Nat Genet. 2018 Mar;50(3):381-389. doi: 10.1038/s41588-018-0059-2. Epub 2018 Feb 26.
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
Pardiñas AF1,
Holmans P1,
Pocklington AJ1,
Escott-Price V1,
Ripke S2,3,
Carrera N1,
Legge SE1,
Bishop S1,
Cameron D1,
Hamshere ML1,
Han J1,
Hubbard L1,
Lynham A1,
Mantripragada K1,
Rees E1,
MacCabe JH4,
McCarroll SA5,
Baune BT6,
Breen G7,8,
Byrne EM9,10,
Dannlowski U11,
Eley TC7,
Hayward C12,
Martin NG13,14,
McIntosh AM15,16,
Plomin R7,
Porteous DJ12,
Wray NR9,10,
Caballero A17,
Geschwind DH18,
Huckins LM19,
Ruderfer DM19,
Santiago E20,
Sklar P19,
Stahl EA19,
Won H18,
Agerbo E21,22,
Als TD21,23,24,
Andreassen OA25,26,
Bækvad-Hansen M21,27,
Mortensen PB21,22,23,
Pedersen CB21,22,
Børglum AD21,23,24,
Bybjerg-Grauholm J21,27,
Djurovic S28,29,
Durmishi N30,
Pedersen MG21,22,
Golimbet V31,
Grove J21,23,24,32,
Hougaard DM21,27,
Mattheisen M21,23,24,
Molden E33,
Mors O21,34,
Nordentoft M21,35,
Pejovic-Milovancevic M36,
Sigurdsson E37,
Silagadze T38,
Hansen CS21,27,
Stefansson K39,
Stefansson H39,
Steinberg S39,
Tosato S40,
Werge T21,41,42;
GERAD1 Consortium;
CRESTAR Consortium,
Collier DA7,43,
Rujescu D44,45,
Kirov G1,
Owen MJ46,
O'Donovan MC47,
Walters JTR48.
Harold D, Sims R, Gerrish A, Chapman J, Escott-Price V, Abraham R, Hollingworth P, Pahwa J, Denning N, Thomas C, Taylor S, Powell J, Proitsi P, Lupton M, Lovestone S, Passmore P, Craig D, McGuinness B, Johnston J, Todd S, Maier W, Jessen F, Heun R, Schurmann B, Ramirez A, Becker T, Herold C, Lacour A, Drichel D, Nothen M, Goate A, Cruchaga C, Nowotny P, Morris JC, Mayo K, Holmans P, O'Donovan M, Owen M, Williams J, Achilla E, Agerbo E, Barr CL, Böttger TW, Breen G, Cohen D, Collier DA, Curran S, Dempster E, Dima D, Sabes-Figuera R, Flanagan RJ, Frangou S, Frank J, Gasse C, Gaughran F, Giegling I, Grove J, Hannon E, Hartmann AM, Heißerer B, Helthuis M, Horsdal HT, Ingimarsson O, Jollie K, Kennedy JL, Köhler O, Konte B, Lang M, Legge SE, Lewis C, MacCabe J, Malhotra AK, McCrone P, Meier SM, Mill J, Mors O, Mortensen PB, Nöthen MM, O'Donovan MC, Owen MJ, Pardiñas AF, Pedersen CB, Rietschel M, Rujescu D, Schwalber A, Sigurdsson E, Sørensen HJ, Spencer B, Stefansson H, Støvring H, Strohmaier J, Sullivan P, Vassos E, Verbelen M, Walters JTR, Werge T.
- 1
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
- 2
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
- 3
- Department of Psychiatry and Psychotherapy, Charité, Campus Mitte, Berlin, Germany.
- 4
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
- 5
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- 6
- Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia.
- 7
- MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
- 8
- NIHR Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
- 9
- Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
- 10
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
- 11
- Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
- 12
- Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
- 13
- School of Psychology, University of Queensland, Brisbane, Queensland, Australia.
- 14
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
- 15
- Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
- 16
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
- 17
- Departamento de Bioquímica, Genética e Inmunología. Facultad de Biología, Universidad de Vigo, Vigo, Spain.
- 18
- Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- 19
- Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- 20
- Departamento de Biología Funcional. Facultad de Biología, Universidad de Oviedo, Oviedo, Spain.
- 21
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
- 22
- National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
- 23
- iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
- 24
- Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark.
- 25
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
- 26
- NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
- 27
- Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
- 28
- NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
- 29
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
- 30
- Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje, Macedonia.
- 31
- Department of Clinical Genetics, Mental Health Research Center, Moscow, Russia.
- 32
- Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
- 33
- Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
- 34
- Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
- 35
- Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
- 36
- Department of Psychiatry, School of Medicine, University of Belgrade, Belgrade, Serbia.
- 37
- Department of Psychiatry, National University Hospital, Reykjavik, Iceland.
- 38
- Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia.
- 39
- deCODE Genetics, Reykjavik, Iceland.
- 40
- Section of Psychiatry, Department of Public Health and Community Medicine, University of Verona, Verona, Italy.
- 41
- Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
- 42
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
- 43
- Discovery Neuroscience Research, Eli Lilly and Company, Lilly Research Laboratories, Windlesham, UK.
- 44
- Department of Psychiatry, University of Halle, Halle, Germany.
- 45
- Department of Psychiatry, University of Munich, Munich, Germany.
- 46
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. owenmj@cardiff.ac.uk.
- 47
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. odonovanmc@cardiff.ac.uk.
- 48
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. waltersjt@cardiff.ac.uk.
Abstract
Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.
Fig. 1Manhattan plot of schizophrenia GWAS associations
Associations are shown from the meta-analysis of CLOZUK and an independent PGC dataset (n = 105,318; 40,675 cases and 64,643 controls). The 145 genome-wide significant loci are highlighted in green. The red horizontal line indicates the genome-wide statistical significance threshold (P = 5×10−8).
Nat Genet. 2018 Mar;50(3):381-389.
Fig. 2Partitioned heritability analysis of gene sets in schizophrenia
a, Heritability of genomic partitions and the six conditionally independent (‘significant’) gene sets (). The radius of each segment indicates the degree of enrichment, while the arc (angle of each slice) indicates the percentage of total SNP-based heritability explained. No relative enrichment (enrichment = 1) is shown by the dashed red line (and depletion equates to enrichment <1, inside red line). b, Heritability of the significant CNS gene sets dissected by their overlap with LoF-intolerant genes. Whiskers represent heritability or enrichment standard errors. Asterisks indicate the significance of each heritability enrichment (*P≤0.05, **P≤0.01, ***P≤0.001).
Nat Genet. 2018 Mar;50(3):381-389.
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