AUTHOR=Drange Ole Kristian , Smeland Olav Bjerkehagen , Shadrin Alexey A. , Finseth Per Ivar , Witoelar Aree , Frei Oleksandr , Psychiatric Genomics Consortium Bipolar Disorder Working Group , Wang Yunpeng , Hassani Sahar , Djurovic Srdjan , Dale Anders M. , Andreassen Ole A. , Stahl Eli A , Breen Gerome , Forstner Andreas J , McQuillin Andrew , Ripke Stephan , Trubetskoy Vassily , Mattheisen Manuel , Wang Yunpeng , Coleman Jonathan R I , Gaspar Heìleìna A , Leeuw Christiaan A de , Steinberg Stacy , Pavlides Jennifer M Whitehead , Trzaskowski Maciej , Pers Tune H , Holmans Peter A , Abbott Liam , Agerbo Esben , Akil Huda , Albani Diego , Alliey-Rodriguez Ney , Als Thomas D , Anjorin Adebayo , Antilla Verneri , Awasthi Swapnil , Badner Judith A , Bækvad-Hansen Marie , Barchas Jack D , Bass Nicholas , Bauer Michael , Belliveau Richard , Bergen Sarah E , Pedersen Carsten Bøcker , Bøen Erlend , Boks Marco , Boocock James , Budde Monika , Bunney William , Burmeister Margit , Bybjerg-Grauholm Jonas , Byerley William , Casas Miquel , Cerrato Felecia , Cervantes Pablo , Chambert Kimberly , Charney Alexander W , Chen Danfeng , Churchhouse Claire , Clarke Toni-Kim , Coryell William , Craig David W , Cruceanu Cristiana , Curtis David , Czerski Piotr M , Dale Anders M , Jong Simone de , Degenhardt Franziska , Del-Favero Jurgen , DePaulo J Raymond , Djurovic Srdjan , Dobbyn Amanda L , Dumont Ashley , Elvsåshagen Torbjørn , Escott-Price Valentina , Fan Chun Chieh , Fischer Sascha B , Flickinger Matthew , Foroud Tatiana M , Forty Liz , Frank Josef , Fraser Christine , Freimer Nelson B , Friseìn Louise , Gade Katrin , Gage Diane , Garnham Julie , Giambartolomei Claudia , Pedersen Marianne Giørtz , Goldstein Jaqueline , Gordon Scott D , Gordon-Smith Katherine , Green Elaine K , Green Melissa J , Greenwood Tiffany A , Grove Jakob , Guan Weihua , Parra Joseì Guzman , Hamshere Marian L , Hautzinger Martin , Heilbronner Urs , Herms Stefan , Hipolito Maria , Hoffmann Per , Holland Dominic , Huckins Laura , Jamain Steìphane , Johnson Jessica S , Jureìus Anders , Kandaswamy Radhika , Karlsson Robert , Kennedy James L , Kittel-Schneider Sarah , Knott Sarah V , Knowles James A , Kogevinas Manolis , Koller Anna C , Kupka Ralph , Lavebratt Catharina , Lawrence Jacob , Lawson William B , Leber Markus , Lee Phil H , Levy Shawn E , Li Jun Z , Liu Chunyu , Lucae Susanne , Maaser Anna , MacIntyre Donald J , Mahon Pamela B , Maier Wolfgang , Martinsson Lina , McCarroll Steve , McGuffin Peter , McInnis Melvin G , McKay James D , Medeiros Helena , Medland Sarah E , Meng Fan , Milani Lili , Montgomery Grant W , Morris Derek W , Mühleisen Thomas W , Mullins Niamh , Nguyen Hoang , Nievergelt Caroline M , Adolfsson Annelie Nordin , Nwulia Evaristus A , O’Donovan Claire , Loohuis Loes M Olde , Ori Anil P S , Oruc Lilijana , Ösby Urban , Perlis Roy H , Perry Amy , Pfennig Andrea , Potash James B , Purcell Shaun M , Regeer Eline J , Reif Andreas , Reinbold Ceìline S , Rice John P , Rivas Fabio , Rivera Margarita , Roussos Panos , Ruderfer Douglas M , Ryu Euijung , Saìnchez-Mora Cristina , Schatzberg Alan F , Scheftner William A , Schork Nicholas J , Weickert Cynthia Shannon , Shehktman Tatyana , Shilling Paul D , Sigurdsson Engilbert , Slaney Claire , Smeland Olav B , Sobell Janet L , Hansen Christine Søholm , Spijker Anne T , Clair David St , Steffens Michael , Strauss John S , Streit Fabian , Strohmaier Jana , Szelinger Szabolcs , Thompson Robert C , Thorgeirsson Thorgeir E , Treutlein Jens , Vedder Helmut , Wang Weiqing , Watson Stanley J , Weickert Thomas W , Witt Stephanie H , Xi Simon , Xu Wei , Young Allan H , Zandi Peter , Zhang Peng , Zollner Sebastian , Adolfsson Rolf , Agartz Ingrid , Alda Martin , Backlund Lena , Baune Bernhard T , Bellivier Frank , Berrettini Wade H , Biernacka Joanna M , Blackwood Douglas H R , Boehnke Michael , Børglum Anders D , Corvin Aiden , Craddock Nicholas , Daly Mark J , Dannlowski Udo , Esko ToÞnu , Etain Bruno , Frye Mark , Fullerton Janice M , Gershon Elliot S , Gill Michael , Goes Fernando , Grigoroiu-Serbanescu Maria , Hauser Joanna , Hougaard David M , Hultman Christina M , Jones Ian , Jones Lisa A , Kahn Reneì S , Kirov George , Landeìn Mikael , Leboyer Marion , Lewis Cathryn M , Li Qingqin S , Lissowska Jolanta , 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 , Posthuma Danielle , Ramos-Quiroga Josep Antoni , Ribaseìs Marta , Rietschel Marcella , Rouleau Guy A , Schalling Martin , Schofield Peter R , Schulze Thomas G , Serretti Alessandro , Smoller Jordan W , Stefansson Hreinn , Stefansson Kari , Stordal Eystein , Sullivan Patrick F , Turecki Gustavo , Vaaler Arne E , Vieta Eduard , Vincent John B , Werge Thomas , Nurnberger John I , Wray Naomi R , Florio Arianna Di , Edenberg Howard J , Cichon Sven , Ophoff Roel A , Scott Laura J , Andreassen Ole A , Kelsoe John , Sklar Pamela
TITLE=Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes
JOURNAL=Frontiers in Neuroscience
VOLUME=13
YEAR=2019
URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2019.00220
DOI=10.3389/fnins.2019.00220
ISSN=1662-453X
ABSTRACT=Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits.
Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework.
Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect).
Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.