Genome-wide association analysis identifies 13 new risk loci for schizophrenia
Open accessAbstract
Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
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Studies show substantial effects on schizophrenia risk of copy number variants and rare damaging coding variants in genes with similar functions, including some of the same genes.
“This is further supported by studies showing substantial effects on schizophrenia risk of CNVs39 and rare damaging coding variants in genes with similar functions, including some of the same genes (SCHEMA; companion paper).”
From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [39]
Cases were ascertained from the Swedish National Hospital Discharge Register, which captures all inpatient hospitalizations; controls were randomly selected from population registers.
“Psychiatric cases with a diagnosis of schizophrenia or bipolar disorder were ascertained from the Swedish National Hospital Discharge Register as described in previous studies9,50, which captures all inpatient hospitalizations. Controls were randomly selected from population registers.”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [50]
The identified common variant associations replicate previously observed associations for this cohort.
“replicating a couple of common variants associations previously observed for this cohort50”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [50]
Genetic susceptibility for schizophrenia is associated with genes encoding PNN components, matrix-regulating molecules, and immune system factors.
“We integrate these considerations with results from recent genetic studies showing genetic susceptibility for schizophrenia associated with genes encoding for PNN components, matrix-regulating molecules and immune system factors.”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as Ripke et al., 2013
Genes encoding PNN structural constituents and regulators of PNN formation have been linked to schizophrenia.
“recent evidence linking genes encoding structural constituents of PNNs and those that regulate their formation to schizophrenia”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Ripke et al., 2013
A recent GWAS identified MMP16 as a schizophrenia risk gene.
“Interestingly, a recent genome-wide association study has identified MMP16 as a schizophrenia risk gene (Ripke et al., 2013).”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Ripke et al., 2013
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Biological insights from 108 schizophrenia-associated genetic loci
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Self-citationVariants in ELL2 influencing immunoglobulin levels associate with multiple myeloma
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Gene expression elucidates functional impact of polygenic risk for schizophrenia
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Self-citationNon-coding genetic variants in human disease.
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Self-citationA major role for common genetic variation in anxiety disorders
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Self-citationMinimal phenotyping yields genome-wide association signals of low specificity for major depression
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The role of schizotypy in the study of the etiology of schizophrenia Spectrum disorders
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Self-citation
- Authors
- Multicenter Genetic Studies of Schizophrenia Consortium, Ripke, S., Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, O'Dushlaine, C., Chambert, K., Moran, J. L., Kähler, A. K., Akterin, S., Bergen, S. E., Collins, A. L., Crowley, J. J., Fromer, M., Kim, Y., Lee, S. H., Magnusson, P. K. E., Sanchez, N., Stahl, E. A., Williams, S., Wray, N. R., Xia, K., Bettella, F., Borglum, A. D., Bulik-Sullivan, B. K., Cormican, P., Craddock, N., de Leeuw, C., Durmishi, N., Gill, M., Golimbet, V., Hamshere, M. L., Holmans, P., Hougaard, D. M., Kendler, K. S., Lin, K., Morris, D. W., Mors, O., Mortensen, P. B., Neale, B. M., O'Neill, F. A., Owen, M. J., Milovancevic, M. P., Posthuma, D., Powell, J., Richards, A. L., Riley, B. P., Ruderfer, D., Rujescu, D., Sigurdsson, E., Silagadze, T., Smit, A. B., Stefansson, H., Steinberg, S., Suvisaari, J., Tosato, S., Verhage, M., Walters, J. T., Bramon, E., Corvin, A. P., O'Donovan, M. C., Stefansson, K., Scolnick, E., Purcell, S., McCarroll, S. A., Sklar, P., Hultman, C. M., & Sullivan, P. F.
- Affiliations
- Broad Institute (US)
- University of North Carolina at Chapel Hill (US)
- Karolinska Institutet (SE)
- The University of Queensland (AU)
- Icahn School of Medicine at Mount Sinai (US)
- deCODE Genetics (Iceland) (IS)
- Massachusetts General Hospital (US)
- Trinity College Dublin (IE)
- Cardiff University (GB)
- PHI University Psychiatric Clinic - Skopje (MK)
- Statens Serum Institut (DK)
- Virginia Commonwealth University (US)
- King's College London (GB)
- Aarhus University Hospital (DK)
- Aarhus University (DK)
- University of Belgrade (RS)
- Martin Luther University Halle-Wittenberg (DE)
- Tbilisi State Medical University (GE)
- Vrije Universiteit Amsterdam (NL)
- Finnish Institute for Health and Welfare (FI)
- University of Verona (IT)
- Corresponding author
- Sullivan, Patrick F
- ORCID
- Ripke, Stephan
- Moran, Jennifer L
- Kähler, Anna K
- Bergen, Sarah E
- Fromer, Menachem
- Kim, Yunjung
- Lee, Sang Hong
- Magnusson, Patrik K E
- Stahl, Eli A
- Williams, Stephanie
- Wray, Naomi R
- Xia, Kai
- Bettella, Francesco
- Bulik-Sullivan, Brendan K
- Craddock, Nick
- Gill, Michael
- Hamshere, Marian L
- Holmans, Peter
- Kendler, Kenneth S
- Lin, Kuang
- Morris, Derek W
- Mors, Ole
- Mortensen, Preben B
- Neale, Benjamin M
- Owen, Michael J
- Powell, John
- Richards, Alexander L
- Riley, Brien P
- Ruderfer, Douglas
- Rujescu, Dan
- Silagadze, Teimuraz
- Smit, August B
- Steinberg, Stacy
- Suvisaari, Jaana
- Tosato, Sarah
- Verhage, Matthijs
- Walters, James T
- Bramon, Elvira
- Corvin, Aiden P
- Scolnick, Edward
- Purcell, Shaun
- McCarroll, Steven A
- Sklar, Pamela
- Sullivan, Patrick F
- Venue
- Nature Genetics
- Published
- 2013-08-25
- Volume
- 45
- Issue
- 10
- Pages
- 1150-1159
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3827979
- OpenAlex
- W2115807273
- Cited by
- 1,496
- References
- 101
- Citations by year
- 2026: 22 · 2025: 42 · 2024: 51 · 2023: 49 · 2022: 87 · 2021: 102 · 2020: 103 · 2019: 115 · 2018: 127 · 2017: 158 · 2016: 184 · 2015: 217 · 2014: 207 · 2013: 30 · 2012: 1
- FWCI
- 150.69
- Type
- journal article
- Language
- en
- Open access
- green
- research.vu.nl
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- QUT ePrints (Queensland University of Technology) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Research Online (University of Wollongong) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- CLOK (University of Central Lancashire) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- RUNE (Research UNE) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Aarhus Universitet
- Wellcome Trust (085475/Z/08/Z, 095552/Z/11/Z, 085475, 095552, 090532, 085475/B/08/Z)
- Cancer Research UK
- National Institute for Health and Care Research (NF-SI-0507-10379, PDA/02/06/016)
- European Commission (223423)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (645-000-003)
- Lundbeckfonden
- Karolinska Institutet
- Vetenskapsrådet (R01 MH077139)
- H. Lundbeck A/S
- Stanley Center for Psychiatric Research, Broad Institute
- Strategic Research Council
- National Institute of Mental Health (R01MH077139, K01MH094406, U01MH094421, R01MH083094, R01MH095034, MH077139)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- schizophrenia, genetic susceptibility loci, single nucleotide polymorphisms, bipolar disorder, neuronal calcium signaling, candidate genes, heritability, genetic susceptibility, parent-offspring trios, meta-analysis
- MeSH terms
- Female, Humans, Male, Schizophrenia, Sweden, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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