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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
Nature Genetics ( IF 31.7 ) Pub Date : 2021-05-17 , DOI: 10.1038/s41588-021-00857-4
Niamh Mullins 1, 2 , Andreas J Forstner 3, 4, 5 , Kevin S O'Connell 6, 7 , Brandon Coombes 8 , Jonathan R I Coleman 9, 10 , Zhen Qiao 11 , Thomas D Als 12, 13, 14 , Tim B Bigdeli 15, 16 , Sigrid Børte 17, 18, 19 , Julien Bryois 20 , Alexander W Charney 2 , Ole Kristian Drange 21, 22 , Michael J Gandal 23 , Saskia P Hagenaars 9, 10 , Masashi Ikeda 24 , Nolan Kamitaki 25, 26 , Minsoo Kim 23 , Kristi Krebs 27 , Georgia Panagiotaropoulou 28 , Brian M Schilder 1, 29, 30, 31 , Laura G Sloofman 1 , Stacy Steinberg 32 , Vassily Trubetskoy 28 , Bendik S Winsvold 19, 33 , Hong-Hee Won 34 , Liliya Abramova 35 , Kristina Adorjan 36, 37 , Esben Agerbo 14, 38, 39 , Mariam Al Eissa 40 , Diego Albani 41 , Ney Alliey-Rodriguez 42, 43 , Adebayo Anjorin 44 , Verneri Antilla 45 , Anastasia Antoniou 46 , Swapnil Awasthi 28 , Ji Hyun Baek 47 , Marie Bækvad-Hansen 14, 48 , Nicholas Bass 40 , Michael Bauer 49 , Eva C Beins 3 , Sarah E Bergen 20 , Armin Birner 50 , Carsten Bøcker Pedersen 14, 38, 39 , Erlend Bøen 51 , Marco P Boks 52 , Rosa Bosch 53, 54, 55, 56 , Murielle Brum 57 , Ben M Brumpton 19 , Nathalie Brunkhorst-Kanaan 57 , Monika Budde 36 , Jonas Bybjerg-Grauholm 14, 48 , William Byerley 58 , Murray Cairns 59 , Miquel Casas 53, 54, 55, 56 , Pablo Cervantes 60 , Toni-Kim Clarke 61 , Cristiana Cruceanu 60, 62 , Alfredo Cuellar-Barboza 63, 64 , Julie Cunningham 65 , David Curtis 66, 67 , Piotr M Czerski 68 , Anders M Dale 69 , Nina Dalkner 50 , Friederike S David 3 , Franziska Degenhardt 3, 70 , Srdjan Djurovic 71, 72 , Amanda L Dobbyn 1, 2 , Athanassios Douzenis 46 , Torbjørn Elvsåshagen 18, 73, 74 , Valentina Escott-Price 75 , I Nicol Ferrier 76 , Alessia Fiorentino 40 , Tatiana M Foroud 77 , Liz Forty 75 , Josef Frank 78 , Oleksandr Frei 6, 18 , Nelson B Freimer 23, 79 , Louise Frisén 80 , Katrin Gade 36, 81 , Julie Garnham 82 , Joel Gelernter 83, 84, 85 , Marianne Giørtz Pedersen 14, 38, 39 , Ian R Gizer 86 , Scott D Gordon 87 , Katherine Gordon-Smith 88 , Tiffany A Greenwood 89 , Jakob Grove 12, 13, 14, 90 , José Guzman-Parra 91 , Kyooseob Ha 92 , Magnus Haraldsson 93 , Martin Hautzinger 94 , Urs Heilbronner 36 , Dennis Hellgren 20 , Stefan Herms 3, 95, 96 , Per Hoffmann 3, 95, 96 , Peter A Holmans 75 , Laura Huckins 1, 2 , Stéphane Jamain 97, 98 , Jessica S Johnson 1, 2 , Janos L Kalman 36, 37, 99 , Yoichiro Kamatani 100, 101 , James L Kennedy 102, 103, 104, 105 , Sarah Kittel-Schneider 57, 106 , James A Knowles 107, 108 , Manolis Kogevinas 109 , Maria Koromina 110 , Thorsten M Kranz 57 , Henry R Kranzler 111, 112 , Michiaki Kubo 113 , Ralph Kupka 114, 115, 116 , Steven A Kushner 117 , Catharina Lavebratt 118, 119 , Jacob Lawrence 120 , Markus Leber 121 , Heon-Jeong Lee 122 , Phil H Lee 123 , Shawn E Levy 124 , Catrin Lewis 75 , Calwing Liao 125, 126 , Susanne Lucae 62 , Martin Lundberg 118, 119 , Donald J MacIntyre 127 , Sigurdur H Magnusson 32 , Wolfgang Maier 128 , Adam Maihofer 89 , Dolores Malaspina 1, 2 , Eirini Maratou 129 , Lina Martinsson 80 , Manuel Mattheisen 12, 13, 14, 106, 130 , Steven A McCarroll 25, 26 , Nathaniel W McGregor 131 , Peter McGuffin 9 , James D McKay 132 , Helena Medeiros 108 , Sarah E Medland 87 , Vincent Millischer 118, 119 , Grant W Montgomery 11 , Jennifer L Moran 25, 133 , Derek W Morris 134 , Thomas W Mühleisen 4, 95 , Niamh O'Brien 40 , Claire O'Donovan 82 , Loes M Olde Loohuis 23, 79 , Lilijana Oruc 135 , Sergi Papiol 36, 37 , Antonio F Pardiñas 75 , Amy Perry 88 , Andrea Pfennig 49 , Evgenia Porichi 46 , James B Potash 136 , Digby Quested 137, 138 , Towfique Raj 1, 29, 30, 31 , Mark H Rapaport 139 , J Raymond DePaulo 136 , Eline J Regeer 140 , John P Rice 141 , Fabio Rivas 91 , Margarita Rivera 142, 143 , Julian Roth 106 , Panos Roussos 1, 2, 29 , Douglas M Ruderfer 144 , Cristina Sánchez-Mora 53, 54, 56, 145 , Eva C Schulte 36, 37 , Fanny Senner 36, 37 , Sally Sharp 40 , Paul D Shilling 89 , Engilbert Sigurdsson 93, 146 , Lea Sirignano 78 , Claire Slaney 82 , Olav B Smeland 6, 7 , Daniel J Smith 147 , Janet L Sobell 148 , Christine Søholm Hansen 14, 48 , Maria Soler Artigas 53, 54, 56, 145 , Anne T Spijker 149 , Dan J Stein 150 , John S Strauss 102 , Beata Świątkowska 151 , Chikashi Terao 101 , Thorgeir E Thorgeirsson 32 , Claudio Toma 152, 153, 154 , Paul Tooney 59 , Evangelia-Eirini Tsermpini 110 , Marquis P Vawter 155 , Helmut Vedder 156 , James T R Walters 75 , Stephanie H Witt 78 , Simon Xi 157 , Wei Xu 158 , Jessica Mei Kay Yang 75 , Allan H Young 159, 160 , Hannah Young 1 , Peter P Zandi 136 , Hang Zhou 83, 84 , Lea Zillich 78 , , Rolf Adolfsson 161 , Ingrid Agartz 51, 130, 162 , Martin Alda 82, 163 , Lars Alfredsson 164 , Gulja Babadjanova 165 , Lena Backlund 118, 119 , Bernhard T Baune 166, 167, 168 , Frank Bellivier 169, 170 , Susanne Bengesser 50 , Wade H Berrettini 171 , Douglas H R Blackwood 61 , Michael Boehnke 172 , Anders D Børglum 14, 173, 174 , Gerome Breen 9, 10 , Vaughan J Carr 175 , Stanley Catts 176 , Aiden Corvin 177 , Nicholas Craddock 75 , Udo Dannlowski 166 , Dimitris Dikeos 178 , Tõnu Esko 26, 27, 179, 180 , Bruno Etain 169, 170 , Panagiotis Ferentinos 9, 46 , Mark Frye 64 , Janice M Fullerton 152, 153 , Micha Gawlik 106 , Elliot S Gershon 42, 181 , Fernando S Goes 136 , Melissa J Green 152, 175 , Maria Grigoroiu-Serbanescu 182 , Joanna Hauser 68 , Frans Henskens 59 , Jan Hillert 80 , Kyung Sue Hong 47 , David M Hougaard 14, 48 , Christina M Hultman 20 , Kristian Hveem 19, 183 , Nakao Iwata 24 , Assen V Jablensky 184 , Ian Jones 75 , Lisa A Jones 88 , René S Kahn 2, 52 , John R Kelsoe 89 , George Kirov 75 , Mikael Landén 20, 185 , Marion Leboyer 97, 98, 186 , Cathryn M Lewis 9, 10, 187 , Qingqin S Li 188 , Jolanta Lissowska 189 , Christine Lochner 190 , Carmel Loughland 59 , Nicholas G Martin 87, 191 , Carol A Mathews 192 , Fermin Mayoral 91 , Susan L McElroy 193 , Andrew M McIntosh 127, 194 , Francis J McMahon 195 , Ingrid Melle 6, 196 , Patricia Michie 59 , Lili Milani 27 , Philip B Mitchell 175 , Gunnar Morken 21, 197 , Ole Mors 14, 198 , Preben Bo Mortensen 12, 14, 38, 39 , Bryan Mowry 176 , Bertram Müller-Myhsok 62, 199, 200 , Richard M Myers 124 , Benjamin M Neale 25, 45, 179 , Caroline M Nievergelt 89, 201 , Merete Nordentoft 14, 202 , Markus M Nöthen 3 , Michael C O'Donovan 75 , Ketil J Oedegaard 203, 204 , Tomas Olsson 205 , Michael J Owen 75 , Sara A Paciga 206 , Chris Pantelis 207 , Carlos Pato 108 , Michele T Pato 108 , George P Patrinos 110, 208, 209 , Roy H Perlis 210, 211 , Danielle Posthuma 212, 213 , Josep Antoni Ramos-Quiroga 53, 54, 55, 56 , Andreas Reif 57 , Eva Z Reininghaus 50 , Marta Ribasés 53, 54, 56, 145 , Marcella Rietschel 78 , Stephan Ripke 25, 28, 45 , Guy A Rouleau 126, 214 , Takeo Saito 24 , Ulrich Schall 59 , Martin Schalling 118, 119 , Peter R Schofield 152, 153 , Thomas G Schulze 36, 78, 81, 136, 215 , Laura J Scott 172 , Rodney J Scott 59 , Alessandro Serretti 216 , Cynthia Shannon Weickert 152, 175, 217 , Jordan W Smoller 25, 133, 218 , Hreinn Stefansson 32 , Kari Stefansson 32, 219 , Eystein Stordal 220, 221 , Fabian Streit 78 , Patrick F Sullivan 20, 222, 223 , Gustavo Turecki 224 , Arne E Vaaler 225 , Eduard Vieta 226 , John B Vincent 102 , Irwin D Waldman 227 , Thomas W Weickert 152, 175, 217 , Thomas Werge 14, 228, 229, 230 , Naomi R Wray 11, 231 , John-Anker Zwart 18, 19, 33 , Joanna M Biernacka 8, 64 , John I Nurnberger 232 , Sven Cichon 3, 4, 95, 96 , Howard J Edenberg 77, 233 , Eli A Stahl 1, 2, 179 , Andrew McQuillin 40 , Arianna Di Florio 75, 223 , Roel A Ophoff 23, 79, 117, 234 , Ole A Andreassen 6, 7
Affiliation  

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.



中文翻译:


对 40,000 多个双相情感障碍病例进行的全基因组关联研究为潜在生物学提供了新的见解



双相情感障碍是一种病因复杂的遗传性精神疾病。我们对 41,917 名双相情感障碍病例和 371,549 名欧洲血统对照进行了全基因组关联研究,确定了 64 个相关基因组位点。双相情感障碍风险等位基因在突触信号通路和大脑表达基因中富集,特别是在前额皮质和海马神经元中具有高特异性表达的基因。在编码抗精神病药、钙通道阻滞剂、抗癫痫药和麻醉药靶标的基因中发现了显着的信号富集。整合表达数量性状基因座数据表明,15 个基因通过基因表达与双相情感障碍密切相关,编码 HTR6、MCHR1、DCLK3 和 FURIN 等可药物靶标。对双相情感障碍亚型的分析表明,双相情感障碍 I 型和 II 型之间存在高度但不完善的遗传相关性,并确定了其他相关位点。总之,这些结果增进了我们对双相情感障碍的生物学病因学的理解,确定了新的治疗线索,并优先考虑基因进行功能性后续研究。

更新日期:2021-05-17
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