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- The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders (2017)
- Hong Chang Naosuke Hoshina Chen Zhang Yina Ma Hongxin Cao Yaling Wang Dong-Dong Wu Sarah E. Bergen Mikael Landén Christina M. Hultman Martin Preisig Zoltán Kutalik Enrique Castelao Maria Grigoroiu-Serbanescu Andreas Josef Forstner Jana Strohmaier Julian Hecker Thomas G. Schulze Bertram Müller-Myhsok Andreas Reif Philip B. Mitchell Nicholas Gordon Martin Peter R. Schofield Sven Cichon Markus Maria Nöthen Henrik Walter Susanne Erk Andreas Heinz Najaf Amin Cornelia M. van Duijn Andreas Meyer-Lindenberg Heike Tost Xiao Xiao Tadashi Yamamoto Marcella Rietschel Ming Li
- Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
- Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits (2013)
- Joshua C. Randall Thomas W. Winkler Zoltán Kutalik Sonja I. Berndt Anne U. Jackson Keri L. Monda Tuomas O. Kilpeläinen Tõnu Esko Reedik Mägi Shengxu Li Tsegaselassie Workalemahu Mary F. Feitosa Damien C. Croteau-Chonka Felix R. Day Tove Fall Teresa Ferreira Stefan Gustafsson Adam E. Locke Iain Mathieson André Scherag Sailaja Vedantam Andrew R. Wood Liming Liang Valgerdur Steinthorsdottir Gudmar Thorleifsson Emmanouil T. Dermitzakis Antigone S. Dimas Fredrik Karpe Josine L. Min George Nicholson Deborah J. Clegg Thomas Person Jon P. Krohn Sabrina Bauer Christa Buechler Kristina Eisinger Amélie Bonnefond Philippe Froguel Jouke-Jan Hottenga Inga Prokopenko Lindsay L. Waite Tamara B. Harris Albert Vernon Smith Alan R. Shuldiner Wendy L. McArdle Mark J. Caulfield Patricia B. Munroe Henrik Grönberg Yii-Der Ida Chen Guo Li Jacques S. Beckmann Toby Johnson Unnur Thorsteinsdottir Maris Teder-Laving Kay-Tee Khaw Nicholas J. Wareham Jing Hua Zhao Najaf Amin Ben A. Oostra Aldi T. Kraja Michael A. Province L. Adrienne Cupples Nancy L. Heard-Costa Jaakko Kaprio Samuli Ripatti Ida Surakka Francis S. Collins Jouko Saramies Jaakko Tuomilehto Antti Jula Veikko Salomaa Jeanette Erdmann Christian Hengstenberg Christina Loley Heribert Schunkert Claudia Lamina Heinz Erich Wichmann Eva Albrecht Christian Gieger Andrew A. Hicks Åsa Johansson Peter P. Pramstaller Sekar Kathiresan Elizabeth K. Speliotes Brenda Penninx Anna-Liisa Hartikainen Marjo-Riitta Jarvelin Ulf Gyllensten Dorret I. Boomsma Harry Campbell James F. Wilson Stephen J. Chanock Martin Farrall Anuj Goel Carolina Medina-Gomez Fernando Rivadeneira Karol Estrada André G. Uitterlinden Albert Hofman M. Carola Zillikens Martin den Heijer Lambertus Adrianus Kiemeney Andrea Maschio Per Hall Jonathan Tyrer Alexander Teumer Henry Völzke Peter Kovacs Anke Tönjes Massimo Mangino Tim D. Spector Caroline Hayward Igor Rudan Alistair S. Hall Nilesh J. Samani Antony Paul Attwood Jennifer G. Sambrook Joseph Hung Lyle J. Palmer Marja-Liisa Lokki Juha Sinisalo Gabrielle Boucher Heikki Huikuri Mattias Lorentzon Claes Ohlsson Niina Eklund Johan G. Eriksson Cristina Barlassina Carlo Rivolta Ilja M. Nolte Harold Snieder Melanie M. van der Klauw Jana V. van Vliet-Ostaptchouk Pablo V. Gejman Jianxin Shi Kevin B. Jacobs Zhaoming Wang Stephan J. L. Bakker Irene Mateo Leach Gerjan Navis Pim van der Harst Nicholas Gordon Martin Sarah E. Medland Grant W. Montgomery Jian Yang Daniel I. Chasman Paul M. Ridker Lynda M. Rose Terho Lehtimäki Olli Raitakari Devin Absher Carlos Iribarren Hanneke Basart Kees G. Hovingh Elina Hyppönen Chris Power Chris Power Denise Anderson John P. Beilby Jennie Hui Jennifer Jolley Hendrik Sager Stefan R. Bornstein Peter E. H. Schwarz Kati Kristiansson Markus Perola Jaana Lindström Amy J. Swift Matti Uusitupa Mustafa Atalay Timo A. Lakka Rainer Rauramaa Jennifer L. Bolton Gerry Fowkes Ross M. Fraser Jackie F. Price Krista Fischer Kaarel KrjutÅ¡kov Andres Metspalu Evelin Mihailov Claudia Langenberg Jian'an Luan Ken K. Ong Peter S. Chines Sirkka M. Keinanen-Kiukaanniemi Timo E. Saaristo Sarah Edkins Paul W. Franks Göran Hallmans Dmitry Shungin Andrew David Morris Colin N. A. Palmer Raimund Erbel Susanne Moebus Markus Maria Nöthen Sonali Pechlivanis Kristian Hveem Narisu Narisu Anders Hamsten Steve E. Humphries Rona J. Strawbridge Elena Tremoli Harald Grallert Barbara Thorand Thomas Illig Wolfgang Koenig Martina Müller-Nurasyid Annette Peters Bernhard O. Böhm Marcus E. Kleber Winfried März Bernhard R. Winkelmann Johanna Kuusisto Markku Laakso Dominique Arveiler Giancarlo Cesana Kari Kuulasmaa Jarmo Virtamo John W. G. Yarnell Diana Kuh Andrew Wong Lars Lind Ulf de Faire Bruna Gigante Patrik K. E. Magnusson Nancy L. Pedersen George Dedoussis Maria Dimitriou Genovefa Kolovou Stavroula Kanoni Kathleen Stirrups Lori L. Bonnycastle Inger Njølstad Tom Wilsgaard Andrea Ganna Emil Rehnberg Aroon Hingorani Mika Kivimaki Meena Kumari Themistocles L. Assimes Inês Barroso Michael Boehnke Ingrid B. Borecki Panos Deloukas Caroline S. Fox Timothy Frayling Leif C. Groop Talin Haritunians David Hunter Erik Ingelsson Robert Kaplan Karen L. Mohlke Kari E. North Cecilia M. Lindgren Lu Qi Ruth J. F. Loos Iris M. Heid Joel N. Hirschhorn Mark I. McCarthy Gonçalo R. Abecasis Kari Stefansson David P. Strachan David Schlessinger Jeffrey R. O'Connell Cornelia M. van Duijn
- Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
- Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease (2014)
- Valentina Escott-Price Céline Bellenguez Li-San Wang Seung-Hoan Choi Denise Harold Lesley Jones Peter Holmans Amy Gerrish Alexey Vedernikov Alexander Richards Anita L. DeStefano Jean-Charles Lambert Carla A. Ibrahim-Verbaas Adam C. Naj Rebecca Sims Gyungah Jun Joshua C. Bis Gary W. Beecham Benjamin Grenier-Boley Giancarlo Russo Tricia A. Thornton-Wells Nicola Denning Albert V. Smith Vincent Chouraki Charlene Thomas M. Arfan Ikram Diana Zelenika Badri N. Vardarajan Yoichiro Kamatani Chiao-Feng Lin Helena Schmidt Brian Kunkle Melanie L. Dunstan Maria Vronskaya Andrew D. Johnson Agustin Ruiz Marie-Thérèse Bihoreau Christiane Reitz Florence Pasquier Paul Hollingworth Olivier Hanon Annette L. Fitzpatrick Joseph D. Buxbaum Dominique Campion Paul K. Crane Clinton Baldwin Tim Becker Vilmundur Gudnason Carlos Cruchaga David Craig Najaf Amin Claudine Berr Oscar L. Lopez Philip L. De Jager Vincent Deramecourt Janet A. Johnston Denis Evans Simon Lovestone Luc Letenneur Isabel Hernández David C. Rubinsztein Gudny Eiriksdottir Kristel Sleegers Alison M. Goate Nathalie Fiévet Matthew J. Huentelman Michael Gill Kristelle Brown M. Ilyas Kamboh Lina Keller Pascale Barberger-Gateau Bernadette McGuinness Eric B. Larson Amanda J. Myers Carole Dufouil Stephen Todd David Wallon Seth Love Ekaterina Rogaeva John Gallacher Peter St George-Hyslop Jordi Clarimon Alberto Lleo Anthony Bayer Debby W. Tsuang Lei Yu Magda Tsolaki Paola Bossù Gianfranco Spalletta Petra Proitsi John Collinge Sandro Sorbi Florentino Sanchez Garcia Nick C. Fox John Hardy Maria Candida Deniz Naranjo Paolo Bosco Robert Clarke Carol Brayne Daniela Galimberti Elio Scarpini Ubaldo Bonuccelli Michelangelo Mancuso Gabriele Siciliano Susanne Moebus Patrizia Mecocci Maria Del Zompo Wolfgang Maier Harald Hampel Alberto Pilotto Ana Frank-García Francesco Panza Vincenzo Solfrizzi Paolo Caffarra Benedetta Nacmias William Perry Manuel Mayhaus Lars Lannfelt Hakon Hakonarson Sabrina Pichler Minerva M. Carrasquillo Martin Ingelsson Duane Beekly Victoria Alvarez Fanggeng Zou Otto Valladares Steven G. Younkin Eliecer Coto Kara L. Hamilton-Nelson Wei Gu Cristina Razquin Pau Pastor Ignacio Mateo Michael J. Owen Kelley M. Faber Palmi V. Jonsson Onofre Combarros Michael C. O'Donovan Laura B. Cantwell Hilkka Soininen Deborah Blacker Simon Mead Thomas H. Mosley David A. Bennett Tamara B. Harris Laura Fratiglioni Clive Holmes Renee F. A. G. de Bruijn Peter Passmore Thomas J. Montine Karolien Bettens Jerome I. Rotter Alexis Brice Kevin Morgan Tatiana M. Foroud Walter A. Kukull Didier Hannequin John F. Powell Michael A. Nalls Karen Ritchie Kathryn L. Lunetta John S. K. Kauwe Eric Boerwinkle Matthias Riemenschneider Mercè Boada Mikko Hiltunen Eden R. Martin Reinhold Schmidt Dan Rujescu Jean-François Dartigues Richard Mayeux Christophe Tzourio Albert Hofman Markus Maria Nöthen Caroline Graff Bruce M. Psaty Jonathan L. Haines Mark Lathrop Margaret Ann Pericak-Vance Lenore J. Launer Christine Van Broeckhoven Lindsay A. Farrer Cornelia M. van Duijn Alfredo Ramirez Sudha Seshadri Gerard D. Schellenberg Philippe Amouyel Julie Williams
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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