Biological Insights From 108 Schizophrenia-Associated Genetic Loci

@article{Ripke2014BiologicalIF,
  title={Biological Insights From 108 Schizophrenia-Associated Genetic Loci},
  author={Stephan Ripke and Benjamin M. Neale and Aiden P. Corvin and James T. R. Walters and Kai-How Farh and Peter A Holmans and Phil H. Lee and Brendan K. Bulik-Sullivan and David A. Collier and Hailiang Huang and Tune H. Pers and Ingrid Agartz and Esben Agerbo and M. Albus and Madeline Alexander and Farooq Amin and Silviu-Alin Bacanu and Martin Begemann and Richard A. Belliveau and Judit Bene and Sarah L Bergen and Elizabeth Bevilacqua and T. Bernard Bigdeli and Donald W. Black and Richard Bruggeman and Nancy G. Buccola and Randy L. Buckner and William Byerley and Wiepke Cahn and Guiqing Cai and Dominique Campion and Rita M. Cantor and Vaughan J. Carr and Noa Carrera and S. V. Catts and Kimberley D. Chambert and Raymond C. K. Chan and Ronald Y. L. Chan and Eric Y. H. Chen and Wei Cheng and Eric F. C. Cheung and Siow Ann Chong and Claude Robert Cloninger and David Cohen and Nadine Cohen and Paul Cormican and Nick Craddock and James J. Crowley and David Curtis and Michael Davidson and Kenneth L. Davis and Franziska Degenhardt and Jurgen Del Favero and Ditte Demontis and Dimitris Dikeos and Timothy G. Dinan and Srdjan Djurovic and Gary Donohoe and Elodie Drapeau and Jubao Duan and Frank Dudbridge and Naser Durmishi and Peter Eichhammer and Johan Gunnar Eriksson and Valentina Escott-Price and Laurent Essioux and Ayman H. Fanous and Martilias S. Farrell and Josef Frank and Lude Franke and Robert Freedman and Nelson B. Freimer and Marion Friedl and Joseph I Friedman and Menachem Fromer and Giulio Genovese and Lyudmila Georgieva and Ina Giegling and Paola Giusti-Rodr{\'i}guez and Stephanie Godard and Jacqueline I. Goldstein and Vera Golimbet and Srihari Gopal and Jacob Gratten and Lieuwe de Haan and Christian Hammer and Marian L. Hamshere and Mark S. T. Hansen and Thomas Hansen and Vahram Haroutunian and Annette M. Hartmann and Frans A. Henskens and Stefan Herms and Joel N. Hirschhorn and Per Hoffmann and Andrea Hofman and Mads Vilhelm Hollegaard and David Michael Hougaard and Masashi Ikeda and Inge Joa and Antonio Juli{\`a} and Ren{\'e} S. Kahn and Luba V Kalaydjieva and Sena Karachanak-Yankova and Juha Karjalainen and David Kavanagh and Matthew C. Keller and James L. Kennedy and Andrey V. Khrunin and Yunjung Kim and Janis Klovins and James A. Knowles and Bettina Konte and Vaidutis Ku{\vc}inskas and Zita Au{\vs}relė Ku{\vc}inskienė and Hana Kuzelova-Ptackova and Anna K. K{\"a}hler and Claudine Laurent and Jimmy Lee and S. Hong Lee and Sophie E. Legge and Bernard Lerer and Miaoxin Li and Tao Li and Kung-yee Liang and Jeffrey A. Lieberman and Svetlana A. Limborska and C. M. Loughland and Jan Lubiński and Jouko L{\"o}nnqvist and Milan Macek and Patrik K. E. Magnusson and Brion S. Maher and Wolfgang Maier and Jacques Mallet and Sara Marsal and Manuel Mattheisen and Morten Mattingsdal and Robert W. McCarley and Colm Mcdonald and Andrew M. McIntosh and Sandra M. Meier and Carin J. Meijer and B{\'e}la Melegh and Ingrid Melle and Raquelle I. Mesholam-Gately and Andres Metspalu and Patricia T. Michie and Lili Milani and Vihra Milanova and Younes Mokrab and Derek W. Morris and Ole Mors and Kieran C. Murphy and Robin M. Murray and Inez Myin-Germeys and Bertram M{\"u}ller-Myhsok and Mari Nelis and Igor Nenadi{\'c} and Deborah A. Nertney and Gerald Nestadt and Kristin K. Nicodemus and Liene Nikitina-Zake and Laura K. Nisenbaum and Annelie Nordin and E. O'callaghan and Colm O'Dushlaine and Francis A. O’Neill and Sang-Yun Oh and Ann Olincy and Line Olsen and Jim van os and Christos Pantelis and George N. Papadimitriou and Sergi Papiol and Elena Parkhomenko and Michele T. Pato and Tiina Paunio and Milica Pejovi{\'c}-Milovan{\vc}evi{\'c} and Diana O. Perkins and Olli Pietil{\"a}inen and Jonathan Pimm and Andrew J. Pocklington and John Powell and Alkes L. Price and Ann E. Pulver and Shaun M Purcell and Digby J. Quested and Henrik Berg Rasmussen and Abraham Reichenberg and Mark A. Reimers and Alexander L. Richards and Joshua L. Roffman and Panos Roussos and Douglas M. Ruderfer and Veikko V Salomaa and Alan R. Sanders and Ulrich Schall and Christian R. Schubert and Thomas G. Schulze and Sibylle G Schwab and Edward M. Scolnick and Rodney J. Scott and Larry J. Seidman and Jianxin Shi and Engilbert Sigurdsson and Teimuraz Silagadze and Jeremy Silverman and Kang Sim and Petr A Slominsky and Jordan W. Smoller and Hon-Cheong So and Chris C. A. Spencer and Eli A. Stahl and Hreinn Stef{\'a}nsson and Stacy Steinberg and Elisabeth Stogmann and Richard E Straub and Eric Strengman and Jana Strohmaier and T. Scott Stroup and Mythily Subramaniam and Jaana Suvisaari and Dragan M. Svrakic and Jin P. Szatkiewicz and Erik S{\"o}derman and Srinivasa Thirumalai and Draga Toncheva and Sarah Tosato and Juha Veijola and John L. Waddington and Dermot Walsh and Dai Wang and Qiang Wang and Bradley Todd Webb and Mark Weiser and Dieter B. Wildenauer and Nigel Melvillle Williams and Stephanie Williams and Stephanie H. Witt and Aaron R Wolen and Emily H. M. Wong and Brandon K. Wormley and Hualin S. Xi and Clement C. Zai and Xue-bin Zheng and Fritz Zimprich and Naomi R. Wray and K{\'a}ri Stef{\'a}nsson and Peter M. Visscher and Rolf Adolfsson and Ole Andreas Andreassen and Douglas H.R. Blackwood and Elvira Bramon and Joseph D. Buxbaum and Anders Dupont B{\o}rglum and Sven Cichon and Ariel Darvasi and Enrico Domenici and Hannelore Ehrenreich and T{\~o}nu Esko and Pablo V. Gejman and Michael Gill and Hugh M D Gurling and Christina M. Hultman and Nakao Iwata and Assen Jablensky and Erik G. J{\"o}nsson and Kenneth S. Kendler and George Kirov and Jo Knight and Todd Lencz and Douglas F. Levinson and Qingqin S. Li and Jianjun Liu and Anil K. Malhotra and Steven Mccarroll and Andrew McQuillin and Jennifer L. Moran and Preben Bo Mortensen and Bryan J. Mowry and Markus M. N{\"o}then and Roel A. Ophoff and Michael J. Owen and Aarno Palotie and Carlos N. Pato and Tracey L. Petryshen and Danielle Posthuma and Marcella Rietschel and Brien P. Riley and Dan Rujescu and Pak Chung Sham and Pamela Sklar and David St. Clair and Daniel R. Weinberger and Jens R. Wendland and Thomas M. Werge and Mark J. Daly and Patrick F. Sullivan and Michael C. O’Donovan},
  journal={Nature},
  year={2014},
  volume={511},
  pages={421 - 427}
}
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations… 
Mapping genomic loci implicates genes and synaptic biology in schizophrenia.
TLDR
A two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals reports common variant associations at 287 distinct genomic loci, and identifies 120 genes that are likely to underpin associations at some of these loci.
Recent genetic findings in schizophrenia and their therapeutic relevance
TLDR
This review summarises recent schizophrenia genetic findings and some key issues they raise, particularly with regard to their implications for identifying and validating novel drug targets.
Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia
TLDR
This work identifies biological processes of pathophysiological relevance to schizophrenia, shows convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders, and provides a rich resource of priority genes and variants to advance mechanistic studies.
Genome-wide association studies suggest limited immune gene enrichment in schizophrenia compared to five autoimmune diseases
TLDR
It is shown that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, and a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity is suggested.
Pathway-wide association study identifies five shared pathways associated with schizophrenia in three ancestral distinct populations
TLDR
Empirical support is provided for schizophrenia as a pathway disorder and it is suggested that schizophrenia is not only a polygenic but likely also a poly-pathway disorder characterized by both genetic and pathway heterogeneity.
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection
TLDR
A new genome-wide association study of schizophrenia is reported, and through meta-analysis with existing data and integrating genomic fine-mapping with brain expression and chromosome conformation data, 50 novel associated loci and 145 loci are identified.
Genome-wide association studies suggest limited immune gene enrichment in schizophrenia compared to six immune diseases
TLDR
It is shown that there is no genome-wide enrichment of immune loci in the largest genetic study of schizophrenia conducted to date, in contrast to six diseases of known immune origin, which indicates a non-genetic etiology for immune processes that may be involved in schizophrenia.
A Transcriptome Wide Association Study implicates specific pre- and post-synaptic abnormalities in Schizophrenia
TLDR
Genes whose expression correlate with schizophrenia were enriched for those involved in nervous system development, abnormal synaptic transmission, reduced long term potentiation, and calcium-dependent cell-cell adhesion and molecules that regulate presynaptic transmitter release.
Genetic combination risk for schizophrenia
TLDR
It is shown that the combination of three functional single nucleotide polymorphisms related to the key factors of dopaminergic signaling can be used to predict the risk of schizophrenia’s development, though none of the SNPs is known to be associated by itself.
Protein Interaction Networks Link Schizophrenia Risk Loci to Synaptic Function
TLDR
It is demonstrated that brain expression of risk-linked genes within the identified processes is strongly modulated during birth and a set of synaptic genes consistently changed across multiple brain regions of adult schizophrenia patients are identified.
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