Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLiGen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

U1 - https://www.ncbi.nlm.nih.gov/pubmed/32203155?dopt=Abstract ER - TY - JOUR T1 - Analysis of shared heritability in common disorders of the brain. JF - Science Y1 - 2018 A1 - Anttila, Verneri A1 - Bulik-Sullivan, Brendan A1 - Finucane, Hilary K A1 - Walters, Raymond K A1 - Bras, Jose A1 - Duncan, Laramie A1 - Escott-Price, Valentina A1 - Falcone, Guido J A1 - Gormley, Padhraig A1 - Malik, Rainer A1 - Patsopoulos, Nikolaos A A1 - Ripke, Stephan A1 - Wei, Zhi A1 - Yu, Dongmei A1 - Lee, Phil H A1 - Turley, Patrick A1 - Grenier-Boley, Benjamin A1 - Chouraki, Vincent A1 - Kamatani, Yoichiro A1 - Berr, Claudine A1 - Letenneur, Luc A1 - Hannequin, Didier A1 - Amouyel, Philippe A1 - Boland, Anne A1 - Deleuze, Jean-François A1 - Duron, Emmanuelle A1 - Vardarajan, Badri N A1 - Reitz, Christiane A1 - Goate, Alison M A1 - Huentelman, Matthew J A1 - Kamboh, M Ilyas A1 - Larson, Eric B A1 - Rogaeva, Ekaterina A1 - St George-Hyslop, Peter A1 - Hakonarson, Hakon A1 - Kukull, Walter A A1 - Farrer, Lindsay A A1 - Barnes, Lisa L A1 - Beach, Thomas G A1 - Demirci, F Yesim A1 - Head, Elizabeth A1 - Hulette, Christine M A1 - Jicha, Gregory A A1 - Kauwe, John S K A1 - Kaye, Jeffrey A A1 - Leverenz, James B A1 - Levey, Allan I A1 - Lieberman, Andrew P A1 - Pankratz, Vernon S A1 - Poon, Wayne W A1 - Quinn, Joseph F A1 - Saykin, Andrew J A1 - Schneider, Lon S A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Stern, Robert A A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Harold, Denise A1 - Russo, Giancarlo A1 - Rubinsztein, David C A1 - Bayer, Anthony A1 - Tsolaki, Magda A1 - Proitsi, Petra A1 - Fox, Nick C A1 - Hampel, Harald A1 - Owen, Michael J A1 - Mead, Simon A1 - Passmore, Peter A1 - Morgan, Kevin A1 - Nöthen, Markus M A1 - Rossor, Martin A1 - Lupton, Michelle K A1 - Hoffmann, Per A1 - Kornhuber, Johannes A1 - Lawlor, Brian A1 - McQuillin, Andrew A1 - Al-Chalabi, Ammar A1 - Bis, Joshua C A1 - Ruiz, Agustin A1 - Boada, Mercè A1 - Seshadri, Sudha A1 - Beiser, Alexa A1 - Rice, Kenneth A1 - van der Lee, Sven J A1 - De Jager, Philip L A1 - Geschwind, Daniel H A1 - Riemenschneider, Matthias A1 - Riedel-Heller, Steffi A1 - Rotter, Jerome I A1 - Ransmayr, Gerhard A1 - Hyman, Bradley T A1 - Cruchaga, Carlos A1 - Alegret, Montserrat A1 - Winsvold, Bendik A1 - Palta, Priit A1 - Farh, Kai-How A1 - Cuenca-Leon, Ester A1 - Furlotte, Nicholas A1 - Kurth, Tobias A1 - Ligthart, Lannie A1 - Terwindt, Gisela M A1 - Freilinger, Tobias A1 - Ran, Caroline A1 - Gordon, Scott D A1 - Borck, Guntram A1 - Adams, Hieab H H A1 - Lehtimäki, Terho A1 - Wedenoja, Juho A1 - Buring, Julie E A1 - Schürks, Markus A1 - Hrafnsdottir, Maria A1 - Hottenga, Jouke-Jan A1 - Penninx, Brenda A1 - Artto, Ville A1 - Kaunisto, Mari A1 - Vepsäläinen, Salli A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Kurki, Mitja I A1 - Hämäläinen, Eija A1 - Huang, Hailiang A1 - Huang, Jie A1 - Sandor, Cynthia A1 - Webber, Caleb A1 - Müller-Myhsok, Bertram A1 - Schreiber, Stefan A1 - Salomaa, Veikko A1 - Loehrer, Elizabeth A1 - Göbel, Hartmut A1 - Macaya, Alfons A1 - Pozo-Rosich, Patricia A1 - Hansen, Thomas A1 - Werge, Thomas A1 - Kaprio, Jaakko A1 - Metspalu, Andres A1 - Kubisch, Christian A1 - Ferrari, Michel D A1 - Belin, Andrea C A1 - van den Maagdenberg, Arn M J M A1 - Zwart, John-Anker A1 - Boomsma, Dorret A1 - Eriksson, Nicholas A1 - Olesen, Jes A1 - Chasman, Daniel I A1 - Nyholt, Dale R A1 - Avbersek, Andreja A1 - Baum, Larry A1 - Berkovic, Samuel A1 - Bradfield, Jonathan A1 - Buono, Russell A1 - Catarino, Claudia B A1 - Cossette, Patrick A1 - De Jonghe, Peter A1 - Depondt, Chantal A1 - Dlugos, Dennis A1 - Ferraro, Thomas N A1 - French, Jacqueline A1 - Hjalgrim, Helle A1 - Jamnadas-Khoda, Jennifer A1 - Kälviäinen, Reetta A1 - Kunz, Wolfram S A1 - Lerche, Holger A1 - Leu, Costin A1 - Lindhout, Dick A1 - Lo, Warren A1 - Lowenstein, Daniel A1 - McCormack, Mark A1 - Møller, Rikke S A1 - Molloy, Anne A1 - Ng, Ping-Wing A1 - Oliver, Karen A1 - Privitera, Michael A1 - Radtke, Rodney A1 - Ruppert, Ann-Kathrin A1 - Sander, Thomas A1 - Schachter, Steven A1 - Schankin, Christoph A1 - Scheffer, Ingrid A1 - Schoch, Susanne A1 - Sisodiya, Sanjay M A1 - Smith, Philip A1 - Sperling, Michael A1 - Striano, Pasquale A1 - Surges, Rainer A1 - Thomas, G Neil A1 - Visscher, Frank A1 - Whelan, Christopher D A1 - Zara, Federico A1 - Heinzen, Erin L A1 - Marson, Anthony A1 - Becker, Felicitas A1 - Stroink, Hans A1 - Zimprich, Fritz A1 - Gasser, Thomas A1 - Gibbs, Raphael A1 - Heutink, Peter A1 - Martinez, Maria A1 - Morris, Huw R A1 - Sharma, Manu A1 - Ryten, Mina A1 - Mok, Kin Y A1 - Pulit, Sara A1 - Bevan, Steve A1 - Holliday, Elizabeth A1 - Attia, John A1 - Battey, Thomas A1 - Boncoraglio, Giorgio A1 - Thijs, Vincent A1 - Chen, Wei-Min A1 - Mitchell, Braxton A1 - Rothwell, Peter A1 - Sharma, Pankaj A1 - Sudlow, Cathie A1 - Vicente, Astrid A1 - Markus, Hugh A1 - Kourkoulis, Christina A1 - Pera, Joana A1 - Raffeld, Miriam A1 - Silliman, Scott A1 - Boraska Perica, Vesna A1 - Thornton, Laura M A1 - Huckins, Laura M A1 - William Rayner, N A1 - Lewis, Cathryn M A1 - Gratacos, Monica A1 - Rybakowski, Filip A1 - Keski-Rahkonen, Anna A1 - Raevuori, Anu A1 - Hudson, James I A1 - Reichborn-Kjennerud, Ted A1 - Monteleone, Palmiero A1 - Karwautz, Andreas A1 - Mannik, Katrin A1 - Baker, Jessica H A1 - O'Toole, Julie K A1 - Trace, Sara E A1 - Davis, Oliver S P A1 - Helder, Sietske G A1 - Ehrlich, Stefan A1 - Herpertz-Dahlmann, Beate A1 - Danner, Unna N A1 - van Elburg, Annemarie A A1 - Clementi, Maurizio A1 - Forzan, Monica A1 - Docampo, Elisa A1 - Lissowska, Jolanta A1 - Hauser, Joanna A1 - Tortorella, Alfonso A1 - Maj, Mario A1 - Gonidakis, Fragiskos A1 - Tziouvas, Konstantinos A1 - Papezova, Hana A1 - Yilmaz, Zeynep A1 - Wagner, Gudrun A1 - Cohen-Woods, Sarah A1 - Herms, Stefan A1 - Julià, Antonio A1 - Rabionet, Raquel A1 - Dick, Danielle M A1 - Ripatti, Samuli A1 - Andreassen, Ole A A1 - Espeseth, Thomas A1 - Lundervold, Astri J A1 - Steen, Vidar M A1 - Pinto, Dalila A1 - Scherer, Stephen W A1 - Aschauer, Harald A1 - Schosser, Alexandra A1 - Alfredsson, Lars A1 - Padyukov, Leonid A1 - Halmi, Katherine A A1 - Mitchell, James A1 - Strober, Michael A1 - Bergen, Andrew W A1 - Kaye, Walter A1 - Szatkiewicz, Jin Peng A1 - Cormand, Bru A1 - Ramos-Quiroga, Josep Antoni A1 - Sánchez-Mora, Cristina A1 - Ribasés, Marta A1 - Casas, Miguel A1 - Hervas, Amaia A1 - Arranz, Maria Jesús A1 - Haavik, Jan A1 - Zayats, Tetyana A1 - Johansson, Stefan A1 - Williams, Nigel A1 - Dempfle, Astrid A1 - Rothenberger, Aribert A1 - Kuntsi, Jonna A1 - Oades, Robert D A1 - Banaschewski, Tobias A1 - Franke, Barbara A1 - Buitelaar, Jan K A1 - Arias Vasquez, Alejandro A1 - Doyle, Alysa E A1 - Reif, Andreas A1 - Lesch, Klaus-Peter A1 - Freitag, Christine A1 - Rivero, Olga A1 - Palmason, Haukur A1 - Romanos, Marcel A1 - Langley, Kate A1 - Rietschel, Marcella A1 - Witt, Stephanie H A1 - Dalsgaard, Soeren A1 - Børglum, Anders D A1 - Waldman, Irwin A1 - Wilmot, Beth A1 - Molly, Nikolas A1 - Bau, Claiton H D A1 - Crosbie, Jennifer A1 - Schachar, Russell A1 - Loo, Sandra K A1 - McGough, James J A1 - Grevet, Eugenio H A1 - Medland, Sarah E A1 - Robinson, Elise A1 - Weiss, Lauren A A1 - Bacchelli, Elena A1 - Bailey, Anthony A1 - Bal, Vanessa A1 - Battaglia, Agatino A1 - Betancur, Catalina A1 - Bolton, Patrick A1 - Cantor, Rita A1 - Celestino-Soper, Patrícia A1 - Dawson, Geraldine A1 - De Rubeis, Silvia A1 - Duque, Frederico A1 - Green, Andrew A1 - Klauck, Sabine M A1 - Leboyer, Marion A1 - Levitt, Pat A1 - Maestrini, Elena A1 - Mane, Shrikant A1 - De-Luca, Daniel Moreno- A1 - Parr, Jeremy A1 - Regan, Regina A1 - Reichenberg, Abraham A1 - Sandin, Sven A1 - Vorstman, Jacob A1 - Wassink, Thomas A1 - Wijsman, Ellen A1 - Cook, Edwin A1 - Santangelo, Susan A1 - Delorme, Richard A1 - Rogé, Bernadette A1 - Magalhaes, Tiago A1 - Arking, Dan A1 - Schulze, Thomas G A1 - Thompson, Robert C A1 - Strohmaier, Jana A1 - Matthews, Keith A1 - Melle, Ingrid A1 - Morris, Derek A1 - Blackwood, Douglas A1 - McIntosh, Andrew A1 - Bergen, Sarah E A1 - Schalling, Martin A1 - Jamain, Stephane A1 - Maaser, Anna A1 - Fischer, Sascha B A1 - Reinbold, Céline S A1 - Fullerton, Janice M A1 - Guzman-Parra, José A1 - Mayoral, Fermin A1 - Schofield, Peter R A1 - Cichon, Sven A1 - Mühleisen, Thomas W A1 - Degenhardt, Franziska A1 - Schumacher, Johannes A1 - Bauer, Michael A1 - Mitchell, Philip B A1 - Gershon, Elliot S A1 - Rice, John A1 - Potash, James B A1 - Zandi, Peter P A1 - Craddock, Nick A1 - Ferrier, I Nicol A1 - Alda, Martin A1 - Rouleau, Guy A A1 - Gustavo Turecki A1 - Ophoff, Roel A1 - Pato, Carlos A1 - Anjorin, Adebayo A1 - Stahl, Eli A1 - Leber, Markus A1 - Czerski, Piotr M A1 - Cruceanu, Cristiana A1 - Jones, Ian R A1 - Posthuma, Danielle A1 - Andlauer, Till F M A1 - Forstner, Andreas J A1 - Streit, Fabian A1 - Baune, Bernhard T A1 - Air, Tracy A1 - Sinnamon, Grant A1 - Wray, Naomi R A1 - MacIntyre, Donald J A1 - Porteous, David A1 - Homuth, Georg A1 - Rivera, Margarita A1 - Grove, Jakob A1 - Middeldorp, Christel M A1 - Hickie, Ian A1 - Pergadia, Michele A1 - Mehta, Divya A1 - Smit, Johannes H A1 - Jansen, Rick A1 - de Geus, Eco A1 - Dunn, Erin A1 - Li, Qingqin S A1 - Nauck, Matthias A1 - Schoevers, Robert A A1 - Beekman, Aartjan Tf A1 - Knowles, James A A1 - Viktorin, Alexander A1 - Arnold, Paul A1 - Barr, Cathy L A1 - Bedoya-Berrio, Gabriel A1 - Bienvenu, O Joseph A1 - Brentani, Helena A1 - Burton, Christie A1 - Camarena, Beatriz A1 - Cappi, Carolina A1 - Cath, Danielle A1 - Cavallini, Maria A1 - Cusi, Daniele A1 - Darrow, Sabrina A1 - Denys, Damiaan A1 - Derks, Eske M A1 - Dietrich, Andrea A1 - Fernandez, Thomas A1 - Figee, Martijn A1 - Freimer, Nelson A1 - Gerber, Gloria A1 - Grados, Marco A1 - Greenberg, Erica A1 - Hanna, Gregory L A1 - Hartmann, Andreas A1 - Hirschtritt, Matthew E A1 - Hoekstra, Pieter J A1 - Huang, Alden A1 - Huyser, Chaim A1 - Illmann, Cornelia A1 - Jenike, Michael A1 - Kuperman, Samuel A1 - Leventhal, Bennett A1 - Lochner, Christine A1 - Lyon, Gholson J A1 - Macciardi, Fabio A1 - Madruga-Garrido, Marcos A1 - Malaty, Irene A A1 - Maras, Athanasios A1 - McGrath, Lauren A1 - Miguel, Eurípedes C A1 - Mir, Pablo A1 - Nestadt, Gerald A1 - Nicolini, Humberto A1 - Okun, Michael S A1 - Pakstis, Andrew A1 - Paschou, Peristera A1 - Piacentini, John A1 - Pittenger, Christopher A1 - Plessen, Kerstin A1 - Ramensky, Vasily A1 - Ramos, Eliana M A1 - Reus, Victor A1 - Richter, Margaret A A1 - Riddle, Mark A A1 - Robertson, Mary M A1 - Roessner, Veit A1 - Rosário, Maria A1 - Samuels, Jack F A1 - Sandor, Paul A1 - Stein, Dan J A1 - Tsetsos, Fotis A1 - Van Nieuwerburgh, Filip A1 - Weatherall, Sarah A1 - Wendland, Jens R A1 - Wolanczyk, Tomasz A1 - Worbe, Yulia A1 - Zai, Gwyneth A1 - Goes, Fernando S A1 - McLaughlin, Nicole A1 - Nestadt, Paul S A1 - Grabe, Hans-Jorgen A1 - Depienne, Christel A1 - Konkashbaev, Anuar A1 - Lanzagorta, Nuria A1 - Valencia-Duarte, Ana A1 - Bramon, Elvira A1 - Buccola, Nancy A1 - Cahn, Wiepke A1 - Cairns, Murray A1 - Chong, Siow A A1 - Cohen, David A1 - Crespo-Facorro, Benedicto A1 - Crowley, James A1 - Davidson, Michael A1 - DeLisi, Lynn A1 - Dinan, Timothy A1 - Donohoe, Gary A1 - Drapeau, Elodie A1 - Duan, Jubao A1 - Haan, Lieuwe A1 - Hougaard, David A1 - Karachanak-Yankova, Sena A1 - Khrunin, Andrey A1 - Klovins, Janis A1 - Kučinskas, Vaidutis A1 - Lee Chee Keong, Jimmy A1 - Limborska, Svetlana A1 - Loughland, Carmel A1 - Lönnqvist, Jouko A1 - Maher, Brion A1 - Mattheisen, Manuel A1 - McDonald, Colm A1 - Murphy, Kieran C A1 - Nenadic, Igor A1 - van Os, Jim A1 - Pantelis, Christos A1 - Pato, Michele A1 - Petryshen, Tracey A1 - Quested, Digby A1 - Roussos, Panos A1 - Sanders, Alan R A1 - Schall, Ulrich A1 - Schwab, Sibylle G A1 - Sim, Kang A1 - So, Hon-Cheong A1 - Stögmann, Elisabeth A1 - Subramaniam, Mythily A1 - Toncheva, Draga A1 - Waddington, John A1 - Walters, James A1 - Weiser, Mark A1 - Cheng, Wei A1 - Cloninger, Robert A1 - Curtis, David A1 - Gejman, Pablo V A1 - Henskens, Frans A1 - Mattingsdal, Morten A1 - Oh, Sang-Yun A1 - Scott, Rodney A1 - Webb, Bradley A1 - Breen, Gerome A1 - Churchhouse, Claire A1 - Bulik, Cynthia M A1 - Daly, Mark A1 - Dichgans, Martin A1 - Faraone, Stephen V A1 - Guerreiro, Rita A1 - Holmans, Peter A1 - Kendler, Kenneth S A1 - Koeleman, Bobby A1 - Mathews, Carol A A1 - Price, Alkes A1 - Scharf, Jeremiah A1 - Sklar, Pamela A1 - Williams, Julie A1 - Wood, Nicholas W A1 - Cotsapas, Chris A1 - Palotie, Aarno A1 - Smoller, Jordan W A1 - Sullivan, Patrick A1 - Rosand, Jonathan A1 - Corvin, Aiden A1 - Neale, Benjamin M AB -Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

VL - 360 IS - 6395 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29930110?dopt=Abstract ER - TY - JOUR T1 - Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder. JF - Front Psychiatry Y1 - 2018 A1 - Reinbold, Céline S A1 - Forstner, Andreas J A1 - Hecker, Julian A1 - Fullerton, Janice M A1 - Hoffmann, Per A1 - Hou, Liping A1 - Heilbronner, Urs A1 - Degenhardt, Franziska A1 - Adli, Mazda A1 - Akiyama, Kazufumi A1 - Akula, Nirmala A1 - Ardau, Raffaella A1 - Arias, Bárbara A1 - Backlund, Lena A1 - Benabarre, Antonio A1 - Bengesser, Susanne A1 - Bhattacharjee, Abesh K A1 - Biernacka, Joanna M A1 - Birner, Armin A1 - Marie-Claire, Cynthia A1 - Cervantes, Pablo A1 - Chen, Guo-Bo A1 - Chen, Hsi-Chung A1 - Chillotti, Caterina A1 - Clark, Scott R A1 - Colom, Francesc A1 - Cousins, David A A1 - Cruceanu, Cristiana A1 - Czerski, Piotr M A1 - Dayer, Alexandre A1 - Étain, Bruno A1 - Falkai, Peter A1 - Frisén, Louise A1 - Gard, Sébastien A1 - Garnham, Julie S A1 - Goes, Fernando S A1 - Grof, Paul A1 - Gruber, Oliver A1 - Hashimoto, Ryota A1 - Hauser, Joanna A1 - Herms, Stefan A1 - Jamain, Stephane A1 - Jiménez, Esther A1 - Kahn, Jean-Pierre A1 - Kassem, Layla A1 - Kittel-Schneider, Sarah A1 - Kliwicki, Sebastian A1 - König, Barbara A1 - Kusumi, Ichiro A1 - Lackner, Nina A1 - Laje, Gonzalo A1 - Landen, Mikael A1 - Lavebratt, Catharina A1 - Leboyer, Marion A1 - Leckband, Susan G A1 - López Jaramillo, Carlos A A1 - MacQueen, Glenda A1 - Manchia, Mirko A1 - Martinsson, Lina A1 - Mattheisen, Manuel A1 - McCarthy, Michael J A1 - McElroy, Susan L A1 - Mitjans, Marina A1 - Mondimore, Francis M A1 - Monteleone, Palmiero A1 - Nievergelt, Caroline M A1 - Ösby, Urban A1 - Ozaki, Norio A1 - Perlis, Roy H A1 - Pfennig, Andrea A1 - Reich-Erkelenz, Daniela A1 - Rouleau, Guy A A1 - Schofield, Peter R A1 - Schubert, K Oliver A1 - Schweizer, Barbara W A1 - Seemüller, Florian A1 - Severino, Giovanni A1 - Shekhtman, Tatyana A1 - Shilling, Paul D A1 - Shimoda, Kazutaka A1 - Simhandl, Christian A1 - Slaney, Claire M A1 - Smoller, Jordan W A1 - Squassina, Alessio A1 - Stamm, Thomas J A1 - Stopkova, Pavla A1 - Tighe, Sarah K A1 - Tortorella, Alfonso A1 - Gustavo Turecki A1 - Volkert, Julia A1 - Witt, Stephanie H A1 - Wright, Adam J A1 - Young, L Trevor A1 - Zandi, Peter P A1 - Potash, James B A1 - DePaulo, J Raymond A1 - Bauer, Michael A1 - Reininghaus, Eva A1 - Novák, Tomas A1 - Aubry, Jean-Michel A1 - Maj, Mario A1 - Baune, Bernhard T A1 - Mitchell, Philip B A1 - Vieta, Eduard A1 - Frye, Mark A A1 - Rybakowski, Janusz K A1 - Kuo, Po-Hsiu A1 - Kato, Tadafumi A1 - Grigoroiu-Serbanescu, Maria A1 - Reif, Andreas A1 - Del Zompo, Maria A1 - Bellivier, Frank A1 - Schalling, Martin A1 - Wray, Naomi R A1 - Kelsoe, John R A1 - Alda, Martin A1 - McMahon, Francis J A1 - Schulze, Thomas G A1 - Rietschel, Marcella A1 - Nöthen, Markus M A1 - Cichon, Sven AB -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 ( = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, 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 showing the strongest association with the continuous trait ( = 9.80E-04) and with the dichotomous phenotype ( = 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.

VL - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29904359?dopt=Abstract ER - TY - JOUR T1 - Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study. JF - JAMA Psychiatry Y1 - 2018 A1 - Amare, Azmeraw T A1 - Schubert, Klaus Oliver A1 - Hou, Liping A1 - Clark, Scott R A1 - Papiol, Sergi A1 - Heilbronner, Urs A1 - Degenhardt, Franziska A1 - Tekola-Ayele, Fasil A1 - Hsu, Yi-Hsiang A1 - Shekhtman, Tatyana A1 - Adli, Mazda A1 - Akula, Nirmala A1 - Akiyama, Kazufumi A1 - Ardau, Raffaella A1 - Arias, Bárbara A1 - Aubry, Jean-Michel A1 - Backlund, Lena A1 - Bhattacharjee, Abesh Kumar A1 - Bellivier, Frank A1 - Benabarre, Antonio A1 - Bengesser, Susanne A1 - Biernacka, Joanna M A1 - Birner, Armin A1 - Brichant-Petitjean, Clara A1 - Cervantes, Pablo A1 - Chen, Hsi-Chung A1 - Chillotti, Caterina A1 - Cichon, Sven A1 - Cruceanu, Cristiana A1 - Czerski, Piotr M A1 - Dalkner, Nina A1 - Dayer, Alexandre A1 - Del Zompo, Maria A1 - DePaulo, J Raymond A1 - Étain, Bruno A1 - Falkai, Peter A1 - Forstner, Andreas J A1 - Frisén, Louise A1 - Frye, Mark A A1 - Fullerton, Janice M A1 - Gard, Sébastien A1 - Garnham, Julie S A1 - Goes, Fernando S A1 - Grigoroiu-Serbanescu, Maria A1 - Grof, Paul A1 - Hashimoto, Ryota A1 - Hauser, Joanna A1 - Herms, Stefan A1 - Hoffmann, Per A1 - Hofmann, Andrea A1 - Jamain, Stephane A1 - Jiménez, Esther A1 - Kahn, Jean-Pierre A1 - Kassem, Layla A1 - Kuo, Po-Hsiu A1 - Kato, Tadafumi A1 - Kelsoe, John A1 - Kittel-Schneider, Sarah A1 - Kliwicki, Sebastian A1 - König, Barbara A1 - Kusumi, Ichiro A1 - Laje, Gonzalo A1 - Landen, Mikael A1 - Lavebratt, Catharina A1 - Leboyer, Marion A1 - Leckband, Susan G A1 - Tortorella, Alfonso A1 - Manchia, Mirko A1 - Martinsson, Lina A1 - McCarthy, Michael J A1 - McElroy, Susan A1 - Colom, Francesc A1 - Mitjans, Marina A1 - Mondimore, Francis M A1 - Monteleone, Palmiero A1 - Nievergelt, Caroline M A1 - Nöthen, Markus M A1 - Novák, Tomas A1 - O'Donovan, Claire A1 - Ozaki, Norio A1 - Ösby, Urban A1 - Pfennig, Andrea A1 - Potash, James B A1 - Reif, Andreas A1 - Reininghaus, Eva A1 - Rouleau, Guy A A1 - Rybakowski, Janusz K A1 - Schalling, Martin A1 - Schofield, Peter R A1 - Schweizer, Barbara W A1 - Severino, Giovanni A1 - Shilling, Paul D A1 - Shimoda, Katzutaka A1 - Simhandl, Christian A1 - Slaney, Claire M A1 - Squassina, Alessio A1 - Stamm, Thomas A1 - Stopkova, Pavla A1 - Maj, Mario A1 - Gustavo Turecki A1 - Vieta, Eduard A1 - Volkert, Julia A1 - Witt, Stephanie A1 - Wright, Adam A1 - Zandi, Peter P A1 - Mitchell, Philip B A1 - Bauer, Michael A1 - Alda, Martin A1 - Rietschel, Marcella A1 - McMahon, Francis J A1 - Schulze, Thomas G A1 - Baune, Bernhard T AB -**Importance: **Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).

**Objectives: **To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.

**Design, Setting, and Participants: **A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.

**Main Outcomes and Measures: **Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.

**Results: **Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 × 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.

**Conclusions and Relevance: **This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

**BACKGROUND: **Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci.

**METHODS: **We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan.

**RESULTS: **Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (P = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (P = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system.

**LIMITATIONS: **Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients.

**CONCLUSIONS: **Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.

**OBJECTIVES: **Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.

**METHODS: **A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.

**RESULTS: **BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.

**CONCLUSIONS: **The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.

VL - 12 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28166306?dopt=Abstract ER - TY - JOUR T1 - Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. JF - Lancet Y1 - 2016 A1 - Hou, Liping A1 - Heilbronner, Urs A1 - Degenhardt, Franziska A1 - Adli, Mazda A1 - Akiyama, Kazufumi A1 - Akula, Nirmala A1 - Ardau, Raffaella A1 - Arias, Bárbara A1 - Backlund, Lena A1 - Banzato, Claudio E M A1 - Benabarre, Antoni A1 - Bengesser, Susanne A1 - Bhattacharjee, Abesh Kumar A1 - Biernacka, Joanna M A1 - Birner, Armin A1 - Brichant-Petitjean, Clara A1 - Bui, Elise T A1 - Cervantes, Pablo A1 - Chen, Guo-Bo A1 - Chen, Hsi-Chung A1 - Chillotti, Caterina A1 - Cichon, Sven A1 - Clark, Scott R A1 - Colom, Francesc A1 - Cousins, David A A1 - Cruceanu, Cristiana A1 - Czerski, Piotr M A1 - Dantas, Clarissa R A1 - Dayer, Alexandre A1 - Étain, Bruno A1 - Falkai, Peter A1 - Forstner, Andreas J A1 - Frisén, Louise A1 - Fullerton, Janice M A1 - Gard, Sébastien A1 - Garnham, Julie S A1 - Goes, Fernando S A1 - Grof, Paul A1 - Gruber, Oliver A1 - Hashimoto, Ryota A1 - Hauser, Joanna A1 - Herms, Stefan A1 - Hoffmann, Per A1 - Hofmann, Andrea A1 - Jamain, Stephane A1 - Jiménez, Esther A1 - Kahn, Jean-Pierre A1 - Kassem, Layla A1 - Kittel-Schneider, Sarah A1 - Kliwicki, Sebastian A1 - König, Barbara A1 - Kusumi, Ichiro A1 - Lackner, Nina A1 - Laje, Gonzalo A1 - Landen, Mikael A1 - Lavebratt, Catharina A1 - Leboyer, Marion A1 - Leckband, Susan G A1 - Jaramillo, Carlos A López A1 - MacQueen, Glenda A1 - Manchia, Mirko A1 - Martinsson, Lina A1 - Mattheisen, Manuel A1 - McCarthy, Michael J A1 - McElroy, Susan L A1 - Mitjans, Marina A1 - Mondimore, Francis M A1 - Monteleone, Palmiero A1 - Nievergelt, Caroline M A1 - Nöthen, Markus M A1 - Ösby, Urban A1 - Ozaki, Norio A1 - Perlis, Roy H A1 - Pfennig, Andrea A1 - Reich-Erkelenz, Daniela A1 - Rouleau, Guy A A1 - Schofield, Peter R A1 - Schubert, K Oliver A1 - Schweizer, Barbara W A1 - Seemüller, Florian A1 - Severino, Giovanni A1 - Shekhtman, Tatyana A1 - Shilling, Paul D A1 - Shimoda, Kazutaka A1 - Simhandl, Christian A1 - Slaney, Claire M A1 - Smoller, Jordan W A1 - Squassina, Alessio A1 - Stamm, Thomas A1 - Stopkova, Pavla A1 - Tighe, Sarah K A1 - Tortorella, Alfonso A1 - Gustavo Turecki A1 - Volkert, Julia A1 - Witt, Stephanie A1 - Wright, Adam A1 - Young, L Trevor A1 - Zandi, Peter P A1 - Potash, James B A1 - DePaulo, J Raymond A1 - Bauer, Michael A1 - Reininghaus, Eva Z A1 - Novák, Tomas A1 - Aubry, Jean-Michel A1 - Maj, Mario A1 - Baune, Bernhard T A1 - Mitchell, Philip B A1 - Vieta, Eduard A1 - Frye, Mark A A1 - Rybakowski, Janusz K A1 - Kuo, Po-Hsiu A1 - Kato, Tadafumi A1 - Grigoroiu-Serbanescu, Maria A1 - Reif, Andreas A1 - Del Zompo, Maria A1 - Bellivier, Frank A1 - Schalling, Martin A1 - Wray, Naomi R A1 - Kelsoe, John R A1 - Alda, Martin A1 - Rietschel, Marcella A1 - McMahon, Francis J A1 - Schulze, Thomas G KW - Bipolar Disorder KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genotype KW - Glial Cell Line-Derived Neurotrophic Factor Receptors KW - Humans KW - Lithium Compounds KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Treatment Outcome AB -**BACKGROUND: **Lithium 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.

**METHODS: **Here, 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.

**FINDINGS: **A 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).

**INTERPRETATION: **The 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.

**FUNDING: **Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 (-) (9); odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 (-) (9); OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

VL - 25 IS - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27329760?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study reveals two new risk loci for bipolar disorder. JF - Nat Commun Y1 - 2014 A1 - Mühleisen, Thomas W A1 - Leber, Markus A1 - Schulze, Thomas G A1 - Strohmaier, Jana A1 - Degenhardt, Franziska A1 - Treutlein, Jens A1 - Mattheisen, Manuel A1 - Forstner, Andreas J A1 - Schumacher, Johannes A1 - Breuer, René A1 - Meier, Sandra A1 - Herms, Stefan A1 - Hoffmann, Per A1 - Lacour, André A1 - Witt, Stephanie H A1 - Reif, Andreas A1 - Müller-Myhsok, Bertram A1 - Lucae, Susanne A1 - Maier, Wolfgang A1 - Schwarz, Markus A1 - Vedder, Helmut A1 - Kammerer-Ciernioch, Jutta A1 - Pfennig, Andrea A1 - Bauer, Michael A1 - Hautzinger, Martin A1 - Moebus, Susanne A1 - Priebe, Lutz A1 - Czerski, Piotr M A1 - Hauser, Joanna A1 - Lissowska, Jolanta A1 - Szeszenia-Dabrowska, Neonila A1 - Brennan, Paul A1 - McKay, James D A1 - Wright, Adam A1 - Mitchell, Philip B A1 - Fullerton, Janice M A1 - Schofield, Peter R A1 - Montgomery, Grant W A1 - Medland, Sarah E A1 - Gordon, Scott D A1 - Martin, Nicholas G A1 - Krasnow, Valery A1 - Chuchalin, Alexander A1 - Babadjanova, Gulja A1 - Pantelejeva, Galina A1 - Abramova, Lilia I A1 - Tiganov, Alexander S A1 - Polonikov, Alexey A1 - Khusnutdinova, Elza A1 - Alda, Martin A1 - Grof, Paul A1 - Rouleau, Guy A A1 - Gustavo Turecki A1 - Laprise, Catherine A1 - Rivas, Fabio A1 - Mayoral, Fermin A1 - Kogevinas, Manolis A1 - Grigoroiu-Serbanescu, Maria A1 - Propping, Peter A1 - Becker, Tim A1 - Rietschel, Marcella A1 - Nöthen, Markus M A1 - Cichon, Sven KW - Adenylyl Cyclases KW - Bipolar Disorder KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Polymorphism, Single Nucleotide AB -Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.

VL - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24618891?dopt=Abstract ER -