Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
Authors: de Jong Simone , Diniz Mateus Jose Abdalla , Saloma Andiara , Gadelha Ary , Santoro Marcos L. , Ota Vanessa K. , Noto Cristiano ,   Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Wray Naomi R. , Ripke Stephan , Mattheisen Manuel , Trzaskowski Maciej , Byrne Enda M. , Abdellaoui Abdel , Adams Mark J. , Agerbo Esben , Air Tracy M. , Andlauer Till F. M. , Bacanu Silviu-Alin , Bækvad-Hansen Marie , Beekman Aartjan T. F. , Bigdeli Tim B. , Binder Elisabeth B. , Blackwood Douglas H. R. , Bryois Julien , Buttenschøn Henriette N. , Bybjerg-Grauholm Jonas , Cai Na , Castelao Enrique , Christensen Jane Hvarregaard , Clarke Toni-Kim , Coleman Jonathan R. I. , Colodro-Conde Lucía , Couvy-Duchesne Baptiste , Craddock Nick , Crawford Gregory E. , Davies Gail , Deary Ian J. , Degenhardt Franziska , Derks Eske M. , Direk Nese , Dolan Conor V. , Dunn Erin C. , Eley Thalia C. , Escott-Price Valentina , Kiadeh Farnush Farhadi Hassan , Finucane Hilary K. , Forstner Andreas J. , Frank Josef , Gaspar Héléna A. , Gill Michael , Goes Fernando S. , Gordon Scott D. , Grove Jakob , Hansen Christine Søholm , Hansen Thomas F. , Herms Stefan , Hickie Ian B. , Hoffmann Per , Homuth Georg , Horn Carsten , Hottenga Jouke-Jan , Hougaard David M. , Ising Marcus , Jansen Rick , Jones Ian , Jones Lisa A , Jorgenson Eric , Knowles James A. , Kohane Isaac S. , Kraft Julia , Kretzschmar Warren W. , Krogh Jesper , Kutalik Zoltán , Li Yihan , Lind Penelope A. , MacIntyre Donald J. , MacKinnon Dean F. , Maier Robert M. , Maier Wolfgang , Marchini Jonathan , Mbarek Hamdi , McGrath Patrick , McGuffin Peter , Medland Sarah E. , Mehta Divya , Middeldorp Christel M. , Mihailov Evelin , Milaneschi Yuri , Milani Lili , Mondimore Francis M. , Montgomery Grant W. , Mostafavi Sara , Mullins Niamh , Nauck Matthias , Ng Bernard , Nivard Michel G. , Nyholt Dale R. , Oskarsson Hogni , Owen Michael J. , Painter Jodie N. , Pedersen Carsten Bøcker , Pedersen Marianne Giørtz , Peterson Roseann E. , Pettersson Erik , Peyrot Wouter J. , Pistis Giorgio , Posthuma Danielle , Quiroz Jorge A. , Qvist Per , Rice John P. , Riley Brien P. , Rivera Margarita , Mirza Saira Saeed , Schoevers Robert , Schulte Eva C. , Shen Ling , Shyn Stanley I. , Sigurdsson Engilbert , Sinnamon Grant C. B. , Smit Johannes H. , Smith Daniel J. , Stefansson Hreinn , Steinberg Stacy , Streit Fabian , Strohmaier Jana , Tansey Katherine E. , Teismann Henning , Teumer Alexander , Thompson Wesley , Thomson Pippa A. , Thorgeirsson Thorgeir E. , Traylor Matthew , Treutlein Jens , Trubetskoy Vassily , Uitterlinden André G. , Umbricht Daniel , Van der Auwera Sandra , van Hemert Albert M. , Viktorin Alexander , Visscher Peter M. , Wang Yunpeng , Webb Bradley T. , Weinsheimer Shantel Marie , Wellmann Jürgen , Willemsen Gonneke , Witt Stephanie H. , Wu Yang , Xi Hualin S. , Yang Jian , Zhang Futao , Arolt Volker , Baune Bernhard T. , Berger Klaus , Boomsma Dorret I. , Cichon Sven , Dannlowski Udo , de Geus E. J. C. , DePaulo J. Raymond , Domenici Enrico , Domschke Katharina , Esko Tõnu , Grabe Hans J. , Hamilton Steven P. , Hayward Caroline , Heath Andrew C. , Kendler Kenneth S. , Kloiber Stefan , Lewis Glyn , Li Qingqin S. , Lucae Susanne , Madden Pamela A. F. , Magnusson Patrik K. , Martin Nicholas G. , McIntosh Andrew M. , Metspalu Andres , Mors Ole , Mortensen Preben Bo , Müller-Myhsok Bertram , Nordentoft Merete , Nöthen Markus M. , O’Donovan Michael C. , Paciga Sara A. , Pedersen Nancy L. , Penninx Brenda W. J. H. , Perlis Roy H. , Porteous David J. , Potash James B. , Preisig Martin , Rietschel Marcella , Schaefer Catherine , Schulze Thomas G. , Smoller Jordan W. , Stefansson Kari , Tiemeier Henning , Uher Rudolf , Völzke Henry , Weissman Myrna M. , Werge Thomas , Lewis Cathryn M. , Levinson Douglas F. , Børglum Anders D. , Sullivan Patrick F. , Meier Sandra , Strauss John , Xu Wei , Vincent John B. , Matthews Keith , Ferreira Manuel , O’Dushlaine Colm , Purcell Shaun , Raychaudhuri Soumya , Ruderfer Douglas M. , Sklar Pamela , Scott Laura J. , Flickinger Matthew , Burmeister Margit , Li Jun , Guan Weihua , Absher Devin , Thompson Robert C. , Meng Fan Guo , Schatzberg Alan F. , Bunney William E. , Barchas Jack D. , Watson Stanley J. , Myers Richard M. , Akil Huda , Boehnke Michael , Chambert Kimberly , Moran Jennifer , Scolnick Edward , Djurovic Srdjan , Melle Ingrid , Morken Gunnar , Corvin Aiden , Anjorin Adebayo , Kandaswamy Radhika , Lawrence Jacob , McLean Alan W. , Pickard Benjamin S. , Bergen Sarah E. , Nimgaonkar Vishwajit , Landén Mikael , Schalling Martin , Osby Urban , Backlund Lena , Frisén Louise , Langstrom Niklas , Stahl Eli , Dobbyn Amanda , Jamain Stéphane , Etain Bruno , Bellivier Frank , Leber Markus , Maaser Anna , Fischer Sascha B. , Reinbold Céline S. , Kittel-Schneider Sarah , Fullerton Janice M. , Oruč Lilijana , Para José G. , Mayoral Fermin , Rivas Fabio , Czerski Piotr M. , Kammerer-Ciernioch Jutta , Vedder Helmut , Borrmann-Hassenbach Margitta , Pfennig Andrea , Brennan Paul , McKay James D. , Kogevinas Manolis , Schwarz Markus , Schofield Peter R. , Mühleisen Thomas W. , Schumacher Johannes , Bauer Michael , Wright Adam , Mitchell Philip B. , Hautzinger Martin , Kelsoe John R. , Greenwood Tiffany A. , Nievergelt Caroline M. , Shilling Paul D. , Smith Erin N. , Bloss Cinnamon S. , Edenberg Howard J. , Koller Daniel L. , Gershon Elliot S. , Liu Chunyu , Badner Judith A. , Scheftner William A. , Lawson William B. , Nwulia Evaristus A. , Hipolito Maria , Coryell William , Rice John , Byerley William , McMahon Francis J. , Lohoff Falk W. , Zandi Peter P. , Mahon Pamela B. , McInnis Melvin G. , Zöllner Sebastian , Zhang Peng , Szelinger Szabolcs , St. Clair David , Caesar Sian , Gordon-Smith Katherine , Fraser Christine , Green Elaine K. , Grozeva Detelina , Hamshere Marian L. , Kirov George , Nikolov Ivan , Collier David A. , Elkin Amanda , Williamson Richard , Young Allan H. , Ferrier I. Nicol , Milanova Vihra , Alda Martin , Cervantes Pablo , Cruceanu Cristiana , Rouleau Guy A. , Turecki Gustavo , Paciga Sara , Winslow Ashley R. , Grigoroiu-Serbanescu Maria , Ophoff Roel , Adolfsson Rolf , Adolfsson Annelie Nordin , Del-Favero Jurgen , Pato Carlos , Biernacka Joanna M. , Frye Mark A. , Morris Derek , Schork Nicholas J. , Reif Andreas , Lissowska Jolanta , Hauser Joanna , Szeszenia-Dabrowska Neonila , McGhee Kevin , Quinn Emma , Moskvina Valentina , Holmans Peter A. , Farmer Anne , Kennedy James L. , Andreassen Ole A. , Mattingsdal Morten , Gill Michael , Bass Nicholas J. , Gurling Hugh , McQuillin Andrew , Breuer René , Hultman Christina , Lichtenstein Paul , Huckins Laura M. , Leboyer Marion , Lathrop Mark , Nurnberger John , Steffens Michael , Foroud Tatiana M. , Berrettini Wade H. , Craig David W. , Shi Jianxin , Curtis Charles , Newhouse Stephen J. , Patel Hamel , Hall Lynsey S. , O`Reilly Paul F. , Belangero Sintia I. , Bressan Rodrigo A. , Breen Gerome 
Published: October 2018

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.