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30 results on '"P. Walters"'

1. Neural stem and progenitor cells support and protect adult hippocampal function via vascular endothelial growth factor secretion

Author

Miller, Lisa N., Walters, Ashley E., Denninger, Jiyeon K., Hanson, Meretta A., Marshall, Alec H., Johantges, Aidan C., Hosawi, Manal, Sebring, Gwendolyn, Rieskamp, Joshua D., Ding, Tianli, Rindani, Raina, Chen, Kelly S., Goldberg, Megan E., Senthilvelan, Sakthi, Volk, Abigail, Zhao, Fangli, Askwith, Candice, Wester, Jason C., and Kirby, Elizabeth D.

Published
2024
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3. 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

5. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.

Author

Cleynen, Isabelle, Engchuan, Worrawat, Hestand, Matthew S, Heung, Tracy, Holleman, Aaron M, Johnston, H Richard, Monfeuga, Thomas, McDonald-McGinn, Donna M, Gur, Raquel E, Morrow, Bernice E, Swillen, Ann, Vorstman, Jacob AS, Bearden, Carrie E, Chow, Eva WC, van den Bree, Marianne, Emanuel, Beverly S, Vermeesch, Joris R, Warren, Stephen T, Owen, Michael J, Chopra, Pankaj, Cutler, David J, Duncan, Richard, Kotlar, Alex V, Mulle, Jennifer G, Voss, Anna J, Zwick, Michael E, Diacou, Alexander, Golden, Aaron, Guo, Tingwei, Lin, Jhih-Rong, Wang, Tao, Zhang, Zhengdong, Zhao, Yingjie, Marshall, Christian, Merico, Daniele, Jin, Andrea, Lilley, Brenna, Salmons, Harold I, Tran, Oanh, Holmans, Peter, Pardinas, Antonio, Walters, James TR, Demaerel, Wolfram, Boot, Erik, Butcher, Nancy J, Costain, Gregory A, Lowther, Chelsea, Evers, Rens, van Amelsvoort, Therese AMJ, van Duin, Esther, Vingerhoets, Claudia, Breckpot, Jeroen, Devriendt, Koen, Vergaelen, Elfi, Vogels, Annick, Crowley, T Blaine, McGinn, Daniel E, Moss, Edward M, Sharkus, Robert J, Unolt, Marta, Zackai, Elaine H, Calkins, Monica E, Gallagher, Robert S, Gur, Ruben C, Tang, Sunny X, Fritsch, Rosemarie, Ornstein, Claudia, Repetto, Gabriela M, Breetvelt, Elemi, Duijff, Sasja N, Fiksinski, Ania, Moss, Hayley, Niarchou, Maria, Murphy, Kieran C, Prasad, Sarah E, Daly, Eileen M, Gudbrandsen, Maria, Murphy, Clodagh M, Murphy, Declan G, Buzzanca, Antonio, Fabio, Fabio Di, Digilio, Maria C, Pontillo, Maria, Marino, Bruno, Vicari, Stefano, Coleman, Karlene, Cubells, Joseph F, Ousley, Opal Y, Carmel, Miri, Gothelf, Doron, Mekori-Domachevsky, Ehud, Michaelovsky, Elena, Weinberger, Ronnie, Weizman, Abraham, Kushan, Leila, Jalbrzikowski, Maria, Armando, Marco, Eliez, Stéphan, Sandini, Corrado, and Schneider, Maude

Subjects
International 22q11.2DS Brain and Behavior Consortium, Prevention, Serious Mental Illness, Genetics, Human Genome, Schizophrenia, Neurosciences, Mental Health, Clinical Research, Pediatric, Brain Disorders, 2.1 Biological and endogenous factors, Mental health, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

Published
2021

8. Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium

Author

Polimanti, Renato, Walters, Raymond K, Johnson, Emma C, McClintick, Jeanette N, Adkins, Amy E, Adkins, Daniel E, Bacanu, Silviu-Alin, Bierut, Laura J, Bigdeli, Tim B, Brown, Sandra, Bucholz, Kathleen K, Copeland, William E, Costello, E Jane, Degenhardt, Louisa, Farrer, Lindsay A, Foroud, Tatiana M, Fox, Louis, Goate, Alison M, Grucza, Richard, Hack, Laura M, Hancock, Dana B, Hartz, Sarah M, Heath, Andrew C, Hewitt, John K, Hopfer, Christian J, Johnson, Eric O, Kendler, Kenneth S, Kranzler, Henry R, Krauter, Kenneth, Lai, Dongbing, Madden, Pamela AF, Martin, Nicholas G, Maes, Hermine H, Nelson, Elliot C, Peterson, Roseann E, Porjesz, Bernice, Riley, Brien P, Saccone, Nancy, Stallings, Michael, Wall, Tamara L, Webb, Bradley T, Wetherill, Leah, Edenberg, Howard J, Agrawal, Arpana, and Gelernter, Joel

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Drug Abuse (NIDA only), Substance Misuse, Neurosciences, Brain Disorders, Human Genome, Genetics, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Analgesics, Opioid, Behavior, Addictive, Female, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Genome-Wide Association Study, Genomics, Humans, Male, Multifactorial Inheritance, Opioid-Related Disorders, Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

Published
2020

10. Identification of genetic overlap and novel risk loci for attention-deficit/hyperactivity disorder and bipolar disorder

Author

O’Connell, Kevin S., Shadrin, Alexey, Bahrami, Shahram, Smeland, Olav B., Bettella, Francesco, Frei, Oleksandr, Krull, Florian, Askeland, Ragna B., Walters, G. Bragi, Davíðsdóttir, Katrín, Haraldsdóttir, Gyða S., Guðmundsson, Ólafur Ó., Stefánsson, Hreinn, Fan, Chun C., Steen, Nils Eiel, Reichborn-Kjennerud, Ted, Dale, Anders M., Stefánsson, Kári, Djurovic, Srdjan, and Andreassen, Ole A.

Published
2021
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13. Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Author

Sønderby, Ida E, Gústafsson, Ómar, Doan, Nhat Trung, Hibar, Derrek P, Martin-Brevet, Sandra, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Michael, Armstrong, Nicola J, Bernard, Manon, Blackburn, Nicholas, Blangero, John, Boomsma, Dorret I, Bralten, Janita, Brattbak, Hans-Richard, Brodaty, Henry, Brouwer, Rachel M, Bülow, Robin, Calhoun, Vince, Caspers, Svenja, Cavalleri, Gianpiero, Chen, Chi-Hua, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E, Dale, Anders M, Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J C, de Zubicaray, Greig I., de Zwarte, Sonja M. C., Delanty, Norman, den Braber, Anouk, Desrivières, Sylvane, Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Espeseth, Thomas, Fisher, Simon E, Franke, Barbara, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C, Grabe, Hans, Groenewold, Nynke A., Haavik, Jan, Håberg, Asta, Hashimoto, Ryota, Hehir-Kwa, Jayne Y, Heinz, Andreas, Hillegers, Manon H. J., Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke-Jan, Hulshoff, Hilleke E, Ikeda, Masashi, Jahanshad, Neda, Jernigan, Terry, Jockwitz, Christiane, Johansson, Stefan, Jonsdottir, Gudrun A, Jönsson, Erik G, Kahn, Rene, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Knowles, Emma E M, Kolskår, Knut K, Kwok, John B, Hellard, Stephanie Le, Leu, Costin, Liu, Jingyu, Lundervold, Astri J, Lundervold, Arvid, Martin, Nicholas G., Mather, Karen, Mathias, Samuel R., McCormack, Mark, McMahon, Katie L., McRae, Allan, Milaneschi, Yuri, Moreau, Clara, Morris, Derek, Mothersill, David, Mühleisen, Thomas W, Murray, Robin, Nordvik, Jan E, Nyberg, Lars, Olde Loohuis, Loes M, Ophoff, Roel, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda, Peralta, Juan M, Pike, Bruce, Prieto, Carlos, Pudas, Sara, Quinlan, Erin, Quintana, Daniel S, Reinbold, Céline S, Marques, Tiago Reis, Reymond, Alexandre, Richard, Genevieve, Rodriguez-Herreros, Borja, Roiz-Santiañez, Roberto, Rokicki, Jarek, Rucker, James, Sachdev, Perminder, Sanders, Anne-Marthe, Sando, Sigrid B, Schmaal, Lianne, Schofield, Peter R, Schork, Andrew J., Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Sisodiya, Sanjay, Steen, Vidar M, Stein, Dan J, Steinberg, Stacy, Strike, Lachlan, Teumer, Alexander, Thalamuthu, Anbu, Tordesillas-Gutierrez, Diana, Turner, Jessica, Ueland, Torill, Uhlmann, Anne, Ulfarsson, Magnus O., van ’t Ent, Dennis, van der Meer, Dennis, van Haren, Neeltje E. M., Vaskinn, Anja, Vassos, Evangelos, Walters, G. Bragi, Wang, Yunpeng, Wen, Wei, Whelan, Christopher D, Wittfeld, Katharina, Wright, Margie, Yamamori, Hidenaga, Zayats, Tetyana, Agartz, Ingrid, Westlye, Lars T, Jacquemont, Sébastien, Djurovic, Srdjan, Stefánsson, Hreinn, Stefánsson, Kári, Thompson, Paul, and Andreassen, Ole A.

Published
2020
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14. Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Author

Sønderby, Ida E., Gústafsson, Ómar, Doan, Nhat Trung, Hibar, Derrek P., Martin-Brevet, Sandra, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Michael, Armstrong, Nicola J., Bernard, Manon, Blackburn, Nicholas, Blangero, John, Boomsma, Dorret I., Bralten, Janita, Brattbak, Hans-Richard, Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Calhoun, Vince, Caspers, Svenja, Cavalleri, Gianpiero, Chen, Chi-Hua, Cichon, Sven, Ciufolini, Simone, Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J. C., de Zubicaray, Greig I., de Zwarte, Sonja M. C., Delanty, Norman, den Braber, Anouk, Desrivières, Sylvane, Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Espeseth, Thomas, Fisher, Simon E., Franke, Barbara, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Glahn, David C., Grabe, Hans, Groenewold, Nynke A., Haavik, Jan, Håberg, Asta, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Heinz, Andreas, Hillegers, Manon H. J., Hoffmann, Per, Holleran, Laurena, Hottenga, Jouke-Jan, Hulshoff, Hilleke E., Ikeda, Masashi, Jahanshad, Neda, Jernigan, Terry, Jockwitz, Christiane, Johansson, Stefan, Jonsdottir, Gudrun A., Jönsson, Erik G., Kahn, Rene, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Knowles, Emma E. M., Kolskår, Knut K., Kwok, John B., Hellard, Stephanie Le, Leu, Costin, Liu, Jingyu, Lundervold, Astri J., Lundervold, Arvid, Martin, Nicholas G., Mather, Karen, Mathias, Samuel R., McCormack, Mark, McMahon, Katie L., McRae, Allan, Milaneschi, Yuri, Moreau, Clara, Morris, Derek, Mothersill, David, Mühleisen, Thomas W., Murray, Robin, Nordvik, Jan E., Nyberg, Lars, Olde Loohuis, Loes M., Ophoff, Roel, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda, Peralta, Juan M., Pike, Bruce, Prieto, Carlos, Pudas, Sara, Quinlan, Erin, Quintana, Daniel S., Reinbold, Céline S., Marques, Tiago Reis, Reymond, Alexandre, Richard, Genevieve, Rodriguez-Herreros, Borja, Roiz-Santiañez, Roberto, Rokicki, Jarek, Rucker, James, Sachdev, Perminder, Sanders, Anne-Marthe, Sando, Sigrid B., Schmaal, Lianne, Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Sisodiya, Sanjay, Steen, Vidar M., Stein, Dan J., Steinberg, Stacy, Strike, Lachlan, Teumer, Alexander, Thalamuthu, Anbu, Tordesillas-Gutierrez, Diana, Turner, Jessica, Ueland, Torill, Uhlmann, Anne, Ulfarsson, Magnus O., van ’t Ent, Dennis, van der Meer, Dennis, van Haren, Neeltje E. M., Vaskinn, Anja, Vassos, Evangelos, Walters, G. Bragi, Wang, Yunpeng, Wen, Wei, Whelan, Christopher D., Wittfeld, Katharina, Wright, Margie, Yamamori, Hidenaga, Zayats, Tetyana, Agartz, Ingrid, Westlye, Lars T., Jacquemont, Sébastien, Djurovic, Srdjan, Stefánsson, Hreinn, Stefánsson, Kári, Thompson, Paul, and Andreassen, Ole A.

Published
2020
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17. 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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18. Copy number variation in schizophrenia in Sweden

Author

Szatkiewicz, J P, O'Dushlaine, C, Chen, G, Chambert, K, Moran, J L, Neale, B M, Fromer, M, Ruderfer, D, Akterin, S, Bergen, S E, Kähler, A, Magnusson, P K E, Kim, Y, Crowley, J J, Rees, E, Kirov, G, O'Donovan, M C, Owen, M J, Walters, J, Scolnick, E, Sklar, P, Purcell, S, Hultman, C M, McCarroll, S A, and Sullivan, P F

Published
2014
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24. Conditional GWAS analysis to identify disorder-specific SNPs for psychiatric disorders

Author

Byrne, Enda M., Zhu, Zhihong, Qi, Ting, Skene, Nathan G., Bryois, Julien, Pardinas, Antonio F., Stahl, Eli, Smoller, Jordan W., Rietschel, Marcella, Owen, Michael J., Walters, James T. R., O’Donovan, Michael C., McGrath, John G., Hjerling-Leffler, Jens, Sullivan, Patrick F., Goddard, Michael E., Visscher, Peter M., Yang, Jian, and Wray, Naomi R.

Abstract

Substantial genetic liability is shared across psychiatric disorders but less is known about risk variants that are specific to a given disorder. We used multi-trait conditional and joint analysis (mtCOJO) to adjust GWAS summary statistics of one disorder for the effects of genetically correlated traits to identify putative disorder-specific SNP associations. We applied mtCOJO to summary statistics for five psychiatric disorders from the Psychiatric Genomics Consortium—schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit hyperactivity disorder (ADHD) and autism (AUT). Most genome-wide significant variants for these disorders had evidence of pleiotropy (i.e., impact on multiple psychiatric disorders) and hence have reduced mtCOJO conditional effect sizes. However, subsets of genome-wide significant variants had larger conditional effect sizes consistent with disorder-specific effects: 15 of 130 genome-wide significant variants for schizophrenia, 5 of 40 for major depression, 3 of 11 for ADHD and 1 of 2 for autism. We show that decreased expression of VPS29in the brain may increase risk to SCZ only and increased expression of CSE1Lis associated with SCZ and MD, but not with BIP. Likewise, decreased expression of PCDHA7in the brain is linked to increased risk of MD but decreased risk of SCZ and BIP.

Published
2021
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25. Erratum: Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC

Author

Hamshere, M L, Walters, J T R, Smith, R, Richards, A L, Green, E, Grozeva, D, Jones, I, Forty, L, Jones, L, Gordon-Smith, K, Riley, B, O'Neill, T, Kendler, K S, Sklar, P, Purcell, S, Kranz, J, Morris, D, Gill, M, Holmans, P, Craddock, N, Corvin, A, Owen, M J, and O'Donovan, M C

Published
2013
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26. Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

Author

Legge, S E, Hamshere, M L, Ripke, S, Pardinas, A F, Goldstein, J I, Rees, E, Richards, A L, Leonenko, G, Jorskog, L F, Chambert, K D, Collier, D A, Genovese, G, Giegling, I, Holmans, P, Jonasdottir, A, Kirov, G, McCarroll, S A, MacCabe, J H, Mantripragada, K, Moran, J L, Neale, B M, Stefansson, H, Rujescu, D, Daly, M J, Sullivan, P F, Owen, M J, O'Donovan, M C, and Walters, J T R

Abstract

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10−8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

Published
2017
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27. Common alleles contribute to schizophrenia in CNV carriers

Author

Tansey, K E, Rees, E, Linden, D E, Ripke, S, Chambert, K D, Moran, J L, McCarroll, S A, Holmans, P, Kirov, G, Walters, J, Owen, M J, and O'Donovan, M C

Abstract

The genetic architecture of schizophrenia is complex, involving risk alleles ranging from common alleles of weak effect to rare alleles of large effect, the best exemplar of the latter being large copy number variants (CNVs). It is currently unknown whether pathophysiology in those with defined rare mutations overlaps with that in other individuals with the disorder who do not share the same rare mutation. Under an extreme heterogeneity model, carriers of specific high-penetrance mutations form distinct subgroups. In contrast, under a polygenic threshold model, high-penetrance rare allele carriers possess many risk factors, of which the rare allele is the only one, albeit an important, factor. Under the latter model, cases with rare mutations can be expected to share some common risk alleles, and therefore pathophysiological mechanisms, with cases without the same mutation. Here we show that, compared with controls, individuals with schizophrenia who have known pathogenic CNVs carry an excess burden of common risk alleles (P=2.25 × 10−17) defined from a genome-wide association study largely based on individuals without known CNVs. Our finding is not consistent with an extreme heterogeneity model for CNV carriers, but does offer support for the polygenic threshold model of schizophrenia. That this is so provides support for the notion that studies aiming to model the effects of rare variation may uncover pathophysiological mechanisms of relevance to those with the disorder more widely.

Published
2016
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28. Copy number variation in bipolar disorder

Author

Green, E K, Rees, E, Walters, J T R, Smith, K-G, Forty, L, Grozeva, D, Moran, J L, Sklar, P, Ripke, S, Chambert, K D, Genovese, G, McCarroll, S A, Jones, I, Jones, L, Owen, M J, O'Donovan, M C, Craddock, N, and Kirov, G

Abstract

Large (>100 kb), rare (<1% in the population) copy number variants (CNVs) have been shown to confer risk for schizophrenia (SZ), but the findings for bipolar disorder (BD) are less clear. In a new BD sample from the United Kingdom (n=2591), we have examined the occurrence of CNVs and compared this with previously reported samples of 6882 SZ and 8842 control subjects. When combined with previous data, we find evidence for a contribution to BD for three SZ-associated CNV loci: duplications at 1q21.1 (P=0.022), deletions at 3q29 (P=0.03) and duplications at 16p11.2 (P=2.3 × 10−4). The latter survives multiple-testing correction for the number of recurrent large CNV loci in the genome. Genes in 20 regions (total of 55 genes) were enriched for rare exonic CNVs among BD cases, but none of these survives correction for multiple testing. Finally, our data provide strong support for the hypothesis of a lesser contribution of very large (>500 kb) CNVs in BD compared with SZ, most notably for deletions >1 Mb (P=9 × 10−4).

Published
2016
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29. Erratum: Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

Author

Legge, S E, Hamshere, M L, Ripke, S, Pardinas, A F, Goldstein, J I, Rees, E, Richards, A L, Leonenko, G, Jorskog, L F, Chambert, K D, Collier, D A, Genovese, G, Giegling, I, Holmans, P, Jonasdottir, A, Kirov, G, McCarroll, S A, MacCabe, J H, Mantripragada, K, Moran, J L, Neale, B M, Stefansson, H, Rujescu, D, Daly, M J, Sullivan, P F, Owen, M J, O'Donovan, M C, and Walters, J T R

Abstract

Correction to: Molecular Psychiatry (2017) 22: 1502-1508; advance online publication, 12 July 2017; doi: 10.1038/mp.2016.97 In the first paragraph of the Results section and Figure 1, the authors incorrectly referred to the finding of SNP rs77897117. The correct SNP is rs77897177. The corrected figure appears in previous page.

Published
2018
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30. Erratum: Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

Author

Legge, S E, Hamshere, M L, Ripke, S, Pardinas, A F, Goldstein, J I, Rees, E, Richards, A L, Leonenko, G, Jorskog, L F, Chambert, K D, Collier, D A, Genovese, G, Giegling, I, Holmans, P, Jonasdottir, A, Kirov, G, McCarroll, S A, MacCabe, J H, Mantripragada, K, Moran, J L, Neale, B M, Stefansson, H, Rujescu, D, Daly, M J, Sullivan, P F, Owen, M J, O'Donovan, M C, and Walters, J T R

Abstract

Correction to: Molecular Psychiatry advance online publication, 12 July 2016; doi:10.1038/mp.2016.97 The ninth author’s name was presented incorrectly. It should have been listed as LF Jarskog.

Published
2017
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