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1. Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Author

Niemsiri, Vipavee, Rosenthal, Sara Brin, Nievergelt, Caroline M, Maihofer, Adam X, Marchetto, Maria C, Santos, Renata, Shekhtman, Tatyana, Alliey-Rodriguez, Ney, Anand, Amit, Balaraman, Yokesh, Berrettini, Wade H, Bertram, Holli, Burdick, Katherine E, Calabrese, Joseph R, Calkin, Cynthia V, Conroy, Carla, Coryell, William H, DeModena, Anna, Eyler, Lisa T, Feeder, Scott, Fisher, Carrie, Frazier, Nicole, Frye, Mark A, Gao, Keming, Garnham, Julie, Gershon, Elliot S, Goes, Fernando S, Goto, Toyomi, Harrington, Gloria J, Jakobsen, Petter, Kamali, Masoud, Kelly, Marisa, Leckband, Susan G, Lohoff, Falk W, McCarthy, Michael J, McInnis, Melvin G, Craig, David, Millett, Caitlin E, Mondimore, Francis, Morken, Gunnar, Nurnberger, John I, Donovan, Claire O’, Øedegaard, Ketil J, Ryan, Kelly, Schinagle, Martha, Shilling, Paul D, Slaney, Claire, Stapp, Emma K, Stautland, Andrea, Tarwater, Bruce, Zandi, Peter P, Alda, Martin, Fisch, Kathleen M, Gage, Fred H, and Kelsoe, John R

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical and Health Psychology, Clinical Sciences, Psychology, Serious Mental Illness, Genetics, Mental Health, Brain Disorders, Human Genome, Mental health, Bipolar Disorder, Humans, Lithium, Gene Regulatory Networks, Focal Adhesions, Transcriptome, Genome-Wide Association Study, Neurons, Induced Pluripotent Stem Cells, Pharmacogenetics, Antimanic Agents, Male, Female, Lithium Compounds, Gene Expression Profiling, Genomics, Multiomics, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Published
2024

2. Exploring the genetics of lithium response in bipolar disorders

Author

Herrera-Rivero, Marisol, Adli, Mazda, Akiyama, Kazufumi, Akula, Nirmala, Amare, Azmeraw T., Ardau, Raffaella, Arias, Bárbara, Aubry, Jean-Michel, Backlund, Lena, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Bhattacharjee, Abesh Kumar, Biernacka, Joanna M., Birner, Armin, Cearns, Micah, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Clark, Scott R., Colom, Francesc, Cruceanu, Cristiana, Czerski, Piotr M., Dalkner, Nina, Degenhardt, Franziska, Del Zompo, Maria, DePaulo, J. Raymond, Etain, Bruno, Falkai, Peter, Ferensztajn-Rochowiak, Ewa, Forstner, Andreas J., Frank, Josef, Frisén, Louise, Frye, Mark A., Fullerton, Janice M., Gallo, Carla, Gard, Sébastien, Garnham, Julie S., Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hasler, Roland, Hauser, Joanna, Heilbronner, Urs, Herms, Stefan, Hoffmann, Per, Hou, Liping, Hsu, Yi-Hsiang, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kato, Tadafumi, Kelsoe, John, Kittel-Schneider, Sarah, Kuo, Po-Hsiu, Kusumi, Ichiro, König, Barbara, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G., Maj, Mario, Manchia, Mirko, Marie-Claire, Cynthia, Martinsson, Lina, McCarthy, Michael J., McElroy, Susan L., Millischer, Vincent, Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Novák, Tomas, Nöthen, Markus M., O’Donovan, Claire, Ozaki, Norio, Papiol, Sergi, Pfennig, Andrea, Pisanu, Claudia, Potash, James B., Reif, Andreas, Reininghaus, Eva, Richard-Lepouriel, Hélène, Roberts, Gloria, Rouleau, Guy A., Rybakowski, Janusz K., Schalling, Martin, Schofield, Peter R., Schubert, Klaus Oliver, Schulte, Eva C., Schweizer, Barbara W., Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D., Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M., Squassina, Alessio, Stamm, Thomas, Stopkova, Pavla, Streit, Fabian, Tekola-Ayele, Fasil, Thalamuthu, Anbupalam, Tortorella, Alfonso, Turecki, Gustavo, Veeh, Julia, Vieta, Eduard, Viswanath, Biju, Witt, Stephanie H., Zandi, Peter P., Alda, Martin, Bauer, Michael, McMahon, Francis J., Mitchell, Philip B., Rietschel, Marcella, Schulze, Thomas G., and Baune, Bernhard T.

Published
2024
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3. Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study

Author

Ou, Anna H., Rosenthal, Sara B., Adli, Mazda, Akiyama, Kazufumi, Akula, Nirmala, Alda, Martin, Amare, Azmeraw T., Ardau, Raffaella, Arias, Bárbara, Aubry, Jean-Michel, Backlund, Lena, Bauer, Michael, Baune, Bernhard T., Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Bhattacharjee, Abesh Kumar, Biernacka, Joanna M., Cervantes, Pablo, Chen, Guo-Bo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Clark, Scott R., Colom, Francesc, Cousins, David A., Cruceanu, Cristiana, Czerski, Piotr M., Dantas, Clarissa R., Dayer, Alexandre, Del Zompo, Maria, Degenhardt, Franziska, DePaulo, J. Raymond, Étain, Bruno, Falkai, Peter, Fellendorf, Frederike Tabea, Ferensztajn-Rochowiak, Ewa, Forstner, Andreas J., Frisén, Louise, Frye, Mark A., Fullerton, Janice M., Gard, Sébastien, Garnham, Julie S., Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Grof, Paul, Gruber, Oliver, Hashimoto, Ryota, Hauser, Joanna, Heilbronner, Urs, Herms, Stefan, Hoffmann, Per, Hofmann, Andrea, Hou, Liping, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kato, Tadafumi, Kittel-Schneider, Sarah, König, Barbara, Kuo, Po-Hsiu, Kusumi, Ichiro, Lackner, Nina, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G., Jaramillo, Carlos A. López, MacQueen, Glenda, Maj, Mario, Manchia, Mirko, Marie-Claire, Cynthia, Martinsson, Lina, Mattheisen, Manuel, McCarthy, Michael J., McElroy, Susan L., McMahon, Francis J., Mitchell, Philip B., Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Nöthen, Markus M., Novák, Tomas, Ösby, Urban, Ozaki, Norio, Papiol, Sergi, Perlis, Roy H., Pisanu, Claudia, Potash, James B., Pfennig, Andrea, Reich-Erkelenz, Daniela, Reif, Andreas, Reininghaus, Eva Z., Rietschel, Marcella, Rouleau, Guy A., Rybakowski, Janusz K., Schalling, Martin, Schofield, Peter R., Schubert, K. Oliver, Schulze, Thomas G., Schweizer, Barbara W., Seemüller, Florian, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D., Shimoda, Kazutaka, Simhandl, Christian, Slaney, Claire M., Squassina, Alessio, Stamm, Thomas, Stopkova, Pavla, Tighe, Sarah K., Tortorella, Alfonso, Turecki, Gustavo, Vieta, Eduard, Volkert, Julia, Witt, Stephanie, Wray, Naomi R., Wright, Adam, Young, L. Trevor, Zandi, Peter P., and Kelsoe, John R.

Published
2024
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5. Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Author

Amare, Azmeraw T., Thalamuthu, Anbupalam, Schubert, Klaus Oliver, Fullerton, Janice M., Ahmed, Muktar, Hartmann, Simon, Papiol, Sergi, Heilbronner, Urs, Degenhardt, Franziska, Tekola-Ayele, Fasil, Hou, Liping, Hsu, Yi-Hsiang, Shekhtman, Tatyana, Adli, Mazda, Akula, Nirmala, Akiyama, Kazufumi, Ardau, Raffaella, Arias, Bárbara, Aubry, Jean-Michel, Hasler, Roland, Richard-Lepouriel, Hélène, Perroud, Nader, Backlund, Lena, Bhattacharjee, Abesh Kumar, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Biernacka, Joanna M., Birner, Armin, Marie-Claire, Cynthia, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Cruceanu, Cristiana, Czerski, Piotr M., Dalkner, Nina, Del Zompo, Maria, DePaulo, J. Raymond, Étain, Bruno, Jamain, Stephane, Falkai, Peter, Forstner, Andreas J., Frisen, Louise, Frye, Mark A., Gard, Sébastien, Garnham, Julie S., Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Fallgatter, Andreas J., Stegmaier, Sophia, Ethofer, Thomas, Biere, Silvia, Petrova, Kristiyana, Schuster, Ceylan, Adorjan, Kristina, Budde, Monika, Heilbronner, Maria, Kalman, Janos L., Kohshour, Mojtaba Oraki, Reich-Erkelenz, Daniela, Schaupp, Sabrina K., Schulte, Eva C., Senner, Fanny, Vogl, Thomas, Anghelescu, Ion-George, Arolt, Volker, Dannlowski, Udo, Dietrich, Detlef, Figge, Christian, Jäger, Markus, Lang, Fabian U., Juckel, Georg, Konrad, Carsten, Reimer, Jens, Schmauß, Max, Schmitt, Andrea, Spitzer, Carsten, von Hagen, Martin, Wiltfang, Jens, Zimmermann, Jörg, Andlauer, Till F. M., Fischer, Andre, Bermpohl, Felix, Ritter, Philipp, Matura, Silke, Gryaznova, Anna, Falkenberg, Irina, Yildiz, Cüneyt, Kircher, Tilo, Schmidt, Julia, Koch, Marius, Gade, Kathrin, Trost, Sarah, Haussleiter, Ida S., Lambert, Martin, Rohenkohl, Anja C., Kraft, Vivien, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kuo, Po-Hsiu, Kato, Tadafumi, Kelsoe, John, Kittel-Schneider, Sarah, Ferensztajn-Rochowiak, Ewa, König, Barbara, Kusumi, Ichiro, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G., Tortorella, Alfonso, Manchia, Mirko, Martinsson, Lina, McCarthy, Michael J., McElroy, Susan, Colom, Francesc, Millischer, Vincent, Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Nöthen, Markus M., Novák, Tomas, O’Donovan, Claire, Ozaki, Norio, Pfennig, Andrea, Pisanu, Claudia, Potash, James B., Reif, Andreas, Reininghaus, Eva, Rouleau, Guy A., Rybakowski, Janusz K., Schalling, Martin, Schofield, Peter R., Schweizer, Barbara W., Severino, Giovanni, Shilling, Paul D., Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M., Squassina, Alessio, Stamm, Thomas, Stopkova, Pavla, Maj, Mario, Turecki, Gustavo, Vieta, Eduard, Veeh, Julia, Witt, Stephanie H., Wright, Adam, Zandi, Peter P., Mitchell, Philip B., Bauer, Michael, Alda, Martin, Rietschel, Marcella, McMahon, Francis J., Schulze, Thomas G., Clark, Scott R., and Baune, Bernhard T.

Published
2023
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8. Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Author

Palmer, Duncan S, Howrigan, Daniel P, Chapman, Sinéad B, Adolfsson, Rolf, Bass, Nick, Blackwood, Douglas, Boks, Marco PM, Chen, Chia-Yen, Churchhouse, Claire, Corvin, Aiden P, Craddock, Nicholas, Curtis, David, Di Florio, Arianna, Dickerson, Faith, Freimer, Nelson B, Goes, Fernando S, Jia, Xiaoming, Jones, Ian, Jones, Lisa, Jonsson, Lina, Kahn, Rene S, Landén, Mikael, Locke, Adam E, McIntosh, Andrew M, McQuillin, Andrew, Morris, Derek W, O’Donovan, Michael C, Ophoff, Roel A, Owen, Michael J, Pedersen, Nancy L, Posthuma, Danielle, Reif, Andreas, Risch, Neil, Schaefer, Catherine, Scott, Laura, Singh, Tarjinder, Smoller, Jordan W, Solomonson, Matthew, Clair, David St, Stahl, Eli A, Vreeker, Annabel, Walters, James TR, Wang, Weiqing, Watts, Nicholas A, Yolken, Robert, Zandi, Peter P, and Neale, Benjamin M

Subjects
Biotechnology, Human Genome, Clinical Research, Serious Mental Illness, Schizophrenia, Brain Disorders, Bipolar Disorder, Mental Health, Genetics, 2.1 Biological and endogenous factors, Aetiology, Mental health, A Kinase Anchor Proteins, Exome, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Exome Sequencing, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Published
2022

10. 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

11. Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies

Author

Mishra, Himanshu K, Ying, Noelle M, Luis, Angelica, Wei, Heather, Nguyen, Metta, Nakhla, Timothy, Vandenburgh, Sara, Alda, Martin, Berrettini, Wade H, Brennand, Kristen J, Calabrese, Joseph R, Coryell, William H, Frye, Mark A, Gage, Fred H, Gershon, Elliot S, McInnis, Melvin G, Nievergelt, Caroline M, Nurnberger, John I, Shilling, Paul D, Oedegaard, Ketil J, Zandi, Peter P, Kelsoe, John R, Welsh, David K, and McCarthy, Michael J

Subjects
Depression, Sleep Research, Bipolar Disorder, Mental Health, Serious Mental Illness, Neurosciences, Brain Disorders, Mental health, Circadian Rhythm, Humans, Lithium, Lithium Compounds, Neurons, Pharmacogenomics of Bipolar Disorder Study, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

Published
2021

12. Contributions of circadian clock genes to cell survival in fibroblast models of lithium-responsive bipolar disorder

Author

Mishra, Himanshu K., Wei, Heather, Rohr, Kayla E., Ko, Insu, Nievergelt, Caroline M., Maihofer, Adam X., Shilling, Paul D., Alda, Martin, Berrettini, Wade H., Brennand, Kristen J., Calabrese, Joseph R., Coryell, William H., Frye, Mark, Gage, Fred, Gershon, Elliot, McInnis, Melvin G., Nurnberger, John, Oedegaard, Ketil J., Zandi, Peter P., Kelsoe, John R., and McCarthy, Michael J.

Published
2023
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13. Investigating the phenotypic and genetic associations between personality traits and suicidal behavior across major mental health diagnoses

Author

Kalman, Janos L., Yoshida, Tomoya, Andlauer, Till F. M., Schulte, Eva C., Adorjan, Kristina, Alda, Martin, Ardau, Raffaela, Aubry, Jean-Michel, Brosch, Katharina, Budde, Monika, Chillotti, Caterina, Czerski, Piotr M., DePaulo, Raymond J., Forstner, Andreas, Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Grof, Paul, Grotegerd, Dominik, Hahn, Tim, Heilbronner, Maria, Hasler, Roland, Heilbronner, Urs, Heilmann-Heimbach, Stefanie, Kapelski, Pawel, Kato, Tadafumi, Kohshour, Mojtaba Oraki, Meinert, Susanne, Meller, Tina, Nenadić, Igor, Nöthen, Markus M., Novak, Tomas, Opel, Nils, Pawlak, Joanna, Pfarr, Julia-Katharina, Potash, James B., Reich-Erkelenz, Daniela, Repple, Jonathan, Richard-Lepouriel, Hélène, Rietschel, Marcella, Ringwald, Kai G., Rouleau, Guy, Schaupp, Sabrina, Senner, Fanny, Severino, Giovanni, Squassina, Alessio, Stein, Frederike, Stopkova, Pavla, Streit, Fabian, Thiel, Katharina, Thomas-Odenthal, Florian, Turecki, Gustavo, Twarowska-Hauser, Joanna, Winter, Alexandra, Zandi, Peter P., Kelsoe, John R., Falkai, Peter, Dannlowski, Udo, Kircher, Tilo, Schulze, Thomas G., and Papiol, Sergi

Published
2022
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14. The association between lithium use and neurocognitive performance in patients with bipolar disorder

Author

Burdick, Katherine E, Millett, Caitlin E, Russo, Manuela, Alda, Martin, Alliey-Rodriguez, Ney, Anand, Amit, Balaraman, Yokesh, Berrettini, Wade, Bertram, Holli, Calabrese, Joseph R, Calkin, Cynthia, Conroy, Carla, Coryell, William, DeModena, Anna, Feeder, Scott, Fisher, Carrie, Frazier, Nicole, Frye, Mark, Gao, Keming, Garnham, Julie, Gershon, Elliot S, Glazer, Kara, Goes, Fernando S, Goto, Toyomi, Harrington, Gloria J, Jakobsen, Petter, Kamali, Masoud, Kelly, Marisa, Leckband, Susan, Løberg, Else Marie, Lohoff, Falk W, Maihofer, Adam X, McCarthy, Michael J, McInnis, Melvin, Morken, Gunnar, Nievergelt, Caroline M, Nurnberger, John, Oedegaard, Ketil J, Ortiz, Abigail, Ritchey, Megan, Ryan, Kelly, Schinagle, Martha, Schwebel, Candice, Shaw, Martha, Shilling, Paul, Slaney, Claire, Stapp, Emma, Tarwater, Bruce, Zandi, Peter, and Kelsoe, John R

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Mental Health, Serious Mental Illness, Brain Disorders, Behavioral and Social Science, Clinical Research, Bipolar Disorder, Clinical Trials and Supportive Activities, Mental health, Cognition, Cross-Sectional Studies, Humans, Lithium, Neuropsychological Tests, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Neurosciences, Biological psychology
Abstract

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1-5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p

Published
2020

15. Rare variants implicate NMDA receptor signaling and cerebellar gene networks in risk for bipolar disorder

Author

Hasin, Naushaba, Riggs, Lace M., Shekhtman, Tatyana, Ashworth, Justin, Lease, Robert, Oshone, Rediet T., Humphries, Elizabeth M., Badner, Judith A., Thomson, Pippa A., Glahn, David C., Craig, David W., Edenberg, Howard J., Gershon, Elliot S., McMahon, Francis J., Nurnberger, John I., Zandi, Peter P., Kelsoe, John R., Roach, Jared C., Gould, Todd D., and Ament, Seth A.

Published
2022
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16. Differential contributions of circadian clock genes to cell survival in bipolar disorder patient derived neuronal progenitor cells distinguishes lithium responders and non-responders

Author

Mishra, Himanshu K., primary, Wei, Heather, additional, LeRoux, Melissa, additional, Ko, Insu, additional, Rohr, Kayla E., additional, Nievergelt, Caroline M, additional, Maihofer, Adam X, additional, Shilling, Paul, additional, Alda, Martin, additional, Berrettini, Wade H, additional, Calabrese, Joseph R., additional, Coryell, William H., additional, Frye, Mark, additional, Gershon, Elliot, additional, McInnis, Melvin G., additional, Nurnberger, John, additional, Oedegaard, Ketil J., additional, Zandi, Peter P., additional, Kelsoe, John R., additional, and McCarthy, Michael J., additional

Published
2024
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17. Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder

Author

McCarthy, Michael J, Wei, Heather, Nievergelt, Caroline M, Stautland, Andrea, Maihofer, Adam X, Welsh, David K, Shilling, Paul, Alda, Martin, Alliey-Rodriguez, Ney, Anand, Amit, Andreasson, Ole A, Balaraman, Yokesh, Berrettini, Wade H, Bertram, Holli, Brennand, Kristen J, Calabrese, Joseph R, Calkin, Cynthia V, Claasen, Ana, Conroy, Clara, Coryell, William H, Craig, David W, D’Arcangelo, Nicole, Demodena, Anna, Djurovic, Srdjan, Feeder, Scott, Fisher, Carrie, Frazier, Nicole, Frye, Mark A, Gage, Fred H, Gao, Keming, Garnham, Julie, Gershon, Elliot S, Glazer, Kara, Goes, Fernando, Goto, Toyomi, Harrington, Gloria, Jakobsen, Petter, Kamali, Masoud, Karberg, Elizabeth, Kelly, Marisa, Leckband, Susan G, Lohoff, Falk, McInnis, Melvin G, Mondimore, Francis, Morken, Gunnar, Nurnberger, John I, Obral, Sarah, Oedegaard, Ketil J, Ortiz, Abigail, Ritchey, Megan, Ryan, Kelly, Schinagle, Martha, Schoeyen, Helle, Schwebel, Candice, Shaw, Martha, Shekhtman, Tatyana, Slaney, Claire, Stapp, Emma, Szelinger, Szabolcs, Tarwater, Bruce, Zandi, Peter P, and Kelsoe, John R

Subjects
Bipolar Disorder, Depression, Sleep Research, Serious Mental Illness, Brain Disorders, Clinical Research, Mental Health, Mental health, Adult, Animals, Antimanic Agents, Cells, Cultured, Circadian Rhythm, Fibroblasts, Genotyping Techniques, Humans, Inositol 1, 4, 5-Trisphosphate Receptors, Lithium Compounds, Luminescent Measurements, Mice, NIH 3T3 Cells, Period Circadian Proteins, Polymorphism, Single Nucleotide, Prospective Studies, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Published
2019

18. Entrainment of Circadian Rhythms to Temperature Reveals Amplitude Deficits in Fibroblasts from Patients with Bipolar Disorder and Possible Links to Calcium Channels

Author

Nudell, Victoria, Wei, Heather, Nievergelt, Caroline, Maihofer, Adam X, Shilling, Paul, Alda, Martin, Berrettini, Wade H, Brennand, Kristen J, Calabrese, Joseph R, Coryell, William H, Covault, Jonathan M, Frye, Mark A, Gage, Fred, Gershon, Elliot, McInnis, Melvin G, Nurnberger, John I, Oedegaard, Ketil J, Shekhtman, Tatyana, Zandi, Peter P, Kelsoe, John R, and McCarthy, Michael J

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Bipolar Disorder, Sleep Research, Brain Disorders, Bipolar disorder, Calcium channel, Circadian rhythm, Gene expression
Abstract

Bipolar disorder (BD) is characterized by recurrent mood episodes, and circadian rhythm disturbances. Past studies have identified calcium channel genes as risk loci for BD. CACNA1C encodes an L-type calcium channel (LTCC) involved in the entrainment of circadian rhythms to light. Another calcium channel, i.e., the ryanodine receptor (RYR), is involved in -circadian phase delays. It is unknown whether variants in CACNA1C or other calcium channels contribute to the circadian phenotype in BD. We hypothesized that, by using temperature cycles, we could model circadian entrainment in fibroblasts from BD patients and controls to interrogate the circadian functions of LTCCs. Using Per2-luc, a bioluminescent reporter, we verified that cells entrain to temperature rhythms in vitro. Under constant temperature conditions, the LTCC antagonist verapamil shortened the circadian period, and the RYR antagonist dantrolene lengthened the period. However, neither drug affected temperature entrainment. Fibroblasts from BD patients and controls also entrained to temperature. In cells from BD patients, the rhythm amplitude was lower under entrained, but not constant, conditions. Temperature entrainment was otherwise similar between BD and control cells. However, the CACNA1C genotype among BD cells predicted the degree to which cells entrained. We conclude that assessment of rhythms under entrained conditions reveals additional rhythm abnormalities in BD that are not observable under constant temperature conditions.

Published
2019

19. Comprehensive functional genomic resource and integrative model for the human brain

Author

Wang, Daifeng, Liu, Shuang, Warrell, Jonathan, Won, Hyejung, Shi, Xu, Navarro, Fabio CP, Clarke, Declan, Gu, Mengting, Emani, Prashant, Yang, Yucheng T, Xu, Min, Gandal, Michael J, Lou, Shaoke, Zhang, Jing, Park, Jonathan J, Yan, Chengfei, Rhie, Suhn Kyong, Manakongtreecheep, Kasidet, Zhou, Holly, Nathan, Aparna, Peters, Mette, Mattei, Eugenio, Fitzgerald, Dominic, Brunetti, Tonya, Moore, Jill, Jiang, Yan, Girdhar, Kiran, Hoffman, Gabriel E, Kalayci, Selim, Gümüş, Zeynep H, Crawford, Gregory E, Roussos, Panos, Akbarian, Schahram, Jaffe, Andrew E, White, Kevin P, Weng, Zhiping, Sestan, Nenad, Geschwind, Daniel H, Knowles, James A, Gerstein, Mark B, Ashley-Koch, Allison E, Garrett, Melanie E, Song, Lingyun, Safi, Alexias, Johnson, Graham D, Wray, Gregory A, Reddy, Timothy E, Goes, Fernando S, Zandi, Peter, Bryois, Julien, Price, Amanda J, Ivanov, Nikolay A, Collado-Torres, Leonardo, Hyde, Thomas M, Burke, Emily E, Kleiman, Joel E, Tao, Ran, Shin, Joo Heon, Kundakovic, Marija, Brown, Leanne, Kassim, Bibi S, Park, Royce B, Wiseman, Jennifer R, Zharovsky, Elizabeth, Jacobov, Rivka, Devillers, Olivia, Flatow, Elie, Lipska, Barbara K, Lewis, David A, Haroutunian, Vahram, Hahn, Chang-Gyu, Charney, Alexander W, Dracheva, Stella, Kozlenkov, Alexey, Belmont, Judson, DelValle, Diane, Francoeur, Nancy, Hadjimichael, Evi, Pinto, Dalila, van Bakel, Harm, Fullard, John F, Bendl, Jaroslav, Hauberg, Mads E, Mangravite, Lara M, Peters, Mette A, Chae, Yooree, Peng, Junmin, Niu, Mingming, Wang, Xusheng, Webster, Maree J, Beach, Thomas G, Chen, Chao, and Jiang, Yi

Subjects
Human Genome, Biotechnology, Schizophrenia, Mental Health, Brain Disorders, Genetics, Neurosciences, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, Mental health, Brain, Datasets as Topic, Deep Learning, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Gene Expression Regulation, Gene Regulatory Networks, Genome-Wide Association Study, Humans, Mental Disorders, Quantitative Trait Loci, Single-Cell Analysis, Transcriptome, PsychENCODE Consortium, General Science & Technology
Abstract

Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.

Published
2018

20. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

Author

Gandal, Michael J, Zhang, Pan, Hadjimichael, Evi, Walker, Rebecca L, Chen, Chao, Liu, Shuang, Won, Hyejung, van Bakel, Harm, Varghese, Merina, Wang, Yongjun, Shieh, Annie W, Haney, Jillian, Parhami, Sepideh, Belmont, Judson, Kim, Minsoo, Moran Losada, Patricia, Khan, Zenab, Mleczko, Justyna, Xia, Yan, Dai, Rujia, Wang, Daifeng, Yang, Yucheng T, Xu, Min, Fish, Kenneth, Hof, Patrick R, Warrell, Jonathan, Fitzgerald, Dominic, White, Kevin, Jaffe, Andrew E, Peters, Mette A, Gerstein, Mark, Liu, Chunyu, Iakoucheva, Lilia M, Pinto, Dalila, Geschwind, Daniel H, Ashley-Koch, Allison E, Crawford, Gregory E, Garrett, Melanie E, Song, Lingyun, Safi, Alexias, Johnson, Graham D, Wray, Gregory A, Reddy, Timothy E, Goes, Fernando S, Zandi, Peter, Bryois, Julien, Price, Amanda J, Ivanov, Nikolay A, Collado-Torres, Leonardo, Hyde, Thomas M, Burke, Emily E, Kleiman, Joel E, Tao, Ran, Shin, Joo Heon, Akbarian, Schahram, Girdhar, Kiran, Jiang, Yan, Kundakovic, Marija, Brown, Leanne, Kassim, Bibi S, Park, Royce B, Wiseman, Jennifer R, Zharovsky, Elizabeth, Jacobov, Rivka, Devillers, Olivia, Flatow, Elie, Hoffman, Gabriel E, Lipska, Barbara K, Lewis, David A, Haroutunian, Vahram, Hahn, Chang-Gyu, Charney, Alexander W, Dracheva, Stella, Kozlenkov, Alexey, DelValle, Diane, Francoeur, Nancy, Roussos, Panos, Fullard, John F, Bendl, Jaroslav, Hauberg, Mads E, Mangravite, Lara M, Chae, Yooree, Peng, Junmin, Niu, Mingming, Wang, Xusheng, Webster, Maree J, Beach, Thomas G, Jiang, Yi, and Grennan, Kay S

Subjects
Pharmacology and Pharmaceutical Sciences, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Neurosciences, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Mental Illness, Bipolar Disorder, Mental Health, Schizophrenia, Biotechnology, Serious Mental Illness, Autism, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Autism Spectrum Disorder, Brain, Genetic Predisposition to Disease, Humans, Protein Isoforms, RNA Splicing, Sequence Analysis, RNA, Transcriptome, PsychENCODE Consortium, General Science & Technology
Abstract

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

Published
2018

21. Detecting significant genotype-phenotype association rules in bipolar disorder: market research meets complex genetics.

Author

Breuer, René, Mattheisen, Manuel, Frank, Josef, Krumm, Bertram, Treutlein, Jens, Kassem, Layla, Strohmaier, Jana, Herms, Stefan, Mühleisen, Thomas, Degenhardt, Franziska, Cichon, Sven, Nöthen, Markus, Karypis, George, Kelsoe, John, Greenwood, Tiffany, Nievergelt, Caroline, Shilling, Paul, Shekhtman, Tatyana, Edenberg, Howard, Craig, David, Szelinger, Szabolcs, Nurnberger, John, Gershon, Elliot, Alliey-Rodriguez, Ney, Zandi, Peter, Goes, Fernando, Schork, Nicholas, Smith, Erin, Koller, Daniel, Zhang, Peng, Badner, Judith, Berrettini, Wade, Bloss, Cinnamon, Byerley, William, Coryell, William, Foroud, Tatiana, Guo, Yirin, Hipolito, Maria, Keating, Brendan, Lawson, William, Liu, Chunyu, Mahon, Pamela, McInnis, Melvin, Murray, Sarah, Nwulia, Evaristus, Potash, James, Rice, John, Scheftner, William, Zöllner, Sebastian, McMahon, Francis, Rietschel, Marcella, and Schulze, Thomas

Subjects
Bipolar disorder, Data mining, Genotype–phenotype patterns, Rule discovery, Subphenotypes
Abstract

BACKGROUND: Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype-phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted. RESULTS: Two of these rules-one associated with eating disorder and the other with anxiety-remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings. CONCLUSION: Our approach detected novel specific genotype-phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype-phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.

Published
2018

23. Correction: Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Author

Schubert, Klaus Oliver, Thalamuthu, Anbupalam, Amare, Azmeraw T., Frank, Joseph, Streit, Fabian, Adl, Mazda, Akula, Nirmala, Akiyama, Kazufumi, Ardau, Raffaella, Arias, Bárbara, Aubry, Jean-Michel, Backlund, Lena, Bhattacharjee, Abesh Kumar, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Biernacka, Joanna M., Birner, Armin, Marie-Claire, Cynthia, Cearns, Micah, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Clark, Scott R., Cruceanu, Cristiana, Czerski, Piotr M., Dalkner, Nina, Dayer, Alexandre, Degenhardt, Franziska, Del Zompo, Maria, DePaulo, J. Raymond, Étain, Bruno, Falkai, Peter, Forstner, Andreas J., Frisen, Louise, Frye, Mark A., Fullerton, Janice M., Gard, Sébastien, Garnham, Julie S., Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Heilbronner, Urs, Herms, Stefan, Hoffmann, Per, Hou, Liping, Hsu, Yi-Hsiang, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kuo, Po-Hsiu, Kato, Tadafumi, Kelsoe, John, Kittel-Schneider, Sarah, Ferensztajn-Rochowiak, Ewa, König, Barbara, Kusumi, Ichiro, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G., Maj, Mario, Manchia, Mirko, Martinsson, Lina, McCarthy, Michael J., McElroy, Susan, Colom, Francesc, Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Nöthen, Markus M., Novák, Tomas, O’Donovan, Claire, Ozaki, Norio, Ösby, Urban, Papiol, Sergi, Pfennig, Andrea, Pisanu, Claudia, Potash, James B., Reif, Andreas, Reininghaus, Eva, Rouleau, Guy A., Rybakowski, Janusz K., Schalling, Martin, Schofield, Peter R., Schweizer, Barbara W., Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D., Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M., Squassina, Alessio, Stamm, Thomas, Stopkova, Pavla, Tekola-Ayele, Fasil, Tortorella, Alfonso, Turecki, Gustavo, Veeh, Julia, Vieta, Eduard, Witt, Stephanie H., Roberts, Gloria, Zandi, Peter P., Alda, Martin, Bauer, Michael, McMahon, Francis J., Mitchell, Philip B., Schulze, Thomas G., Rietschel, Marcella, and Baune, Bernhard T.

Published
2022
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24. Developing Treatments for Alzheimer’s and Related Disorders with Precision Medicine: A Vision

Author

Avramopoulos, Dimitrios, Kapogiannis, Dimitrios, Leoutsakos, Jeannie-Marie, Lyketsos, Constantine G., Mahairaki, Vasiliki, Nowrangi, Milap, Oishi, Kenichi, Oh, Esther S., Rosenberg, Paul B., Samus, Quincy, Smith, Gwenn S., Witwer, Kenneth, Yasar, Sevil, Zandi, Peter P., Crusio, Wim E., Series Editor, Dong, Haidong, Series Editor, Radeke, Heinfried H., Series Editor, Rezaei, Nima, Series Editor, Steinlein, Ortrud, Series Editor, Xiao, Junjie, Series Editor, and Vlamos, Panayiotis, editor

Published
2021
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25. 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

26. Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder

Author

Reinbold, Céline S, Forstner, Andreas J, Hecker, Julian, Fullerton, Janice M, Hoffmann, Per, Hou, Liping, Heilbronner, Urs, Degenhardt, Franziska, Adli, Mazda, Akiyama, Kazufumi, Akula, Nirmala, Ardau, Raffaella, Arias, Bárbara, Backlund, Lena, Benabarre, Antonio, Bengesser, Susanne, Bhattacharjee, Abesh K, Biernacka, Joanna M, Birner, Armin, Marie-Claire, Cynthia, Cervantes, Pablo, Chen, Guo-Bo, Chen, Hsi-Chung, Chillotti, Caterina, Clark, Scott R, Colom, Francesc, Cousins, David A, Cruceanu, Cristiana, Czerski, Piotr M, Dayer, Alexandre, Étain, Bruno, Falkai, Peter, Frisén, Louise, Gard, Sébastien, Garnham, Julie S, Goes, Fernando S, Grof, Paul, Gruber, Oliver, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Jamain, Stéphane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kittel-Schneider, Sarah, Kliwicki, Sebastian, König, Barbara, Kusumi, Ichiro, Lackner, Nina, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G, Jaramillo, Carlos A López, MacQueen, Glenda, Manchia, Mirko, Martinsson, Lina, Mattheisen, Manuel, McCarthy, Michael J, McElroy, Susan L, Mitjans, Marina, Mondimore, Francis M, Monteleone, Palmiero, Nievergelt, Caroline M, Ösby, Urban, Ozaki, Norio, Perlis, Roy H, Pfennig, Andrea, Reich-Erkelenz, Daniela, Rouleau, Guy A, Schofield, Peter R, Schubert, K Oliver, Schweizer, Barbara W, Seemüller, Florian, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D, Shimoda, Kazutaka, Simhandl, Christian, Slaney, Claire M, Smoller, Jordan W, Squassina, Alessio, Stamm, Thomas J, Stopkova, Pavla, Tighe, Sarah K, Tortorella, Alfonso, Turecki, Gustavo, Volkert, Julia, Witt, Stephanie H, Wright, Adam J, Young, L Trevor, Zandi, Peter P, Potash, James B, DePaulo, J Raymond, Bauer, Michael, Reininghaus, Eva, Novák, Tomáš, and Aubry, Jean-Michel

Subjects
Mental Health, Brain Disorders, Clinical Research, Serious Mental Illness, Bipolar Disorder, Human Genome, Genetics, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Mental health, bipolar disorder, lithium response, microRNA, common variants, genome-wide association study, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

Published
2018

29. 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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30. The Pharmacogenomics of Bipolar Disorder study (PGBD): identification of genes for lithium response in a prospective sample

Author

Oedegaard, Ketil J, Alda, Martin, Anand, Anit, Andreassen, Ole A, Balaraman, Yokesh, Berrettini, Wade H, Bhattacharjee, Abesh, Brennand, Kristen J, Burdick, Katherine E, Calabrese, Joseph R, Calkin, Cynthia V, Claasen, Ana, Coryell, William H, Craig, David, DeModena, Anna, Frye, Mark, Gage, Fred H, Gao, Keming, Garnham, Julie, Gershon, Elliot, Jakobsen, Petter, Leckband, Susan G, McCarthy, Michael J, McInnis, Melvin G, Maihofer, Adam X, Mertens, Jerome, Morken, Gunnar, Nievergelt, Caroline M, Nurnberger, John, Pham, Son, Schoeyen, Helle, Shekhtman, Tatyana, Shilling, Paul D, Szelinger, Szabolcs, Tarwater, Bruce, Yao, Jun, Zandi, Peter P, and Kelsoe, John R

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Health Sciences, Brain Disorders, Human Genome, Genetics, Depression, Mental Health, Clinical Research, Prevention, Behavioral and Social Science, Detection, screening and diagnosis, Evaluation of treatments and therapeutic interventions, 4.2 Evaluation of markers and technologies, 6.1 Pharmaceuticals, Mental health, Aged, Antidepressive Agents, Bipolar Disorder, Diagnostic and Statistical Manual of Mental Disorders, Female, Follow-Up Studies, Genome-Wide Association Study, Humans, Lithium Compounds, Male, Middle Aged, Pharmacogenetics, Prospective Studies, Retrospective Studies, Secondary Prevention, Valproic Acid, Bipolar disorder, Lithium, Mood stabilizer, GWAS, Prospective trial, Personalized medicine, Precision medicine, Clinical Sciences, Public Health and Health Services, Psychology, Psychiatry, Clinical sciences, Epidemiology, Clinical and health psychology
Abstract

BackgroundBipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response.Methods/designThis study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response.DiscussionLithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30-40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost.Trial registrationClinicalTrials.gov Identifier: NCT01272531 Registered: January 6, 2011.

Published
2016

32. 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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36. Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.

Author

Hou, Liping, Heilbronner, Urs, Degenhardt, Franziska, Adli, Mazda, Akiyama, Kazufumi, Akula, Nirmala, Ardau, Raffaella, Arias, Bárbara, Backlund, Lena, Banzato, Claudio EM, Benabarre, Antoni, Bengesser, Susanne, Bhattacharjee, Abesh Kumar, Biernacka, Joanna M, Birner, Armin, Brichant-Petitjean, Clara, Bui, Elise T, Cervantes, Pablo, Chen, Guo-Bo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Clark, Scott R, Colom, Francesc, Cousins, David A, Cruceanu, Cristiana, Czerski, Piotr M, Dantas, Clarissa R, Dayer, Alexandre, Étain, Bruno, Falkai, Peter, Forstner, Andreas J, Frisén, Louise, Fullerton, Janice M, Gard, Sébastien, Garnham, Julie S, Goes, Fernando S, Grof, Paul, Gruber, Oliver, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Hofmann, Andrea, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kittel-Schneider, Sarah, Kliwicki, Sebastian, König, Barbara, Kusumi, Ichiro, Lackner, Nina, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G, Jaramillo, Carlos A López, MacQueen, Glenda, Manchia, Mirko, Martinsson, Lina, Mattheisen, Manuel, McCarthy, Michael J, McElroy, Susan L, Mitjans, Marina, Mondimore, Francis M, Monteleone, Palmiero, Nievergelt, Caroline M, Nöthen, Markus M, Ösby, Urban, Ozaki, Norio, Perlis, Roy H, Pfennig, Andrea, Reich-Erkelenz, Daniela, Rouleau, Guy A, Schofield, Peter R, Schubert, K Oliver, Schweizer, Barbara W, Seemüller, Florian, Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D, Shimoda, Kazutaka, Simhandl, Christian, Slaney, Claire M, Smoller, Jordan W, Squassina, Alessio, Stamm, Thomas, Stopkova, Pavla, Tighe, Sarah K, Tortorella, Alfonso, Turecki, Gustavo, Volkert, Julia, Witt, Stephanie, Wright, Adam, Young, L Trevor, Zandi, Peter P, Potash, James B, and DePaulo, J Raymond

Subjects
Humans, Lithium Compounds, Treatment Outcome, Prospective Studies, Bipolar Disorder, Genotype, Phenotype, Polymorphism, Single Nucleotide, Middle Aged, Female, Male, Glial Cell Line-Derived Neurotrophic Factor Receptors, Genetic Variation, Genome-Wide Association Study, Serious Mental Illness, Genetics, Mental Health, Human Genome, Brain Disorders, Genetic Testing, Mental health, Good Health and Well Being, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundLithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.MethodsHere, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis.FindingsA single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0).InterpretationThe response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.FundingDeutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

Published
2016

37. Digital Phenotyping for Mood Disorders: Methodology-Oriented Pilot Feasibility Study

Author

Breitinger, Scott, primary, Gardea-Resendez, Manuel, additional, Langholm, Carsten, additional, Xiong, Ashley, additional, Laivell, Joseph, additional, Stoppel, Cynthia, additional, Harper, Laura, additional, Volety, Rama, additional, Walker, Alex, additional, D'Mello, Ryan, additional, Byun, Andrew Jin Soo, additional, Zandi, Peter, additional, Goes, Fernando S, additional, Frye, Mark, additional, and Torous, John, additional

Published
2023
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38. The Human Phenotype Ontology in 2024: phenotypes around the world

Author

Gargano, Michael A, primary, Matentzoglu, Nicolas, additional, Coleman, Ben, additional, Addo-Lartey, Eunice B, additional, Anagnostopoulos, Anna V, additional, Anderton, Joel, additional, Avillach, Paul, additional, Bagley, Anita M, additional, Bakštein, Eduard, additional, Balhoff, James P, additional, Baynam, Gareth, additional, Bello, Susan M, additional, Berk, Michael, additional, Bertram, Holli, additional, Bishop, Somer, additional, Blau, Hannah, additional, Bodenstein, David F, additional, Botas, Pablo, additional, Boztug, Kaan, additional, Čady, Jolana, additional, Callahan, Tiffany J, additional, Cameron, Rhiannon, additional, Carbon, Seth J, additional, Castellanos, Francisco, additional, Caufield, J Harry, additional, Chan, Lauren E, additional, Chute, Christopher G, additional, Cruz-Rojo, Jaime, additional, Dahan-Oliel, Noémi, additional, Davids, Jon R, additional, de Dieuleveult, Maud, additional, de Souza, Vinicius, additional, de Vries, Bert B A, additional, de Vries, Esther, additional, DePaulo, J Raymond, additional, Derfalvi, Beata, additional, Dhombres, Ferdinand, additional, Diaz-Byrd, Claudia, additional, Dingemans, Alexander J M, additional, Donadille, Bruno, additional, Duyzend, Michael, additional, Elfeky, Reem, additional, Essaid, Shahim, additional, Fabrizzi, Carolina, additional, Fico, Giovanna, additional, Firth, Helen V, additional, Freudenberg-Hua, Yun, additional, Fullerton, Janice M, additional, Gabriel, Davera L, additional, Gilmour, Kimberly, additional, Giordano, Jessica, additional, Goes, Fernando S, additional, Moses, Rachel Gore, additional, Green, Ian, additional, Griese, Matthias, additional, Groza, Tudor, additional, Gu, Weihong, additional, Guthrie, Julia, additional, Gyori, Benjamin, additional, Hamosh, Ada, additional, Hanauer, Marc, additional, Hanušová, Kateřina, additional, He, Yongqun (Oliver), additional, Hegde, Harshad, additional, Helbig, Ingo, additional, Holasová, Kateřina, additional, Hoyt, Charles Tapley, additional, Huang, Shangzhi, additional, Hurwitz, Eric, additional, Jacobsen, Julius O B, additional, Jiang, Xiaofeng, additional, Joseph, Lisa, additional, Keramatian, Kamyar, additional, King, Bryan, additional, Knoflach, Katrin, additional, Koolen, David A, additional, Kraus, Megan L, additional, Kroll, Carlo, additional, Kusters, Maaike, additional, Ladewig, Markus S, additional, Lagorce, David, additional, Lai, Meng-Chuan, additional, Lapunzina, Pablo, additional, Laraway, Bryan, additional, Lewis-Smith, David, additional, Li, Xiarong, additional, Lucano, Caterina, additional, Majd, Marzieh, additional, Marazita, Mary L, additional, Martinez-Glez, Victor, additional, McHenry, Toby H, additional, McInnis, Melvin G, additional, McMurry, Julie A, additional, Mihulová, Michaela, additional, Millett, Caitlin E, additional, Mitchell, Philip B, additional, Moslerová, Veronika, additional, Narutomi, Kenji, additional, Nematollahi, Shahrzad, additional, Nevado, Julian, additional, Nierenberg, Andrew A, additional, Čajbiková, Nikola Novák, additional, Nurnberger, John I, additional, Ogishima, Soichi, additional, Olson, Daniel, additional, Ortiz, Abigail, additional, Pachajoa, Harry, additional, Perez de Nanclares, Guiomar, additional, Peters, Amy, additional, Putman, Tim, additional, Rapp, Christina K, additional, Rath, Ana, additional, Reese, Justin, additional, Rekerle, Lauren, additional, Roberts, Angharad M, additional, Roy, Suzy, additional, Sanders, Stephan J, additional, Schuetz, Catharina, additional, Schulte, Eva C, additional, Schulze, Thomas G, additional, Schwarz, Martin, additional, Scott, Katie, additional, Seelow, Dominik, additional, Seitz, Berthold, additional, Shen, Yiping, additional, Similuk, Morgan N, additional, Simon, Eric S, additional, Singh, Balwinder, additional, Smedley, Damian, additional, Smith, Cynthia L, additional, Smolinsky, Jake T, additional, Sperry, Sarah, additional, Stafford, Elizabeth, additional, Stefancsik, Ray, additional, Steinhaus, Robin, additional, Strawbridge, Rebecca, additional, Sundaramurthi, Jagadish Chandrabose, additional, Talapova, Polina, additional, Tenorio Castano, Jair A, additional, Tesner, Pavel, additional, Thomas, Rhys H, additional, Thurm, Audrey, additional, Turnovec, Marek, additional, van Gijn, Marielle E, additional, Vasilevsky, Nicole A, additional, Vlčková, Markéta, additional, Walden, Anita, additional, Wang, Kai, additional, Wapner, Ron, additional, Ware, James S, additional, Wiafe, Addo A, additional, Wiafe, Samuel A, additional, Wiggins, Lisa D, additional, Williams, Andrew E, additional, Wu, Chen, additional, Wyrwoll, Margot J, additional, Xiong, Hui, additional, Yalin, Nefize, additional, Yamamoto, Yasunori, additional, Yatham, Lakshmi N, additional, Yocum, Anastasia K, additional, Young, Allan H, additional, Yüksel, Zafer, additional, Zandi, Peter P, additional, Zankl, Andreas, additional, Zarante, Ignacio, additional, Zvolský, Miroslav, additional, Toro, Sabrina, additional, Carmody, Leigh C, additional, Harris, Nomi L, additional, Munoz-Torres, Monica C, additional, Danis, Daniel, additional, Mungall, Christopher J, additional, Köhler, Sebastian, additional, Haendel, Melissa A, additional, and Robinson, Peter N, additional

Published
2023
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39. Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study

Author

Kelsoe, John, primary, Ou, Anna, additional, Rosenthal, Sara, additional, Adli, Mazda, additional, Akiyama, Kazufumi, additional, Akula, Nirmala, additional, Alda, Martin, additional, Amare, Azmeraw T., additional, Ardau, Raffaella, additional, Arias, Bárbara, additional, Aubry, Jean-Michel, additional, Backlund, Lena, additional, Banzato, Claudio, additional, Bauer, Michael, additional, Baune, Bernhard, additional, Bellivier, Frank, additional, Benabarre, Antonio, additional, Bengesser, Susanne, additional, Abesh, Bhattacharjee, additional, Biernacka, Joanna, additional, Bui, Elise, additional, Cervantes, Pablo, additional, Chen, Guo-Bo, additional, Chen, Hsi-Chung, additional, Chillotti, Caterina, additional, Cichon, Sven, additional, Clark, Scott, additional, Colom, Francesc, additional, Cousins, David, additional, Cruceanu, Cristiana, additional, Czerski, Piotr, additional, Dantas, Clarissa, additional, Dayer, Alexandre, additional, Degenhardt, Franziska, additional, DePaulo, J. Raymond, additional, Etain, Bruno, additional, Falkai, Peter, additional, Fellendorf, Frederike, additional, Ferensztajn-Rochowiak, Ewa, additional, Forstner, Andreas J., additional, Frisen, Louise, additional, Frye, Mark, additional, Fullerton, Janice, additional, Gard, Sebastien, additional, Garnham, Julie, additional, Goes, Fernando, additional, Grigoroiu-Serbanescu, Maria, additional, Grof, Paul, additional, Gruber, Oliver, additional, Hashimoto, Ryota, additional, Hauser, Joanna, additional, Heilbronner, Urs, additional, Herms, Stefan, additional, Hoffmann, Per, additional, Hofmann, Andrea, additional, Hou, Liping, additional, Jamain, Stéphane, additional, Jiménez, Esther, additional, Kahn, Jean-Pierre, additional, Kassem, Layla, additional, Kato, Tadafumi, additional, Kittel-Schneider, Sarah, additional, König, Barbara, additional, kuo, Po-Hsiu, additional, Kusumi, Ichiro, additional, Dalkner, Nina, additional, Laje, Gonzalo, additional, Landén, Mikael, additional, Lavebratt, Catharina, additional, Leboyer, Marion, additional, Leckband, Susan, additional, Jaramillo, Carlos López, additional, MacQueen, Glenda, additional, Maj, Mario, additional, Manchia, Mirko, additional, Marie-Claire, Cynthia, additional, Martinsson, Lina, additional, Mattheisen, Manuel, additional, McCarthy, Michael, additional, McElroy, Susan, additional, McMahon, Francis, additional, Mitchell, Philip, additional, Mitjans, Marina, additional, Mondimore, Francis, additional, Monteleone, Palmiero, additional, Nievergelt, Caroline, additional, Nöthen, Markus, additional, Novak, Tomas, additional, Osby, Urban, additional, Ozaki, Norio, additional, Papiol, Sergi, additional, Perlis, Roy, additional, Pfennig, Andrea, additional, Potash, James, additional, Reich-Erkelenz, Daniela, additional, Reif, Andreas, additional, Reininghaus, Eva, additional, Rietschel, Marcella, additional, Rouleau, Guy, additional, Rybakowski, Janusz K., additional, Schalling, Martin, additional, Schofield, Peter, additional, Schubert, Klaus Oliver, additional, Schulze, Thomas, additional, SCHWEIZER, BARBARA, additional, Seemüller, Florian, additional, Severino, Giovanni, additional, Shekhtman, Tatyana, additional, Shilling, Paul, additional, Shimoda, Kazutaka, additional, Simhandl, Christian, additional, slaney, claire, additional, Squassina, Alessio, additional, Stamm, Thomas, additional, Stopkova, Pavla, additional, Tighe, Sarah, additional, Tortorella, Alfonso, additional, Turecki, Gustavo, additional, Vieta, Eduard, additional, Volkert, Julia, additional, Witt, Stephanie, additional, Wray, Naomi, additional, Wright, Adam, additional, Young, Trevor, additional, Zandi, Peter, additional, and Zompo, Maria Del, additional

Published
2023
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41. International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic)

Author

Soda, Takahiro, McLoughlin, Declan M., Clark, Scott R., Oltedal, Leif, Kessler, Ute, Haavik, Jan, Bousman, Chad, Smith, Daniel J., Bioque, Miquel, Clements, Caitlin C., Loo, Colleen, Vila-Rodriguez, Fidel, Minelli, Alessandra, Mickey, Brian J., Milev, Roumen, Docherty, Anna R., Langan Martin, Julie, Achtyes, Eric D., Arolt, Volker, Redlich, Ronny, Dannlowski, Udo, Cardoner, Narcis, Clare, Emily, Craddock, Nick, Di Florio, Arianna, Dmitrzak-Weglarz, Monika, Forty, Liz, Gordon-Smith, Katherine, Husain, Mustafa, Ingram, Wendy M., Jones, Lisa, Jones, Ian, Juruena, Mario, Kirov, George, Landén, Mikael, Müller, Daniel J., Nordensköld, Axel, Pålsson, Erik, Paul, Meethu, Permoda, Agnieszka, Pliszka, Bartlomiej, Rea, Jamie, Schubert, Klaus O., Sonnen, Joshua A., Soria, Virginia, Stageman, Will, Takamiya, Akihiro, Urretavizacaya, Mikel, Watson, Stuart, Zavorotny, Maxim, Young, Allan H., Vieta, Eduard, Rybakowski, Janusz K., Gennarelli, Massimo, Zandi, Peter P., Sullivan, Patrick F., and Baune, Bernhard T.

Published
2020
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42. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder

Author

Mertens, Jerome, Wang, Qiu-Wen, Kim, Yongsung, Yu, Diana X, Pham, Son, Yang, Bo, Zheng, Yi, Diffenderfer, Kenneth E, Zhang, Jian, Soltani, Sheila, Eames, Tameji, Schafer, Simon T, Boyer, Leah, Marchetto, Maria C, Nurnberger, John I, Calabrese, Joseph R, Oedegaard, Ketil J, McCarthy, Michael J, Zandi, Peter P, Alda, Martin, Nievergelt, Caroline M, Mi, Shuangli, Brennand, Kristen J, Kelsoe, John R, Gage, Fred H, and Yao, Jun

Subjects
Stem Cell Research - Induced Pluripotent Stem Cell, Bipolar Disorder, Serious Mental Illness, Regenerative Medicine, Neurosciences, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Mental Health, Stem Cell Research, Brain Disorders, Mental health, Action Potentials, Antipsychotic Agents, Calcium Signaling, Dentate Gyrus, Endophenotypes, Humans, Induced Pluripotent Stem Cells, Lithium Compounds, Male, Mitochondria, Neurons, Patch-Clamp Techniques, Pharmacogenomics of Bipolar Disorder Study, General Science & Technology
Abstract

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

Published
2015

43. Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Author

Schubert, Klaus Oliver, Thalamuthu, Anbupalam, Amare, Azmeraw T., Frank, Joseph, Streit, Fabian, Adl, Mazda, Akula, Nirmala, Akiyama, Kazufumi, Ardau, Raffaella, Arias, Bárbara, Aubry, Jean-Michel, Backlund, Lena, Bhattacharjee, Abesh Kumar, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Biernacka, Joanna M., Birner, Armin, Marie-Claire, Cynthia, Cearns, Micah, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Clark, Scott R., Cruceanu, Cristiana, Czerski, Piotr M., Dalkner, Nina, Dayer, Alexandre, Degenhardt, Franziska, Del Zompo, Maria, DePaulo, J. Raymond, Étain, Bruno, Falkai, Peter, Forstner, Andreas J., Frisen, Louise, Frye, Mark A., Fullerton, Janice M., Gard, Sébastien, Garnham, Julie S., Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Heilbronner, Urs, Herms, Stefan, Hoffmann, Per, Hou, Liping, Hsu, Yi-Hsiang, Jamain, Stephane, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kuo, Po-Hsiu, Kato, Tadafumi, Kelsoe, John, Kittel-Schneider, Sarah, Ferensztajn-Rochowiak, Ewa, König, Barbara, Kusumi, Ichiro, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leboyer, Marion, Leckband, Susan G., Maj, Mario, Manchia, Mirko, Martinsson, Lina, McCarthy, Michael J., McElroy, Susan, Colom, Francesc, Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Nöthen, Markus M., Novák, Tomas, O’Donovan, Claire, Ozaki, Norio, Ösby, Urban, Papiol, Sergi, Pfennig, Andrea, Pisanu, Claudia, Potash, James B., Reif, Andreas, Reininghaus, Eva, Rouleau, Guy A., Rybakowski, Janusz K., Schalling, Martin, Schofield, Peter R., Schweizer, Barbara W., Severino, Giovanni, Shekhtman, Tatyana, Shilling, Paul D., Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M., Squassina, Alessio, Stamm, Thomas, Stopkova, Pavla, Tekola-Ayele, Fasil, Tortorella, Alfonso, Turecki, Gustavo, Veeh, Julia, Vieta, Eduard, Witt, Stephanie H., Roberts, Gloria, Zandi, Peter P., Alda, Martin, Bauer, Michael, McMahon, Francis J., Mitchell, Philip B., Schulze, Thomas G., Rietschel, Marcella, and Baune, Bernhard T.

Published
2021
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44. HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

Author

Le Clerc, Sigrid, Lombardi, Laura, Baune, Bernhard T., Amare, Azmeraw T., Schubert, Klaus Oliver, Hou, Liping, Clark, Scott R., Papiol, Sergi, Cearns, Micah, Heilbronner, Urs, Degenhardt, Franziska, Tekola-Ayele, Fasil, Hsu, Yi-Hsiang, Shekhtman, Tatyana, Adli, Mazda, Akula, Nirmala, Akiyama, Kazufumi, Ardau, Raffaella, Arias, Bárbara, Aubry, Jean-Michel, Backlund, Lena, Bhattacharjee, Abesh Kumar, Bellivier, Frank, Benabarre, Antonio, Bengesser, Susanne, Biernacka, Joanna M., Birner, Armin, Brichant-Petitjean, Clara, Cervantes, Pablo, Chen, Hsi-Chung, Chillotti, Caterina, Cichon, Sven, Cruceanu, Cristiana, Czerski, Piotr M., Dalkner, Nina, Dayer, Alexandre, Del Zompo, Maria, DePaulo, J. Raymond, Étain, Bruno, Jamain, Stephane, Falkai, Peter, Forstner, Andreas J., Frisen, Louise, Frye, Mark A., Fullerton, Janice M., Gard, Sébastien, Garnham, Julie S., Goes, Fernando S., Grigoroiu-Serbanescu, Maria, Grof, Paul, Hashimoto, Ryota, Hauser, Joanna, Herms, Stefan, Hoffmann, Per, Jiménez, Esther, Kahn, Jean-Pierre, Kassem, Layla, Kuo, Po-Hsiu, Kato, Tadafumi, Kelsoe, John R., Kittel-Schneider, Sarah, Ferensztajn-Rochowiak, Ewa, König, Barbara, Kusumi, Ichiro, Laje, Gonzalo, Landén, Mikael, Lavebratt, Catharina, Leckband, Susan G., Tortorella, Alfonso, Manchia, Mirko, Martinsson, Lina, McCarthy, Michael J., McElroy, Susan L., Colom, Francesc, Millischer, Vincent, Mitjans, Marina, Mondimore, Francis M., Monteleone, Palmiero, Nievergelt, Caroline M., Nöthen, Markus M., Novák, Tomas, O’Donovan, Claire, Ozaki, Norio, Ösby, Urban, Pfennig, Andrea, Potash, James B., Reif, Andreas, Reininghaus, Eva, Rouleau, Guy A., Rybakowski, Janusz K., Schalling, Martin, Schofield, Peter R., Schweizer, Barbara W., Severino, Giovanni, Shilling, Paul D., Shimoda, Katzutaka, Simhandl, Christian, Slaney, Claire M., Pisanu, Claudia, Squassina, Alessio, Stamm, Thomas, Stopkova, Pavla, Maj, Mario, Turecki, Gustavo, Vieta, Eduard, Veeh, Julia, Witt, Stephanie H., Wright, Adam, Zandi, Peter P., Mitchell, Philip B., Bauer, Michael, Alda, Martin, Rietschel, Marcella, McMahon, Francis J., Schulze, Thomas G., Spadoni, Jean-Louis, Boukouaci, Wahid, Richard, Jean-Romain, Le Corvoisier, Philippe, Barrau, Caroline, Zagury, Jean-François, Leboyer, Marion, and Tamouza, Ryad

Published
2021
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45. Developing Treatments for Alzheimer’s and Related Disorders with Precision Medicine: A Vision

Author

Avramopoulos, Dimitrios, primary, Kapogiannis, Dimitrios, additional, Leoutsakos, Jeannie-Marie, additional, Lyketsos, Constantine G., additional, Mahairaki, Vasiliki, additional, Nowrangi, Milap, additional, Oishi, Kenichi, additional, Oh, Esther S., additional, Rosenberg, Paul B., additional, Samus, Quincy, additional, Smith, Gwenn S., additional, Witwer, Kenneth, additional, Yasar, Sevil, additional, and Zandi, Peter P., additional

Published
2021
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46. Host–parasite interaction associated with major mental illness

Author

Kano, Shin-ichi, Hodgkinson, Colin A., Jones-Brando, Lorraine, Eastwood, Sharon, Ishizuka, Koko, Niwa, Minae, Choi, Eric Y., Chang, Daniel J., Chen, Yian, Velivela, Swetha D., Leister, Flora, Wood, Joel, Chowdari, Kodavali, Ducci, Francesca, Caycedo, Daniel A., Heinz, Elizabeth, Newman, Emily R., Cascella, Nicola, Mortensen, Preben B., Zandi, Peter P., Dickerson, Faith, Nimgaonkar, Vishwajit, Goldman, David, Harrison, Paul J., Yolken, Robert H., and Sawa, Akira

Published
2020
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47. Rare variants in neuronal excitability genes influence risk for bipolar disorder

Author

Ament, Seth A, Szelinger, Szabolcs, Glusman, Gustavo, Ashworth, Justin, Hou, Liping, Akula, Nirmala, Shekhtman, Tatyana, Badner, Judith A, Brunkow, Mary E, Mauldin, Denise E, Stittrich, Anna-Barbara, Rouleau, Katherine, Detera-Wadleigh, Sevilla D, Nurnberger, John I, Edenberg, Howard J, Gershon, Elliot S, Schork, Nicholas, Price, Nathan D, Gelinas, Richard, Hood, Leroy, Craig, David, McMahon, Francis J, Kelsoe, John R, Roach, Jared C, Greenwood, Tiffany A, Nievergelt, Caroline M, Shilling, Paul D, Foroud, Tatiana, Koller, Daniel L, Liu, Chunyu, Scheftner, William A, Lawson, William B, Coryell, William, Potash, James B, Rice, John, Byerley, William, Berrettini, Wade H, Zandi, Peter P, McInnis, Melvin G, Craig, David W, Schulze, Thomas G, Schork, Nicholas J, and Quarless, Danjuma

Subjects
Human Genome, Mental Health, Genetics, Bipolar Disorder, Prevention, Brain Disorders, Neurosciences, Serious Mental Illness, 2.1 Biological and endogenous factors, Aetiology, Neurological, Case-Control Studies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Neurons, Pedigree, Polymorphism, Single Nucleotide, Risk Factors, Signal Transduction, White People, bipolar disorder, family genomics, regulatory variants, GABA(A) receptor, voltage-gated calcium channel, Bipolar Genome Study, GABAA receptor
Abstract

We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5' and 3' UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.

Published
2015

48. Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder

Author

Jacobsen, Kaya K, Nievergelt, Caroline M, Zayats, Tetyana, Greenwood, Tiffany A, Anttila, Verneri, Akiskal, Hagop S, Consortium, BiGS, Consortium, IHG, include:, BiGS Consortium Co-Authors, Kelsoe, John R, McKinney, Rebecca, Shilling, Paul D, Smith, Erin N, Schork, Nicholas J, Bloss, Cinnamon S, Nurnberger, John I, Edenberg, Howard J, Foroud, Tatiana, Koller, Daniel L, Gershon, Elliot S, Badner, Judith A, Liu, Chunyu, Scheftner, William A, Lawson, William B, Nwulia, Evaristus A, Hipolito, Maria, Potash, James, Coryell, William, Rice, John, Byerley, William, McMahon, Francis J, Berrettini, Wade H, Zandi, Peter P, Mahon, Pamela B, McInnis, Melvin G, Zöllner, Sebastian, Zhang, Peng, Craig, David W, Szelinger, Szabolics, Barrett, Thomas B, Schulze, Thomas G, include:, IHG Consortium Co-Authors, Wedenoja, Juho, Kaunisto, Mari A, Heikkilä, Kauko, Kaprio, Jaakko, Wessman, Maija, Kallela, Mikko, Färkkilä, Markus, Artto, Ville, Aromaa, Arpo, Eriksson, Johan G, Winsvold, Bendik S, Zwart, John-Anker, Gormley, Padhraig, Palotie, Aarno, Kurth, Tobias, Rose, Lynda M, Buring, Julie E, Ridker, Paul M, Chasman, Daniel I, Bettella, Francesco, Steinberg, Stacy, Stefansson, Hreinn, Stefansson, Kari, McMahon, George, Davey-Smith, George, Malik, Rainer, Freilinger, Tobias, Wichmann, Heinz Erich, Dichgans, Martin, Muller-Myhsok, Bertram, Meitinger, Thomas, de Vries, Boukje, Terwindt, Gisela, Stam, Anine H, Frants, Rune R, Pelzer, Nadine, Weller, Claudia M, Zielman, Ronald, Ferrari, Michel D, van den Maagdenberg, Arn MJM, Medland, Sarah E, Montgomery, Grant W, Martin, Nicholas G, Nyholt, Dale R, Todt, Unda, Borck, Guntram, Kubisch, Christian, Quaye, Lydia, Williams, Frances MK, Cherkas, Lynn, Koiranen, Markku, Hartikainen, Anna-Liisa, Pouta, Anneli, Jarvelin, Marjo-Riitta, Ikram, M Arfan, and van den Ende, Joyce

Subjects
Biomedical and Clinical Sciences, Neurosciences, Pain Research, Bipolar Disorder, Mental Health, Serious Mental Illness, Brain Disorders, Chronic Pain, Genetics, Mental Illness, Headaches, Migraines, Human Genome, 2.1 Biological and endogenous factors, Neurological, Adult, Carrier Proteins, Comorbidity, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Migraine Disorders, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Bipolar disorder, Migraine, NBEA, Neurobeachin, BiGS Consortium, IHG Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

BackgroundMigraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine.MethodsWe performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS).ResultsWe identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene (P=2.97 × 10(-8), OR: 1.82, 95% CI: 1.47-2.25), although this was not replicated in a smaller sample of 289 migraine cases.LimitationsOur study is based on self-reported migraine.ConclusionsNBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium (n=118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder.

Published
2015

50. Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder

Author

Budde, Monika, Friedrichs, Stefanie, Alliey-Rodriguez, Ney, Ament, Seth, Badner, Judith A., Berrettini, Wade H., Bloss, Cinnamon S., Byerley, William, Cichon, Sven, Comes, Ashley L., Coryell, William, Craig, David W., Degenhardt, Franziska, Edenberg, Howard J., Foroud, Tatiana, Forstner, Andreas J., Frank, Josef, Gershon, Elliot S., Goes, Fernando S., Greenwood, Tiffany A., Guo, Yiran, Hipolito, Maria, Hood, Leroy, Keating, Brendan J., Koller, Daniel L., Lawson, William B., Liu, Chunyu, Mahon, Pamela B., McInnis, Melvin G., McMahon, Francis J., Meier, Sandra M., Mühleisen, Thomas W., Murray, Sarah S., Nievergelt, Caroline M., Nurnberger, John I., Jr., Nwulia, Evaristus A., Potash, James B., Quarless, Danjuma, Rice, John, Roach, Jared C., Scheftner, William A., Schork, Nicholas J., Shekhtman, Tatyana, Shilling, Paul D., Smith, Erin N., Streit, Fabian, Strohmaier, Jana, Szelinger, Szabolcs, Treutlein, Jens, Witt, Stephanie H., Zandi, Peter P., Zhang, Peng, Zöllner, Sebastian, Bickeböller, Heike, Falkai, Peter G., Kelsoe, John R., Nöthen, Markus M., Rietschel, Marcella, Schulze, Thomas G., and Malzahn, Dörthe

Published
2019
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