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Meta-Analysis
. 2021 Jun;53(6):817-829.
doi: 10.1038/s41588-021-00857-4. Epub 2021 May 17.

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

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  21 , Ole Kristian Drange  22   23 , Michael J Gandal  24 , Saskia P Hagenaars  9   10 , Masashi Ikeda  25 , Nolan Kamitaki  26   27 , Minsoo Kim  24 , Kristi Krebs  28 , Georgia Panagiotaropoulou  29 , Brian M Schilder  30   31   32   33 , Laura G Sloofman  30 , Stacy Steinberg  34 , Vassily Trubetskoy  29 , Bendik S Winsvold  19   35 , Hong-Hee Won  36 , Liliya Abramova  37 , Kristina Adorjan  38   39 , Esben Agerbo  14   40   41 , Mariam Al Eissa  42 , Diego Albani  43 , Ney Alliey-Rodriguez  44   45 , Adebayo Anjorin  46 , Verneri Antilla  47 , Anastasia Antoniou  48 , Swapnil Awasthi  29 , Ji Hyun Baek  49 , Marie Bækvad-Hansen  14   50 , Nicholas Bass  42 , Michael Bauer  51 , Eva C Beins  3 , Sarah E Bergen  20 , Armin Birner  52 , Carsten Bøcker Pedersen  14   40   41 , Erlend Bøen  53 , Marco P Boks  54 , Rosa Bosch  55   56   57   58 , Murielle Brum  59 , Ben M Brumpton  19 , Nathalie Brunkhorst-Kanaan  59 , Monika Budde  38 , Jonas Bybjerg-Grauholm  14   50 , William Byerley  60 , Murray Cairns  61 , Miquel Casas  55   56   57   58 , Pablo Cervantes  62 , Toni-Kim Clarke  63 , Cristiana Cruceanu  62   64 , Alfredo Cuellar-Barboza  65   66 , Julie Cunningham  67 , David Curtis  68   69 , Piotr M Czerski  70 , Anders M Dale  71 , Nina Dalkner  52 , Friederike S David  3 , Franziska Degenhardt  3   72 , Srdjan Djurovic  73   74 , Amanda L Dobbyn  30   21 , Athanassios Douzenis  48 , Torbjørn Elvsåshagen  18   75   76 , Valentina Escott-Price  77 , I Nicol Ferrier  78 , Alessia Fiorentino  42 , Tatiana M Foroud  79 , Liz Forty  77 , Josef Frank  80 , Oleksandr Frei  6   18 , Nelson B Freimer  24   81 , Louise Frisén  82 , Katrin Gade  38   83 , Julie Garnham  84 , Joel Gelernter  85   86   87 , Marianne Giørtz Pedersen  14   40   41 , Ian R Gizer  88 , Scott D Gordon  89 , Katherine Gordon-Smith  90 , Tiffany A Greenwood  91 , Jakob Grove  12   13   14   92 , José Guzman-Parra  93 , Kyooseob Ha  94 , Magnus Haraldsson  95 , Martin Hautzinger  96 , Urs Heilbronner  38 , Dennis Hellgren  20 , Stefan Herms  3   97   98 , Per Hoffmann  3   97   98 , Peter A Holmans  77 , Laura Huckins  30   21 , Stéphane Jamain  99   100 , Jessica S Johnson  30   21 , Janos L Kalman  38   39   101 , Yoichiro Kamatani  102   103 , James L Kennedy  104   105   106   107 , Sarah Kittel-Schneider  59   108 , James A Knowles  109   110 , Manolis Kogevinas  111 , Maria Koromina  112 , Thorsten M Kranz  59 , Henry R Kranzler  113   114 , Michiaki Kubo  115 , Ralph Kupka  116   117   118 , Steven A Kushner  119 , Catharina Lavebratt  120   121 , Jacob Lawrence  122 , Markus Leber  123 , Heon-Jeong Lee  124 , Phil H Lee  125 , Shawn E Levy  126 , Catrin Lewis  77 , Calwing Liao  127   128 , Susanne Lucae  64 , Martin Lundberg  120   121 , Donald J MacIntyre  129 , Sigurdur H Magnusson  34 , Wolfgang Maier  130 , Adam Maihofer  91 , Dolores Malaspina  30   21 , Eirini Maratou  131 , Lina Martinsson  82 , Manuel Mattheisen  12   13   14   108   132 , Steven A McCarroll  26   27 , Nathaniel W McGregor  133 , Peter McGuffin  9 , James D McKay  134 , Helena Medeiros  110 , Sarah E Medland  89 , Vincent Millischer  120   121 , Grant W Montgomery  11 , Jennifer L Moran  26   135 , Derek W Morris  136 , Thomas W Mühleisen  4   97 , Niamh O'Brien  42 , Claire O'Donovan  84 , Loes M Olde Loohuis  24   81 , Lilijana Oruc  137 , Sergi Papiol  38   39 , Antonio F Pardiñas  77 , Amy Perry  90 , Andrea Pfennig  51 , Evgenia Porichi  48 , James B Potash  138 , Digby Quested  139   140 , Towfique Raj  30   31   32   33 , Mark H Rapaport  141 , J Raymond DePaulo  138 , Eline J Regeer  142 , John P Rice  143 , Fabio Rivas  93 , Margarita Rivera  144   145 , Julian Roth  108 , Panos Roussos  30   21   31 , Douglas M Ruderfer  146 , Cristina Sánchez-Mora  55   56   58   147 , Eva C Schulte  38   39 , Fanny Senner  38   39 , Sally Sharp  42 , Paul D Shilling  91 , Engilbert Sigurdsson  95   148 , Lea Sirignano  80 , Claire Slaney  84 , Olav B Smeland  6   7 , Daniel J Smith  149 , Janet L Sobell  150 , Christine Søholm Hansen  14   50 , Maria Soler Artigas  55   56   58   147 , Anne T Spijker  151 , Dan J Stein  152 , John S Strauss  104 , Beata Świątkowska  153 , Chikashi Terao  103 , Thorgeir E Thorgeirsson  34 , Claudio Toma  154   155   156 , Paul Tooney  61 , Evangelia-Eirini Tsermpini  112 , Marquis P Vawter  157 , Helmut Vedder  158 , James T R Walters  77 , Stephanie H Witt  80 , Simon Xi  159 , Wei Xu  160 , Jessica Mei Kay Yang  77 , Allan H Young  161   162 , Hannah Young  30 , Peter P Zandi  138 , Hang Zhou  85   86 , Lea Zillich  80 ; HUNT All-In Psychiatry; Rolf Adolfsson  163 , Ingrid Agartz  53   132   164 , Martin Alda  84   165 , Lars Alfredsson  166 , Gulja Babadjanova  167 , Lena Backlund  120   121 , Bernhard T Baune  168   169   170 , Frank Bellivier  171   172 , Susanne Bengesser  52 , Wade H Berrettini  173 , Douglas H R Blackwood  63 , Michael Boehnke  174 , Anders D Børglum  14   175   176 , Gerome Breen  9   10 , Vaughan J Carr  177 , Stanley Catts  178 , Aiden Corvin  179 , Nicholas Craddock  77 , Udo Dannlowski  168 , Dimitris Dikeos  180 , Tõnu Esko  27   28   181   182 , Bruno Etain  171   172 , Panagiotis Ferentinos  9   48 , Mark Frye  66 , Janice M Fullerton  154   155 , Micha Gawlik  108 , Elliot S Gershon  44   183 , Fernando S Goes  138 , Melissa J Green  154   177 , Maria Grigoroiu-Serbanescu  184 , Joanna Hauser  70 , Frans Henskens  61 , Jan Hillert  82 , Kyung Sue Hong  49 , David M Hougaard  14   50 , Christina M Hultman  20 , Kristian Hveem  19   185 , Nakao Iwata  25 , Assen V Jablensky  186 , Ian Jones  77 , Lisa A Jones  90 , René S Kahn  21   54 , John R Kelsoe  91 , George Kirov  77 , Mikael Landén  20   187 , Marion Leboyer  99   100   188 , Cathryn M Lewis  9   10   189 , Qingqin S Li  190 , Jolanta Lissowska  191 , Christine Lochner  192 , Carmel Loughland  61 , Nicholas G Martin  89   193 , Carol A Mathews  194 , Fermin Mayoral  93 , Susan L McElroy  195 , Andrew M McIntosh  129   196 , Francis J McMahon  197 , Ingrid Melle  6   198 , Patricia Michie  61 , Lili Milani  28 , Philip B Mitchell  177 , Gunnar Morken  22   199 , Ole Mors  14   200 , Preben Bo Mortensen  12   14   40   41 , Bryan Mowry  178 , Bertram Müller-Myhsok  64   201   202 , Richard M Myers  126 , Benjamin M Neale  26   47   181 , Caroline M Nievergelt  91   203 , Merete Nordentoft  14   204 , Markus M Nöthen  3 , Michael C O'Donovan  77 , Ketil J Oedegaard  205   206 , Tomas Olsson  207 , Michael J Owen  77 , Sara A Paciga  208 , Chris Pantelis  209 , Carlos Pato  110 , Michele T Pato  110 , George P Patrinos  112   210   211 , Roy H Perlis  212   213 , Danielle Posthuma  214   215 , Josep Antoni Ramos-Quiroga  55   56   57   58 , Andreas Reif  59 , Eva Z Reininghaus  52 , Marta Ribasés  55   56   58   147 , Marcella Rietschel  80 , Stephan Ripke  26   29   47 , Guy A Rouleau  128   216 , Takeo Saito  25 , Ulrich Schall  61 , Martin Schalling  120   121 , Peter R Schofield  154   155 , Thomas G Schulze  38   80   83   138   217 , Laura J Scott  174 , Rodney J Scott  61 , Alessandro Serretti  218 , Cynthia Shannon Weickert  154   177   219 , Jordan W Smoller  26   135   220 , Hreinn Stefansson  34 , Kari Stefansson  34   221 , Eystein Stordal  222   223 , Fabian Streit  80 , Patrick F Sullivan  20   224   225 , Gustavo Turecki  226 , Arne E Vaaler  227 , Eduard Vieta  228 , John B Vincent  104 , Irwin D Waldman  229 , Thomas W Weickert  154   177   219 , Thomas Werge  14   230   231   232 , Naomi R Wray  11   233 , John-Anker Zwart  18   19   35 , Joanna M Biernacka  8   66 , John I Nurnberger  234 , Sven Cichon  3   4   97   98 , Howard J Edenberg  79   235 , Eli A Stahl  30   21   181 , Andrew McQuillin  42 , Arianna Di Florio  77   225 , Roel A Ophoff  24   81   119   236 , Ole A Andreassen  237   238
Affiliations
Meta-Analysis

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

Niamh Mullins et al. Nat Genet. 2021 Jun.

Abstract

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.

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Conflict of interest statement

Competing interests

T.E. Thorgeirsson, S. Steinberg, H. Stefansson and K. Stefansson are employed by deCODE Genetics/Amgen. Multiple additional authors work for pharmaceutical or biotechnology companies in a manner directly analogous to academic co-authors and collaborators. A.H. Young has given paid lectures and advisory boards for the following companies with drugs used in affective and related disorders:

Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma. A.H. Young was Lead Investigator for Embolden Study (Astra Zeneca), BCI Neuroplasticity study and Aripiprazole Mania Study. Also an investigator for Janssen, Lundbeck, Livanova, Compass. J. Nurnberger is an investigator for Janssen. P.F. Sullivan reports the following potentially competing financial interests: Lundbeck (advisory committee), Pfizer (Scientific Advisory Board member), and Roche (grant recipient, speaker reimbursement). G. Breen reports consultancy and speaker fees from Eli Lilly and Illumina and grant funding from Eli Lilly. M. Landén has received speaker fees from Lundbeck. O.A. Andreassen has received speaker fees from Lundbeck. J.Antoni Ramos-Quiroga was on the speakers bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, and Eli- Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli-Lilly, Lundbeck, Janssen- Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió. Dr. E. Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Catalan Government (AGAUR and PERIS), the Spanish Ministry of Science, Innovation, and Universities (AES and CIBERSAM), the Seventh European Framework Programme and Horizon 2020, and the Stanley Medical Research Institute. T. Elvsåshagen has received speaker fees from Lundbeck. S. Kittel-Schneider received author’s and consultant honoraria from Medice Arzneimittel Pütter GmbH and Shire/Takeda. Prof. Serretti is or has been consultant/speaker for: Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier. J.R. DePaulo has served as an unpaid consultant to Myriad – Neuroscience (formerly Assurex Health) in 2017 and 2019 and owns stock in CVS Health. H.R. Kranzler serves as an advisory board member for Dicerna Pharmaceuticals, is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was sponsored in the past three years by AbbVie, Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. HRK is named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. ALM and CL are employees of Indivior, Inc. AA was an employee of Indivior, Inc. at the time the work was performed.

All other authors declare no financial interests or potential conflicts of interest.

Figures

Figure 1 |
Figure 1 |. Manhattan plot of genome-wide association meta-analysis of 41,917 bipolar disorder cases and 371,549 controls.
The x-axis shows genomic position (chromosomes 1–22 and X), and the y-axis shows statistical significance as −log10(P value). P values are two-sided and based on an inverse variance weighted fixed effects meta-analysis. The red line shows the genome-wide significance threshold (P < 5 × 10−8). SNPs in genome-wide significant loci are colored green for loci previously associated with bipolar disorder (BD) and yellow for novel associations from this study. The genes labeled are those prioritized by integrative eQTL analyses or notable genes in novel loci (MHC, CACNB2, KCNB1).
Figure 2 |
Figure 2 |. Phenotypic variance in bipolar disorder explained by polygenic risk scores.
Variance explained is presented on the liability scale, assuming a 2% population prevalence of bipolar disorder. For European ancestries, the results shown are the weighted mean R2 values across all 57 cohorts in the PGC3 meta-analysis, weighted by the effective n per cohort. The numbers of cases and controls are shown from left to right under the barplot for each study. GWAS PT, the color of the bars represents the P value threshold used to select SNPs from the discovery GWAS; GAIN-AA, Genetic Association Information Network African American cohort; AA-GPC, African American Genomic Psychiatry Cohort.
Figure 3 |
Figure 3 |. Relationships between bipolar disorder and modifiable risk factors based on genetic correlations, generalized summary statistics-based Mendelian randomization, and bivariate gaussian mixture modeling.
Venn diagrams depict MiXeR results of the estimated number of influencing variants shared between bipolar disorder (BD) and each trait of interest (grey), unique to BD (blue) and unique to the trait of interest (orange). The number of influencing variants and standard error are shown in thousands. The size of the circles reflects the polygenicity of each trait, with larger circles corresponding to greater polygenicity. The estimated genetic correlation (rg) between BD and each trait of interest and standard error from LD Score regression is shown below the corresponding Venn diagram, with an accompanying scale (-1 to +1). The arrows above and below the Venn diagrams indicate the results of generalized summary statistics-based Mendelian randomization (GSMR) of BD on the trait of interest, and the trait of interest on BD, respectively. The GSMR effect size and standard error is shown inside the corresponding arrow. Solid arrows indicate a significant relationship between the exposure and the outcome, after correction for multiple comparisons (P < 1.47 × 10−3), and dashed arrows indicate a non-significant relationship.
See this image and copyright information in PMC

Comment in

References

    1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 390, 1211–1259 (2017). - PMC - PubMed
    1. Plans L et al. Association between completed suicide and bipolar disorder: A systematic review of the literature. J. Affect. Disord 242, 111–122 (2019). - PubMed
    1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th edn. (American Psychiatric Association Publishing, 2013).
    1. Merikangas KR et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch. Gen. Psychiatry 64, 543–552 (2007). - PMC - PubMed
    1. Merikangas KR et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch. Gen. Psychiatry 68, 241–251 (2011). - PMC - PubMed

Methods-only references

    1. Moon S et al. The Korea Biobank Array: design and identification of coding variants associated with blood biochemical traits. Sci. Rep 9, 1382 (2019). - PMC - PubMed
    1. Bigdeli TB et al. Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry. Mol. Psychiatry 25, 2455–2467 (2020). - PMC - PubMed
    1. Lam M et al. RICOPILI: Rapid Imputation for COnsortias PIpeLIne. Bioinformatics 36, 930–933 (2020). - PMC - PubMed
    1. Price AL et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet 38, 904–909 (2006). - PubMed
    1. Loh P-R et al. Reference-based phasing using the Haplotype Reference Consortium panel. Nat. Genet 48, 1443–1448 (2016). - PMC - PubMed

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