collier, David A, Cormican, Paul, Coryell, William, and Craddock, Nicholas

Subjects
Human Genome, Neurosciences, Serious Mental Illness, Bipolar Disorder, Biotechnology, Schizophrenia, Brain Disorders, Genetics, Mental Health, Mental health, Good Health and Well Being, Case-Control Studies, Genetic Loci, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Odds Ratio, Phenotype, Risk, White People, Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address: douglas.ruderfer@vanderbilt.edu, Bipolar Disorder and Schizophrenia Working Group of the Psychiatric Genomics Consortium, bipolar disorder, polygenic risk, psychosis, schizophrenia, subphenotypes, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.

Published
2018

19. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

Author

Pardiñas, Antonio F, Holmans, Peter, Pocklington, Andrew J, Escott-Price, Valentina, Ripke, Stephan, Carrera, Noa, Legge, Sophie E, Bishop, Sophie, Cameron, Darren, Hamshere, Marian L, Han, Jun, Hubbard, Leon, Lynham, Amy, Mantripragada, Kiran, Rees, Elliott, MacCabe, James H, McCarroll, Steven A, Baune, Bernhard T, Breen, Gerome, Byrne, Enda M, Dannlowski, Udo, Eley, Thalia C, Hayward, Caroline, Martin, Nicholas G, McIntosh, Andrew M, Plomin, Robert, Porteous, David J, Wray, Naomi R, Caballero, Armando, Geschwind, Daniel H, Huckins, Laura M, Ruderfer, Douglas M, Santiago, Enrique, Sklar, Pamela, Stahl, Eli A, Won, Hyejung, Agerbo, Esben, Als, Thomas D, Andreassen, Ole A, Bækvad-Hansen, Marie, Mortensen, Preben Bo, Pedersen, Carsten Bøcker, Børglum, Anders D, Bybjerg-Grauholm, Jonas, Djurovic, Srdjan, Durmishi, Naser, Pedersen, Marianne Giørtz, Golimbet, Vera, Grove, Jakob, Hougaard, David M, Mattheisen, Manuel, Molden, Espen, Mors, Ole, Nordentoft, Merete, Pejovic-Milovancevic, Milica, Sigurdsson, Engilbert, Silagadze, Teimuraz, Hansen, Christine Søholm, Stefansson, Kari, Stefansson, Hreinn, Steinberg, Stacy, Tosato, Sarah, Werge, Thomas, GERAD1 Consortium, CRESTAR Consortium, Collier, David A, Rujescu, Dan, Kirov, George, Owen, Michael J, O’Donovan, Michael C, and Walters, James TR

Subjects
Serious Mental Illness, Brain Disorders, Human Genome, Genetics, Mental Health, Biotechnology, Schizophrenia, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Alleles, Case-Control Studies, Gene Frequency, Genes, Lethal, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inheritance Patterns, Polymorphism, Single Nucleotide, Selection, Genetic, GERAD1 Consortium, CRESTAR Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

Published
2018

20. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap

Author

Gandal, Michael J, Haney, Jillian R, Parikshak, Neelroop N, Leppa, Virpi, Ramaswami, Gokul, Hartl, Chris, Schork, Andrew J, Appadurai, Vivek, Buil, Alfonso, Werge, Thomas M, Liu, Chunyu, White, Kevin P, Horvath, Steve, Geschwind, Daniel H, Sestan, Nenad, Vaccarino, Flora, Gerstein, Mark, Weissman, Sherman, Pochareddy, Sirisha, State, Matthew, Knowles, James, Farnham, Peggy, Akbarian, Schahram, Pinto, Dalila, Van Baekl, Harm, Dracheva, Stella, Jaffe, Andrew, Hyde, Thomas, Zandi, Peter, Crawford, Gregory, Sullivan, Pat, Thompson, Wesley Kurt, Mortensen, Preben Bo, Agerbo, Esben, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Mors, Ole, Børglum, Anders D, Nordentoft, Merete, Hougaard, David M, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Martin, Alicia R, Dumont, Ashley, Stevens, Christine, Churchhouse, Claire, Howrigan, Daniel P, Palmer, Duncan S, Robinson, Elise B, Satterstrom, Kyle F, Cerrato, Felecia, Huang, Hailiang, Goldstein, Jacqueline, Moran, Jennifer, Julian, Joanna Martin, Kimberly, Maller, Patrick, Chambert, Turley, Patrick, Walters, Raymond, Belliveau, Rich, Ripke, Stephan, Poterba, Timothy, Daly, Mark J, Neale, Benjamin, Fromer, Menachem, Roussos, Panos, Johnson, Jessica S, Shah, Hardik R, Mahajan, Milind C, Schadt, Eric, Haroutunian, Vahram, Ruderfer, Douglas M, Buxbaum, Joseph D, Sieberts, Solveig K, Dang, Kristen, Logsdon, Ben, Mangravite, Lara M, Peters, Mette, Gur, Raquel E, Hahn, Chang-Gyu, Devlin, Bernie, Klei, Lambertus L, Lewis, David, Lipska, Barbara, Hirai, Keisuke, Toyoshiba, Hiroyoshi, and Domenici, Enrico

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biological Psychology, Psychology, Pharmacology and Pharmaceutical Sciences, Serious Mental Illness, Brain Disorders, Human Genome, Mental Health, Schizophrenia, Neurosciences, Bipolar Disorder, Depression, Mental Illness, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Cerebral Cortex, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Mental Disorders, Multifactorial Inheritance, Nervous System Diseases, Polymorphism, Single Nucleotide, Transcription, Genetic, CommonMind Consortium, PsychENCODE Consortium, iPSYCH-BROAD Working Group, General Science & Technology
Abstract

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.

Published
2018

21. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, Niamh, Forstner, Andreas J., O’Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R. I., Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Børte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bækvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøcker Pedersen, Carsten, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Giørtz Pedersen, Marianne, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lucae, Susanne, Lundberg, Martin, MacIntyre, Donald J., Magnusson, Sigurdur H., Maier, Wolfgang, Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, Mattheisen, Manuel, McCarroll, Steven A., McGregor, Nathaniel W., McGuffin, Peter, McKay, James D., Medeiros, Helena, Medland, Sarah E., Millischer, Vincent, Montgomery, Grant W., Moran, Jennifer L., Morris, Derek W., Mühleisen, Thomas W., O’Brien, Niamh, O’Donovan, Claire, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Potash, James B., Quested, Digby, Raj, Towfique, Rapaport, Mark H., DePaulo, J. Raymond, Regeer, Eline J., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sánchez-Mora, Cristina, Schulte, Eva C., Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sigurdsson, Engilbert, Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Smith, Daniel J., Sobell, Janet L., Søholm Hansen, Christine, Soler Artigas, Maria, Spijker, Anne T., Stein, Dan J., Strauss, John S., Świątkowska, Beata, Terao, Chikashi, Thorgeirsson, Thorgeir E., Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Xi, Simon, Xu, Wei, Yang, Jessica Mei Kay, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Børglum, Anders D., Breen, Gerome, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dannlowski, Udo, Dikeos, Dimitris, Esko, Tõnu, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Goes, Fernando S., Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hougaard, David M., Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen V., Jones, Ian, Jones, Lisa A., Kahn, René S., Kelsoe, John R., Kirov, George, Landén, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Martin, Nicholas G., Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Milani, Lili, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Nordentoft, Merete, Nöthen, Markus M., O’Donovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Owen, Michael J., Paciga, Sara A., Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Perlis, Roy H., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Ripke, Stephan, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Streit, Fabian, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Werge, Thomas, Wray, Naomi R., Zwart, John-Anker, Biernacka, Joanna M., Nurnberger, John I., Cichon, Sven, Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., and Andreassen, Ole A.

Published
2021
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24. The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls

Author

Byrne, Enda M., Forstner, Andreas J., Holmans, Peter A., de Leeuw, Christiaan A., Mattheisen, Manuel, McQuillin, Andrew, Whitehead Pavlides, Jennifer M., Pers, Tune H., Ripke, Stephan, Stahl, Eli A., Steinberg, Stacy, Trubetskoy, Vassily, Trzaskowski, Maciej, Wang, Yunpeng, Abbott, Liam, Abdellaoui, Abdel, Adams, Mark J., Adolfsson, Annelie Nordin, Agerbo, Esben, Akil, Huda, Albani, Diego, Alliey-Rodriguez, Ney, Als, Thomas D., Andlauer, Till F.M., Anjorin, Adebayo, Antilla, Verneri, Van der Auwera, Sandra, Awasthi, Swapnil, Bacanu, Silviu-Alin, Badner, Judith A., Bækvad-Hansen, Marie, Barchas, Jack D., Bass, Nicholas, Bauer, Michael, Beekman, Aartjan T.F., Belliveau, Richard, Bergen, Sarah E., Bigdeli, Tim B., Binder, Elisabeth B., Bøen, Erlend, Boks, Marco, Boocock, James, Budde, Monika, Bunney, William, Burmeister, Margit, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Byerley, William, Cai, Na, Casas, Miquel, Castelao, Enrique, Cerrato, Felecia, Cervantes, Pablo, Chambert, Kimberly, Charney, Alexander W., Chen, Danfeng, Christensen, Jane Hvarregaard, Churchhouse, Claire, St Clair, David, Clarke, Toni-Kim, Colodro-Conde, Lucía, Coryell, William, Couvy-Duchesne, Baptiste, Craig, David W., Crawford, Gregory E., Cruceanu, Cristiana, Czerski, Piotr M., Dale, Anders M., Davies, Gail, Deary, Ian J., Degenhardt, Franziska, Del-Favero, Jurgen, DePaulo, J Raymond, Derks, Eske M., Direk, Nese, Djurovic, Srdjan, Dobbyn, Amanda L., Dolan, Conor V., Dumont, Ashley, Dunn, Erin C., Eley, Thalia C., Elvsåshagen, Torbjørn, Escott-Price, Valentina, Fan, Chun Chieh, Finucane, Hilary K., Fischer, Sascha B., Flickinger, Matthew, Foo, Jerome C., Foroud, Tatiana M., Forty, Liz, Frank, Josef, Fraser, Christine, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Gage, Diane, Garnham, Julie, Giambartolomei, Claudia, Goes, Fernando S., Goldstein, Jaqueline, Gordon, Scott D., Gordon-Smith, Katherine, Green, Elaine K., Green, Melissa J., Greenwood, Tiffany A., Grove, Jakob, Guan, Weihua, Hall, Lynsey S., Hamshere, Marian L., Hansen, Christine Søholm, Hansen, Thomas F., Hautzinger, Martin, Heilbronner, Urs, van Hemert, Albert M., Herms, Stefan, Hickie, Ian B., Hipolito, Maria, Hoffmann, Per, Holland, Dominic, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Huckins, Laura, Ising, Marcus, Jamain, Stéphane, Jansen, Rick, Johnson, Jessica S., de Jong, Simone, Jorgenson, Eric, Juréus, Anders, Kandaswamy, Radhika, Karlsson, Robert, Kennedy, James L., Hassan Kiadeh, Farnush Farhadi, Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Kohane, Isaac S., Koller, Anna C., Kraft, Julia, Kretzschmar, Warren W., Krogh, Jesper, Kupka, Ralph, Kutalik, Zoltán, Lavebratt, Catharina, Lawrence, Jacob, Lawson, William B., Leber, Markus, Lee, Phil H., Levy, Shawn E., Li, Jun Z., Li, Yihan, Lind, Penelope A., Liu, Chunyu, Olde Loohuis, Loes M., Maaser, Anna, MacIntyre, Donald J., MacKinnon, Dean F., Mahon, Pamela B., Maier, Wolfgang, Maier, Robert M., Marchini, Jonathan, Martinsson, Lina, Mbarek, Hamdi, McCarroll, Steve, McGrath, Patrick, McGuffin, Peter, McInnis, Melvin G., McKay, James D., Medeiros, Helena, Medland, Sarah E., Mehta, Divya, Meng, Fan, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Mirza, Saira Saeed, Mondimore, Francis M., Montgomery, Grant W., Morris, Derek W., Mostafavi, Sara, Mühleisen, Thomas W., Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nguyen, Hoang, Nievergelt, Caroline M., Nivard, Michel G., Nwulia, Evaristus A., Nyholt, Dale R., O'Donovan, Claire, O'Reilly, Paul F., Ori, Anil P.S., Oruc, Lilijana, Ösby, Urban, Oskarsson, Hogni, Painter, Jodie N., Parra, José Guzman, Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Perry, Amy, Peterson, Roseann E., Pettersson, Erik, Peyrot, Wouter J., Pfennig, Andrea, Pistis, Giorgio, Purcell, Shaun M., Quiroz, Jorge A., Qvist, Per, Regeer, Eline J., Reif, Andreas, Reinbold, Céline S., Rice, John P., Riley, Brien P., Rivas, Fabio, Rivera, Margarita, Roussos, Panos, Ruderfer, Douglas M., Ryu, Euijung, Sánchez-Mora, Cristina, Schatzberg, Alan F., Scheftner, William A., Schoevers, Robert, Schork, Nicholas J., Schulte, Eva C., Shehktman, Tatyana, Shen, Ling, Shi, Jianxin, Shilling, Paul D., Shyn, Stanley I., Sigurdsson, Engilbert, Slaney, Claire, Smeland, Olav B., Smit, Johannes H., Smith, Daniel J., Sobell, Janet L., Spijker, Anne T., Steffens, Michael, Strauss, John S., Streit, Fabian, Strohmaier, Jana, Szelinger, Szabolcs, Tansey, Katherine E., Teismann, Henning, Teumer, Alexander, Thompson, Robert C., Thompson, Wesley, Thomson, Pippa A., Thorgeirsson, Thorgeir E., Traylor, Matthew, Treutlein, Jens, Uitterlinden, André G., Umbricht, Daniel, Vedder, Helmut, Viktorin, Alexander, Visscher, Peter M., Wang, Weiqing, Watson, Stanley J., Webb, Bradley T., Weickert, Cynthia Shannon, Weickert, Thomas W., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Xu, Wei, Yang, Jian, Young, Allan H., Zandi, Peter, Zhang, Peng, Zhang, Futao, Zollner, Sebastian, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Arolt, Volker, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Berrettini, Wade H., Biernacka, Joanna M., Blackwood, Douglas H.R., Boehnke, Michael, Boomsma, Dorret I., Corvin, Aiden, Craddock, Nicholas, Daly, Mark J., Dannlowski, Udo, Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Etain, Bruno, Frye, Mark, Fullerton, Janice M., Gershon, Elliot S., de Geus, E.J.C., Gill, Michael, Goes, Fernando, Grabe, Hans J., Grigoroiu-Serbanescu, Maria, Hamilton, Steven P., Hauser, Joanna, Hayward, Caroline, Heath, Andrew C., Hougaard, David M., Hultman, Christina M., Jones, Ian, Jones, Lisa A., Kahn, René S., Kendler, Kenneth S., Kirov, George, Kloiber, Stefan, Landén, Mikael, Leboyer, Marion, Lewis, Glyn, Li, Qingqin S., Lissowska, Jolanta, Lucae, Susanne, Madden, Pamela A.F., Magnusson, Patrik K., Martin, Nicholas G., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Metspalu, Andres, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nimgaonkar, Vishwajit, Nordentoft, Merete, Nöthen, Markus M., O'Donovan, Michael C., Oedegaard, Ketil J., Owen, Michael J., Paciga, Sara A., Pato, Carlos, Pato, Michele T., Pedersen, Nancy L., Penninx, Brenda W.J. H., Perlis, Roy H., Porteous, David J., Posthuma, Danielle, Potash, James B., Preisig, Martin, Ramos-Quiroga, Josep Antoni, Ribasés, Marta, Rietschel, Marcella, Rouleau, Guy A., Schaefer, Catherine, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Serretti, Alessandro, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Tiemeier, Henning, Turecki, Gustavo, Uher, Rudolf, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Völzke, Henry, Weissman, Myrna M., Werge, Thomas, Andreassen, Ole A., Børglum, Anders D., Cichon, Sven, Edenberg, Howard J., Di Florio, Arianna, Kelsoe, John, Levinson, Douglas F., Lewis, Cathryn M., Nurnberger, John I., Ophoff, Roel A., Scott, Laura J., Sklar, Pamela, Sullivan, Patrick F., Wray, Naomi R., Coleman, Jonathan R.I., Gaspar, Héléna A., Bryois, Julien, and Breen, Gerome

Published
2020
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25. Characterization of Single Gene Copy Number Variants in Schizophrenia

Author

Szatkiewicz, Jin P., Fromer, Menachem, Nonneman, Randal J., Ancalade, NaEshia, Johnson, Jessica S., Stahl, Eli A., Rees, Elliott, Bergen, Sarah E., Hultman, Christina M., Kirov, George, O’Donovan, Michael, Owen, Michael, Holmans, Peter, Sklar, Pamela, Sullivan, Patrick F., Purcell, Shaun M., Crowley, James J., and Ruderfer, Douglas M.

Published
2020
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27. Analysis of protein-coding genetic variation in 60,706 humans.

Author

Lek, Monkol, Karczewski, Konrad J, Minikel, Eric V, Samocha, Kaitlin E, Banks, Eric, Fennell, Timothy, O'Donnell-Luria, Anne H, Ware, James S, Hill, Andrew J, Cummings, Beryl B, Tukiainen, Taru, Birnbaum, Daniel P, Kosmicki, Jack A, Duncan, Laramie E, Estrada, Karol, Zhao, Fengmei, Zou, James, Pierce-Hoffman, Emma, Berghout, Joanne, Cooper, David N, Deflaux, Nicole, DePristo, Mark, Do, Ron, Flannick, Jason, Fromer, Menachem, Gauthier, Laura, Goldstein, Jackie, Gupta, Namrata, Howrigan, Daniel, Kiezun, Adam, Kurki, Mitja I, Moonshine, Ami Levy, Natarajan, Pradeep, Orozco, Lorena, Peloso, Gina M, Poplin, Ryan, Rivas, Manuel A, Ruano-Rubio, Valentin, Rose, Samuel A, Ruderfer, Douglas M, Shakir, Khalid, Stenson, Peter D, Stevens, Christine, Thomas, Brett P, Tiao, Grace, Tusie-Luna, Maria T, Weisburd, Ben, Won, Hong-Hee, Yu, Dongmei, Altshuler, David M, Ardissino, Diego, Boehnke, Michael, Danesh, John, Donnelly, Stacey, Elosua, Roberto, Florez, Jose C, Gabriel, Stacey B, Getz, Gad, Glatt, Stephen J, Hultman, Christina M, Kathiresan, Sekar, Laakso, Markku, McCarroll, Steven, McCarthy, Mark I, McGovern, Dermot, McPherson, Ruth, Neale, Benjamin M, Palotie, Aarno, Purcell, Shaun M, Saleheen, Danish, Scharf, Jeremiah M, Sklar, Pamela, Sullivan, Patrick F, Tuomilehto, Jaakko, Tsuang, Ming T, Watkins, Hugh C, Wilson, James G, Daly, Mark J, MacArthur, Daniel G, and Exome Aggregation Consortium

Subjects
Exome Aggregation Consortium, Humans, Rare Diseases, Proteome, Sample Size, DNA Mutational Analysis, Phenotype, Genetic Variation, Exome, Datasets as Topic, Clinical Research, Biotechnology, Human Genome, Genetics, Genetic Testing, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, General Science & Technology
Abstract

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

Published
2016

28. Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach

Author

Ruderfer, Douglas M, Charney, Alexander W, Readhead, Ben, Kidd, Brian A, Kähler, Anna K, Kenny, Paul J, Keiser, Michael J, Moran, Jennifer L, Hultman, Christina M, Scott, Stuart A, Sullivan, Patrick F, Purcell, Shaun M, Dudley, Joel T, and Sklar, Pamela

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Schizophrenia, Mental Health, Genetics, Prevention, Biotechnology, Serious Mental Illness, Clinical Research, Brain Disorders, Human Genome, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aetiology, Development of treatments and therapeutic interventions, Mental health, Good Health and Well Being, Antipsychotic Agents, Case-Control Studies, Clozapine, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Multifactorial Inheritance, Registries, Sweden, Treatment Outcome, Clinical Sciences, Public Health and Health Services, Clinical sciences, Applied and developmental psychology, Clinical and health psychology
Abstract

BackgroundTherapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia.MethodsWe defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36 989 cases and 113 075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance.FindingsWe combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029).InterpretationOur results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism.FundingUS National Institutes of Health.

Published
2016

29. Evaluating the impact of modeling choices on the performance of integrated genetic and clinical models

Author

Morley, Theodore J., primary, Willimitis, Drew, additional, Ripperger, Michael, additional, Lee, Hyunjoon, additional, Han, Lide, additional, Zhou, Yu, additional, Kang, Jooeun, additional, Davis, Lea K., additional, Smoller, Jordan W., additional, Choi, Karmel W., additional, Walsh, Colin G., additional, and Ruderfer, Douglas M., additional

Published
2023
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31. Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia.

Author

Ruderfer, Douglas M, Fanous, Ayman H, Ripke, Stephan, McQuillin, Andrew, Amdur, Richard L, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Gejman, Pablo V, O'Donovan, Michael C, Andreassen, Ole A, Djurovic, Srdjan, Hultman, Christina M, Kelsoe, John R, Jamain, Stephane, Landén, Mikael, Leboyer, Marion, Nimgaonkar, Vishwajit, Nurnberger, John, Smoller, Jordan W, Craddock, Nick, Corvin, Aiden, Sullivan, Patrick F, Holmans, Peter, Sklar, Pamela, and Kendler, Kenneth S

Subjects
Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Humans, Genetic Predisposition to Disease, Calcium Channels, L-Type, Cell Cycle Proteins, Nuclear Proteins, Factor Analysis, Statistical, Odds Ratio, Case-Control Studies, Bipolar Disorder, Schizophrenia, Schizophrenic Psychology, Phenotype, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Phosphatidylinositol 3-Kinases, bipolar, clinical symptoms, cross disorder, polygenic, schizophrenia, Calcium Channels, L-Type, Factor Analysis, Statistical, Polymorphism, Single Nucleotide, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.

Published
2014

32. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Maury, Eduardo A., primary, Sherman, Maxwell A., additional, Genovese, Giulio, additional, Gilgenast, Thomas G., additional, Kamath, Tushar, additional, Burris, S.J., additional, Rajarajan, Prashanth, additional, Flaherty, Erin, additional, Akbarian, Schahram, additional, Chess, Andrew, additional, McCarroll, Steven A., additional, Loh, Po-Ru, additional, Phillips-Cremins, Jennifer E., additional, Brennand, Kristen J., additional, Macosko, Evan Z., additional, Walters, James T.R., additional, O’Donovan, Michael, additional, Sullivan, Patrick, additional, Sebat, Jonathan, additional, Lee, Eunjung A., additional, Walsh, Christopher A., additional, Marshall, Christian R., additional, Merico, Daniele, additional, Thiruvahindrapuram, Bhooma, additional, Wang, Zhouzhi, additional, Scherer, Stephen W., additional, Howrigan, Daniel P, additional, Ripke, Stephan, additional, Bulik-Sullivan, Brendan, additional, Farh, Kai-How, additional, Fromer, Menachem, additional, Goldstein, Jacqueline I., additional, Huang, Hailiang, additional, Lee, Phil, additional, Daly, Mark J., additional, Neale, Benjamin M., additional, Belliveau, Richard A., additional, Bergen, Sarah E., additional, Bevilacqua, Elizabeth, additional, Chambert, Kimberley D., additional, O'Dushlaine, Colm, additional, Scolnick, Edward M., additional, Smoller, Jordan W., additional, Moran, Jennifer L., additional, Palotie, Aarno, additional, Petryshen, Tracey L., additional, Wu, Wenting, additional, Greer, Douglas S., additional, Antaki, Danny, additional, Shetty, Aniket, additional, Gujral, Madhusudan, additional, Brandler, William M., additional, Malhotra, Dheeraj, additional, Fuentes Fajarado, Karin V., additional, Maile, Michelle S., additional, Holmans, Peter A., additional, Carrera, Noa, additional, Craddock, Nick, additional, Escott-Price, Valentina, additional, Georgieva, Lyudmila, additional, Hamshere, Marian L., additional, Kavanagh, David, additional, Legge, Sophie E., additional, Pocklington, Andrew J., additional, Richards, Alexander L., additional, Ruderfer, Douglas M., additional, Williams, Nigel M., additional, Kirov, George, additional, Owen, Michael J., additional, Pinto, Dalila, additional, Cai, Guiqing, additional, Davis, Kenneth L., additional, Drapeau, Elodie, additional, Friedman, Joseph I, additional, Haroutunian, Vahram, additional, Parkhomenko, Elena, additional, Reichenberg, Abraham, additional, Silverman, Jeremy M., additional, Buxbaum, Joseph D., additional, Domenici, Enrico, additional, Agartz, Ingrid, additional, Djurovic, Srdjan, additional, Mattingsdal, Morten, additional, Melle, Ingrid, additional, Andreassen, Ole A., additional, Jönsson, Erik G., additional, Söderman, Erik, additional, Albus, Margot, additional, Alexander, Madeline, additional, Laurent, Claudine, additional, Levinson, Douglas F., additional, Amin, Farooq, additional, Atkins, Joshua, additional, Cairns, Murray J., additional, Scott, Rodney J., additional, Tooney, Paul A., additional, Wu, Jing Qin, additional, Bacanu, Silviu A., additional, Bigdeli, Tim B., additional, Reimers, Mark A., additional, Webb, Bradley T., additional, Wolen, Aaron R., additional, Wormley, Brandon K., additional, Kendler, Kenneth S., additional, Riley, Brien P., additional, Kähler, Anna K., additional, Magnusson, Patrik K.E., additional, Hultman, Christina M., additional, Bertalan, Marcelo, additional, Hansen, Thomas, additional, Olsen, Line, additional, Rasmussen, Henrik B., additional, Werge, Thomas, additional, Mattheisen, Manuel, additional, Black, Donald W., additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buckner, Randy L., additional, Roffman, Joshua L., additional, Byerley, William, additional, Cahn, Wiepke, additional, Kahn, René S, additional, Strengman, Eric, additional, Ophoff, Roel A., additional, Carr, Vaughan J., additional, Catts, Stanley V., additional, Henskens, Frans A., additional, Loughland, Carmel M., additional, Michie, Patricia T., additional, Pantelis, Christos, additional, Schall, Ulrich, additional, Jablensky, Assen V., additional, Kelly, Brian J., additional, Campion, Dominique, additional, Cantor, Rita M., additional, Cheng, Wei, additional, Cloninger, C. Robert, additional, Svrakic, Dragan M, additional, Cohen, David, additional, Cormican, Paul, additional, Donohoe, Gary, additional, Morris, Derek W., additional, Corvin, Aiden, additional, Gill, Michael, additional, Crespo-Facorro, Benedicto, additional, Crowley, James J., additional, Farrell, Martilias S., additional, Giusti-Rodríguez, Paola, additional, Kim, Yunjung, additional, Szatkiewicz, Jin P., additional, Williams, Stephanie, additional, Curtis, David, additional, Pimm, Jonathan, additional, Gurling, Hugh, additional, McQuillin, Andrew, additional, Davidson, Michael, additional, Weiser, Mark, additional, Degenhardt, Franziska, additional, Forstner, Andreas J., additional, Herms, Stefan, additional, Hoffmann, Per, additional, Hofman, Andrea, additional, Cichon, Sven, additional, Nöthen, Markus M., additional, Del Favero, Jurgen, additional, DeLisi, Lynn E., additional, McCarley, Robert W., additional, Levy, Deborah L., additional, Mesholam-Gately, Raquelle I., additional, Seidman, Larry J., additional, Dikeos, Dimitris, additional, Papadimitriou, George N., additional, Dinan, Timothy, additional, Duan, Jubao, additional, Sanders, Alan R., additional, Gejman, Pablo V., additional, Gershon, Elliot S., additional, Dudbridge, Frank, additional, Eichhammer, Peter, additional, Eriksson, Johan, additional, Salomaa, Veikko, additional, Essioux, Laurent, additional, Fanous, Ayman H., additional, Knowles, James A., additional, Pato, Michele T., additional, Pato, Carlos N., additional, Frank, Josef, additional, Meier, Sandra, additional, Schulze, Thomas G., additional, Strohmaier, Jana, additional, Witt, Stephanie H., additional, Rietschel, Marcella, additional, Franke, Lude, additional, Karjalainen, Juha, additional, Freedman, Robert, additional, Olincy, Ann, additional, Freimer, Nelson B., additional, Purcell, Shaun M., additional, Roussos, Panos, additional, Stahl, Eli A., additional, Sklar, Pamela, additional, Giegling, Ina, additional, Hartmann, Annette M., additional, Konte, Bettina, additional, Rujescu, Dan, additional, Godard, Stephanie, additional, Hirschhorn, Joel N., additional, Pers, Tune H., additional, Price, Alkes, additional, Esko, Tõnu, additional, Gratten, Jacob, additional, Lee, S. Hong, additional, Visscher, Peter M., additional, Wray, Naomi R., additional, Mowry, Bryan J., additional, de Haan, Lieuwe, additional, Meijer, Carin J., additional, Hansen, Mark, additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Joa, Inge, additional, Kalaydjieva, Luba, additional, Keller, Matthew C., additional, Kennedy, James L., additional, Zai, Clement C., additional, Knight, Jo, additional, Lerer, Bernard, additional, Liang, Kung-Yee, additional, Lieberman, Jeffrey, additional, Stroup, T. Scott, additional, Lönnqvist, Jouko, additional, Suvisaari, Jaana, additional, Maher, Brion S., additional, Maier, Wolfgang, additional, Mallet, Jacques, additional, McDonald, Colm, additional, McIntosh, Andrew M., additional, Blackwood, Douglas H.R., additional, Metspalu, Andres, additional, Milani, Lili, additional, Milanova, Vihra, additional, Mokrab, Younes, additional, Collier, David A., additional, Müller-Myhsok, Bertram, additional, Murphy, Kieran C., additional, Murray, Robin M., additional, Powell, John, additional, Myin-Germeys, Inez, additional, Van Os, Jim, additional, Nenadic, Igor, additional, Nertney, Deborah A., additional, Nestadt, Gerald, additional, Pulver, Ann E., additional, Nicodemus, Kristin K., additional, Nisenbaum, Laura, additional, Nordin, Annelie, additional, Adolfsson, Rolf, additional, O'Callaghan, Eadbhard, additional, Oh, Sang-Yun, additional, O'Neill, F. Anthony, additional, Paunio, Tiina, additional, Pietiläinen, Olli, additional, Perkins, Diana O., additional, Quested, Digby, additional, Savitz, Adam, additional, Li, Qingqin S., additional, Schwab, Sibylle G., additional, Shi, Jianxin, additional, Spencer, Chris C.A., additional, Thirumalai, Srinivas, additional, Veijola, Juha, additional, Waddington, John, additional, Walsh, Dermot, additional, Wildenauer, Dieter B., additional, Bramon, Elvira, additional, Darvasi, Ariel, additional, Posthuma, Danielle, additional, St. Clair, David, additional, Shanta, Omar, additional, Klein, Marieke, additional, Park, Peter J., additional, Weinberger, Daniel, additional, Moran, John V., additional, Gage, Fred H., additional, Vaccarino, Flora M., additional, Gleeson, Joseph, additional, Mathern, Gary, additional, Courchesne, Eric, additional, Roy, Subhojit, additional, Bizzotto, Sara, additional, Coulter, Michael, additional, Dias, Caroline, additional, D'Gama, Alissa, additional, Ganz, Javier, additional, Hill, Robert, additional, Huang, August Yue, additional, Khoshkhoo, Sattar, additional, Kim, Sonia, additional, Lodato, Michael, additional, Miller, Michael, additional, Borges-Monroy, Rebeca, additional, Rodin, Rachel, additional, Zhou, Zinan, additional, Bohrson, Craig, additional, Chu, Chong, additional, Cortes-Ciriano, Isidro, additional, Dou, Yanmei, additional, Galor, Alon, additional, Gulhan, Doga, additional, Kwon, Minseok, additional, Luquette, Joe, additional, Viswanadham, Vinay, additional, Jones, Attila, additional, Rosenbluh, Chaggai, additional, Cho, Sean, additional, Langmead, Ben, additional, Thorpe, Jeremy, additional, Erwin, Jennifer, additional, Jaffe, Andrew, additional, McConnell, Michael, additional, Narurkar, Rujuta, additional, Paquola, Apua, additional, Shin, Jooheon, additional, Straub, Richard, additional, Abyzov, Alexej, additional, Bae, Taejeong, additional, Jang, Yeongjun, additional, Wang, Yifan, additional, Gage, Fred, additional, Linker, Sara, additional, Reed, Patrick, additional, Wang, Meiyan, additional, Urban, Alexander, additional, Zhou, Bo, additional, Zhu, Xiaowei, additional, Pattni, Reenal, additional, Amero, Aitor Serres, additional, Juan, David, additional, Lobon, Irene, additional, Marques-Bonet, Tomas, additional, Moruno, Manuel Solis, additional, Perez, Raquel Garcia, additional, Povolotskaya, Inna, additional, Soriano, Eduardo, additional, Averbuj, Dan, additional, Ball, Laurel, additional, Breuss, Martin, additional, Yang, Xiaoxu, additional, Chung, Changuk, additional, Emery, Sarah B., additional, Flasch, Diane A., additional, Kidd, Jeffrey M., additional, Kopera, Huira C., additional, Kwan, Kenneth Y., additional, Mills, Ryan E., additional, Moldovan, John B., additional, Sun, Chen, additional, Zhao, Xuefang, additional, Zhou, Weichen, additional, Frisbie, Trenton J., additional, Cherskov, Adriana, additional, Fasching, Liana, additional, Jourdon, Alexandre, additional, Pochareddy, Sirisha, additional, Scuderi, Soraya, additional, and Sestan, Nenad, additional

Published
2023
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33. PheMIME: An Interactive Web App and Knowledge Base for Phenome-Wide, Multi-Institutional Multimorbidity Analysis

Author

Zhang, Siwei, primary, Strayer, Nick, additional, Vessels, Tess, additional, Choi, Karmel, additional, Wang, Geoffrey W, additional, Li, Yajing, additional, Bejan, Cosmin A, additional, Hsi, Ryan S, additional, Bick, Alexander G., additional, Velez Edwards, Digna R, additional, Savona, Michael R, additional, Philips, Elizabeth J, additional, Pulley, Jill, additional, Self, Wesley H, additional, Hopkins, Wilkins Consuelo, additional, Roden, Dan M, additional, Smoller, Jordan W., additional, Ruderfer, Douglas M, additional, and Xu, Yaomin, additional

Published
2023
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36. Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network

Author

Chen, Zhao, Tang, Hua, Qayyum, Rehan, Schick, Ursula M, Nalls, Michael A, Handsaker, Robert, Li, Jin, Lu, Yingchang, Yanek, Lisa R, Keating, Brendan, Meng, Yan, van Rooij, Frank JA, Okada, Yukinori, Kubo, Michiaki, Rasmussen-Torvik, Laura, Keller, Margaux F, Lange, Leslie, Evans, Michele, Bottinger, Erwin P, Linderman, Michael D, Ruderfer, Douglas M, Hakonarson, Hakon, Papanicolaou, George, Zonderman, Alan B, Gottesman, Omri, Project, CHARGE Consortium BioBank Japan, Thomson, Cynthia, Ziv, Elad, Singleton, Andrew B, Loos, Ruth JF, Sleiman, Patrick MA, Ganesh, Santhi, McCarroll, Steven, Becker, Diane M, Wilson, James G, Lettre, Guillaume, and Reiner, Alexander P

Subjects
Biological Sciences, Genetics, Human Genome, Clinical Research, Hematology, Aetiology, 2.1 Biological and endogenous factors, Blood, Adolescent, Adult, Black or African American, Child, Chromosomes, Human, Pair 16, Cohort Studies, Erythrocyte Count, Erythrocyte Indices, Erythrocytes, Female, Genome-Wide Association Study, Hemoglobins, Humans, Male, Polymorphism, Single Nucleotide, White People, Young Adult, alpha-Globins, BioBank Japan Project, CHARGE Consortium, Medical and Health Sciences, Genetics & Heredity
Abstract

Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.

Published
2013

37. Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders

Author

Lim, Elaine T, Raychaudhuri, Soumya, Sanders, Stephan J, Stevens, Christine, Sabo, Aniko, MacArthur, Daniel G, Neale, Benjamin M, Kirby, Andrew, Ruderfer, Douglas M, Fromer, Menachem, Lek, Monkol, Liu, Li, Flannick, Jason, Ripke, Stephan, Nagaswamy, Uma, Muzny, Donna, Reid, Jeffrey G, Hawes, Alicia, Newsham, Irene, Wu, Yuanqing, Lewis, Lora, Dinh, Huyen, Gross, Shannon, Wang, Li-San, Lin, Chiao-Feng, Valladares, Otto, Gabriel, Stacey B, dePristo, Mark, Altshuler, David M, Purcell, Shaun M, Project, NHLBI Exome Sequencing, State, Matthew W, Boerwinkle, Eric, Buxbaum, Joseph D, Cook, Edwin H, Gibbs, Richard A, Schellenberg, Gerard D, Sutcliffe, James S, Devlin, Bernie, Roeder, Kathryn, and Daly, Mark J

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Human Genome, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Pediatric, Genetics, Mental Health, Clinical Research, Autism, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, Child Development Disorders, Pervasive, Child, Preschool, Chromosomes, Human, X, Demography, Female, Gene Deletion, Genetic Variation, Homozygote, Humans, Linkage Disequilibrium, Loss of Heterozygosity, Male, Risk Factors, NHLBI Exome Sequencing Project, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤ 5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.

Published
2013

39. Correction: Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

Author

Jia, Xiaoming, Goes, Fernando S., Locke, Adam E., Palmer, Duncan, Wang, Weiqing, Cohen-Woods, Sarah, Genovese, Giulio, Jackson, Anne U., Jiang, Chen, Kvale, Mark, Mullins, Niamh, Nguyen, Hoang, Pirooznia, Mehdi, Rivera, Margarita, Ruderfer, Douglas M., Shen, Ling, Thai, Khanh, Zawistowski, Matthew, Zhuang, Yongwen, Abecasis, Gonçalo, Akil, Huda, Bergen, Sarah, Burmeister, Margit, Chapman, Sinéad, DelaBastide, Melissa, Juréus, Anders, Kang, Hyun Min, Kwok, Pui-Yan, Li, Jun Z., Levy, Shawn E., Monson, Eric T., Moran, Jennifer, Sobell, Janet, Watson, Stanley, Willour, Virginia, Zöllner, Sebastian, Adolfsson, Rolf, Blackwood, Douglas, Boehnke, Michael, Breen, Gerome, Corvin, Aiden, Craddock, Nick, DiFlorio, Arianna, Hultman, Christina M., Landen, Mikael, Lewis, Cathryn, McCarroll, Steven A., Richard McCombie, W., McGuffin, Peter, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, Myers, Richard M., O’Donovan, Michael, Ophoff, Roel, Boks, Marco, Kahn, Rene, Ouwehand, Willem, Owen, Michael, Pato, Carlos, Pato, Michele, Posthuma, Danielle, Potash, James B., Reif, Andreas, Sklar, Pamela, Smoller, Jordan, Sullivan, Patrick F., Vincent, John, Walters, James, Neale, Benjamin, Purcell, Shaun, Risch, Neil, Schaefer, Catherine, Stahl, Eli A., Zandi, Peter P., and Scott, Laura J.

Published
2021
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40. Using expression and genotype to predict drug response in yeast.

Author

Ruderfer, Douglas M, Roberts, David C, Schreiber, Stuart L, Perlstein, Ethan O, and Kruglyak, Leonid

Subjects
RNA, Messenger, Genetic Markers, Reproducibility of Results, Drug Evaluation, Preclinical, Gene Expression Profiling, Computational Biology, Genomics, Gene Expression Regulation, Fungal, Genotype, Chemistry, Pharmaceutical, Algorithms, Genetic Linkage, Chemistry, Pharmaceutical, Drug Evaluation, Preclinical, Gene Expression Regulation, Fungal, RNA, Messenger, General Science & Technology
Abstract

Personalized, or genomic, medicine entails tailoring pharmacological therapies according to individual genetic variation at genomic loci encoding proteins in drug-response pathways. It has been previously shown that steady-state mRNA expression can be used to predict the drug response (i.e., sensitivity or resistance) of non-genotyped mammalian cancer cell lines to chemotherapeutic agents. In a real-world setting, clinicians would have access to both steady-state expression levels of patient tissue(s) and a patient's genotypic profile, and yet the predictive power of transcripts versus markers is not well understood. We have previously shown that a collection of genotyped and expression-profiled yeast strains can provide a model for personalized medicine. Here we compare the predictive power of 6,229 steady-state mRNA transcript levels and 2,894 genotyped markers using a pattern recognition algorithm. We were able to predict with over 70% accuracy the drug sensitivity of 104 individual genotyped yeast strains derived from a cross between a laboratory strain and a wild isolate. We observe that, independently of drug mechanism of action, both transcripts and markers can accurately predict drug response. Marker-based prediction is usually more accurate than transcript-based prediction, likely reflecting the genetic determination of gene expression in this cross.

Published
2009

41. Sleep patterns and risk of chronic disease as measured by long-term monitoring with commercial wearable devices in the All of Us Research Program

Author

Zheng, Neil S., Annis, Jeffrey, Master, Hiral, Han, Lide, Gleichauf, Karla, Ching, Jack H., Nasser, Melody, Coleman, Peyton, Desine, Stacy, Ruderfer, Douglas M., Hernandez, John, Schneider, Logan D., and Brittain, Evan L.

Abstract

Poor sleep health is associated with increased all-cause mortality and incidence of many chronic conditions. Previous studies have relied on cross-sectional and self-reported survey data or polysomnograms, which have limitations with respect to data granularity, sample size and longitudinal information. Here, using objectively measured, longitudinal sleep data from commercial wearable devices linked to electronic health record data from the All of Us Research Program, we show that sleep patterns, including sleep stages, duration and regularity, are associated with chronic disease incidence. Of the 6,785 participants included in this study, 71% were female, 84% self-identified as white and 71% had a college degree; the median age was 50.2 years (interquartile range = 35.7, 61.5) and the median sleep monitoring period was 4.5 years (2.5, 6.5). We found that rapid eye movement sleep and deep sleep were inversely associated with the odds of incident atrial fibrillation and that increased sleep irregularity was associated with increased odds of incident obesity, hyperlipidemia, hypertension, major depressive disorder and generalized anxiety disorder. Moreover, J-shaped associations were observed between average daily sleep duration and hypertension, major depressive disorder and generalized anxiety disorder. These findings show that sleep stages, duration and regularity are all important factors associated with chronic disease development and may inform evidence-based recommendations on healthy sleeping habits.

Published
2024
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42. Genome-wide analysis of nucleotide-level variation in commonly used Saccharomyces cerevisiae strains.

Author

Schacherer, Joseph, Ruderfer, Douglas M, Gresham, David, Dolinski, Kara, Botstein, David, and Kruglyak, Leonid

Subjects
Chromosomes, Fungal, Saccharomyces cerevisiae, Spores, Fungal, Nucleotides, Oligonucleotide Array Sequence Analysis, Nucleic Acid Hybridization, Species Specificity, Sequence Deletion, Polymorphism, Single Nucleotide, Genome, Fungal, Genetic Variation, Genome-Wide Association Study, Chromosomes, Fungal, Genome, Polymorphism, Single Nucleotide, Spores, General Science & Technology
Abstract

Ten years have passed since the genome of Saccharomyces cerevisiae-more precisely, the S288c strain-was completely sequenced. However, experimental work in yeast is commonly performed using strains that are of unknown genetic relationship to S288c. Here, we characterized the nucleotide-level similarity between S288c and seven commonly used lab strains (A364A, W303, FL100, CEN.PK, summation 1278b, SK1 and BY4716) using 25mer oligonucleotide microarrays that provide complete and redundant coverage of the approximately 12 Mb Saccharomyces cerevisiae genome. Using these data, we assessed the frequency and distribution of nucleotide variation in comparison to the sequenced reference genome. These data allow us to infer the relationships between experimentally important strains of yeast and provide insight for experimental designs that are sensitive to sequence variation. We propose a rational approach for near complete sequencing of strains related to the reference using these data and directed re-sequencing. These data and new visualization tools are accessible online in a new resource: the Yeast SNPs Browser (YSB; http://gbrowse.princeton.edu/cgi-bin/gbrowse/yeast_strains_snps) that is available to all researchers.

Published
2007

43. Telomere length as a quantitative trait: genome-wide survey and genetic mapping of telomere length-control genes in yeast.

Author

Gatbonton, Tonibelle, Imbesi, Maria, Nelson, Melisa, Akey, Joshua M, Ruderfer, Douglas M, Kruglyak, Leonid, Simon, Julian A, and Bedalov, Antonio

Subjects
Chromosomes, Fungal, Telomere, Saccharomyces cerevisiae, Fungal Proteins, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Chromosome Mapping, Gene Deletion, Sister Chromatid Exchange, Polymorphism, Genetic, Genes, Fungal, Genome, Fungal, Quantitative Trait Loci, Chromosomes, Fungal, Genes, Genome, Polymorphism, Genetic, Silent Information Regulator Proteins, Genetics, Developmental Biology
Abstract

Telomere length-variation in deletion strains of Saccharomyces cerevisiae was used to identify genes and pathways that regulate telomere length. We found 72 genes that when deleted confer short telomeres, and 80 genes that confer long telomeres relative to those of wild-type yeast. Among identified genes, 88 have not been previously implicated in telomere length control. Genes that regulate telomere length span a variety of functions that can be broadly separated into telomerase-dependent and telomerase-independent pathways. We also found 39 genes that have an important role in telomere maintenance or cell proliferation in the absence of telomerase, including genes that participate in deoxyribonucleotide biosynthesis, sister chromatid cohesion, and vacuolar protein sorting. Given the large number of loci identified, we investigated telomere lengths in 13 wild yeast strains and found substantial natural variation in telomere length among the isolates. Furthermore, we crossed a wild isolate to a laboratory strain and analyzed telomere length in 122 progeny. Genome-wide linkage analysis among these segregants revealed two loci that account for 30%-35% of telomere length-variation between the strains. These findings support a general model of telomere length-variation in outbred populations that results from polymorphisms at a large number of loci. Furthermore, our results laid the foundation for studying genetic determinants of telomere length-variation and their roles in human disease.

Published
2006

45. Interactive network-based clustering and investigation of multimorbidity association matrices with associationSubgraphs

Author

Strayer, Nick, primary, Zhang, Siwei, additional, Yao, Lydia, additional, Vessels, Tess, additional, Bejan, Cosmin A, additional, Hsi, Ryan S, additional, Shirey-Rice, Jana K, additional, Balko, Justin M, additional, Johnson, Douglas B, additional, Phillips, Elizabeth J, additional, Bick, Alex, additional, Edwards, Todd L, additional, Velez Edwards, Digna R, additional, Pulley, Jill M, additional, Wells, Quinn S, additional, Savona, Michael R, additional, Cox, Nancy J, additional, Roden, Dan M, additional, Ruderfer, Douglas M, additional, and Xu, Yaomin, additional

Published
2022
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46. Effect of predicted protein-truncating genetic variants on the human transcriptome

Author

The GTEx Consortium, The Geuvadis Consortium, Rivas, Manuel A., Pirinen, Matti, Conrad, Donald F., Lek, Monkol, Tsang, Emily K., Karczewski, Konrad J., Maller, Julian B., Kukurba, Kimberly R., DeLuca, David S., Fromer, Menachem, Ferreira, Pedro G., Smith, Kevin S., Zhang, Rui, Zhao, Fengmei, Banks, Eric, Poplin, Ryan, Ruderfer, Douglas M., Purcell, Shaun M., Tukiainen, Taru, Minikel, Eric V., Stenson, Peter D., Cooper, David N., Huang, Katharine H., Sullivan, Timothy J., Nedzel, Jared, Bustamante, Carlos D., Li, Jin Billy, Daly, Mark J., Guigo, Roderic, Donnelly, Peter, Ardlie, Kristin, Sammeth, Michael, Dermitzakis, Emmanouil T., McCarthy, Mark I., Montgomery, Stephen B., Lappalainen, Tuuli, and MacArthur, Daniel G.

Published
2015

47. Genome-wide association study of treatment resistant depression highlights shared biology with metabolic traits

Author

Kang, JooEun, primary, Castro, Victor M., additional, Ripperger, Michael, additional, Venkatesh, Sanan, additional, Burstein, David, additional, Linnér, Richard Karlsson, additional, Rocha, Daniel B., additional, Hu, Yirui, additional, Wilimitis, Drew, additional, Morley, Theodore, additional, Han, Lide, additional, Kim, Rachel Youngjung, additional, Feng, Yen-Chen Anne, additional, Ge, Tian, additional, Heckers, Stephan, additional, Voloudakis, Georgios, additional, Chabris, Christopher, additional, Roussos, Panos, additional, McCoy, Thomas H, additional, Walsh, Colin G., additional, Perlis, Roy H., additional, and Ruderfer, Douglas M., additional

Published
2022
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48. A cross-disorder dosage sensitivity map of the human genome

Author

Collins, Ryan L., primary, Glessner, Joseph T., additional, Porcu, Eleonora, additional, Lepamets, Maarja, additional, Brandon, Rhonda, additional, Lauricella, Christopher, additional, Han, Lide, additional, Morley, Theodore, additional, Niestroj, Lisa-Marie, additional, Ulirsch, Jacob, additional, Everett, Selin, additional, Howrigan, Daniel P., additional, Boone, Philip M., additional, Fu, Jack, additional, Karczewski, Konrad J., additional, Kellaris, Georgios, additional, Lowther, Chelsea, additional, Lucente, Diane, additional, Mohajeri, Kiana, additional, Nõukas, Margit, additional, Nuttle, Xander, additional, Samocha, Kaitlin E., additional, Trinh, Mi, additional, Ullah, Farid, additional, Võsa, Urmo, additional, Hurles, Matthew E., additional, Aradhya, Swaroop, additional, Davis, Erica E., additional, Finucane, Hilary, additional, Gusella, James F., additional, Janze, Aura, additional, Katsanis, Nicholas, additional, Matyakhina, Ludmila, additional, Neale, Benjamin M., additional, Sanders, David, additional, Warren, Stephanie, additional, Hodge, Jennelle C., additional, Lal, Dennis, additional, Ruderfer, Douglas M., additional, Meck, Jeanne, additional, Mägi, Reedik, additional, Esko, Tõnu, additional, Reymond, Alexandre, additional, Kutalik, Zoltán, additional, Hakonarson, Hakon, additional, Sunyaev, Shamil, additional, Brand, Harrison, additional, Talkowski, Michael E., additional, Metspalu, Andres, additional, Nelis, Mari, additional, and Milani, Lili, additional

Published
2022
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50. A polygenic resilience score moderates the genetic risk for schizophrenia

Author

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

Subjects
Multifactorial Inheritance, Schizophrenia/genetics, Genome-wide association study, Disease, Medical and Health Sciences, 0302 clinical medicine, Risk Factors, schizophrenia, genetics, risk, 2.1 Biological and endogenous factors, genetics, polygenic score, Aetiology, genome wide association study, risk, Genetics, Psychiatry, 0303 health sciences, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Genetic Predisposition to Disease/genetics, Single Nucleotide, Genomics, Biological Sciences, Serious Mental Illness, Polymorphism, Single Nucleotide/genetics, Penetrance, 3. Good health, Psychiatry and Mental health, Mental Health, Mendelian disease, Erfðarannsóknir, Life Sciences & Biomedicine, Single Nucleotide/genetics, Biochemistry & Molecular Biology, Schizophrenia (object-oriented programming), high risk, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Geðklofi, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Polymorphism, Resilience (network), Molecular Biology, resilience, Multifactorial Inheritance/genetics, Alleles, 030304 developmental biology, Science & Technology, Prevention, Human Genome, Psychology and Cognitive Sciences, Neurosciences, Brain Disorders, Lundbeck Foundation Initiative for Integrative Psychiatric Research, schizophrenia, Good Health and Well Being, Schizophrenia, Neurosciences & Neurology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531–538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known “polygenic resilience score” that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder., SJG is supported by grants from the U.S. National Institutes of Health (5R01MH101519, 5R01AG054002), the Sidney R. Baer, Jr. Foundation, and NARSAD: The Brain & Behavior Research Foundation. SVF is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreement number 667302 and NIMH grants 5R01MH101519 and U01 MH109536-01. HJE is supported by grants from the U.S. National Institutes of Health (U10 AA008401; U01 MH109532). Statistical analyses were conducted on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003) along with a supplement from the Dutch Brain Foundation and VU University. The Danish iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) and GEMS2 teams acknowledge funding from The Lundbeck Foundation (grant no R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project no: 294838), the Danish Strategic Research Council and grants from Aarhus University to the iSEQ and CIRRAU centers. The Danish National Biobank resource at Statens Serum Institut was supported by the Novo Nordisk Foundation. Computational resources for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility were provided by the iSEQ center, Aarhus University, Denmark (grant to ADB).

Published
2021

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