Cited by 1,552Schizophrenia research and treatmentGenetic Associations and EpidemiologyGenomic variations and chromosomal abnormalities

Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

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GERAD1 Consortium, Pardiñas, Antonio F., CRESTAR Consortium, Holmans, Peter, Pocklington, Andrew J., Escott-Price, Valentina, Ripke, Stephan, Carrera, Noa +63 more·2018·Nature Genetics

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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. A new GWAS of schizophrenia (11,260 cases and 24,542 controls) and meta-analysis identifies 50 new associated loci and 145 loci in total. The common variant association signal is highly enriched in mutation-intolerant genes and in regions under strong background selection.

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  • The set of 158 schizophrenia-associated genomic loci was used.

    “Using the set of 158 schizophrenia-associated genomic loci, we used Brown’s method (Brown, 1975) to calculate a combined p-value across all probes located within each region (based on hg19) using the probe-level p-values and correlation coefficients between all pairs of probes calculated from the DNA methylation values.”

    From DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia (2021) · cites this paper as Pardiñas et al., 2018

    The Results (GWAS and meta-analysis; page unavailable) report 145 independent schizophrenia-associated loci, not 158. The Methods (Fine-mapping, Hi-C and SMR; page unavailable) likewise refer to 145 identified loci. The source therefore does not identify the attributed set of 158 loci. (LLM, conf=0.88)

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  • Large-scale GWAS have identified approximately 160 regions of the genome harboring common variants robustly associated with the diagnosis of schizophrenia, with evidence for a substantial polygenic component in signals that individually fall below genome-wide levels of significance.

    “Large-scale genome-wide association studies (GWAS) have identified approximately 160 regions of the genome harboring common variants robustly associated with the diagnosis of schizophrenia, with evidence for a substantial polygenic component in signals that individually fall below genome-wide levels of significance (Pardiñas et al., 2018; Ripke et al., 2014)”

    From DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia (2021) · cites this paper as Pardiñas et al., 2018

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  • The GWAS regions were taken from the largest published schizophrenia GWAS to date by Pardiñas et al., 2018.

    “The GWAS regions were taken from the largest published schizophrenia GWAS to date by Pardiñas et al., 2018 made available through the Psychiatric Genomics Consortium (PGC) website (https://www.med.unc.edu/pgc/results-and-downloads).”
  • Functionally important regions of the genome contribute to SNP-h2 to a different extent compared to the other annotations tested.

    “In our evolution-focused SNP-h2 enrichment analysis, we detected an overabundance of genic and LoF intolerant loci in both EAS and EUR, suggesting that functionally important regions of the genome contribute to SNP-h2 to a different extent compared to the other annotations tested [10, 33, 40, 44].”
  • A more recent study demonstrated that when accounting for purifying selection there is no evidence for a significant Neandertal contribution.

    “A more recent study subsequently demonstrated that when accounting for purifying selection there is no evidence for a significant Neandertal contribution [44].”

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Authors
GERAD1 Consortium, Pardiñas, A. F., CRESTAR Consortium, Holmans, P., Pocklington, A. J., Escott-Price, V., Ripke, S., Carrera, N., Legge, S. E., Bishop, S., Cameron, D., Hamshere, M. L., Han, J., Hubbard, L., Lynham, A., Mantripragada, K., Rees, E., MacCabe, J. H., McCarroll, S. A., Baune, B. T., Breen, G., Byrne, E. M., Dannlowski, U., Eley, T. C., Hayward, C., Martin, N. G., McIntosh, A. M., Plomin, R., Porteous, D. J., Wray, N. R., Caballero, A., Geschwind, D. H., Huckins, L. M., Ruderfer, D. M., Santiago, E., Sklar, P., Stahl, E. A., Won, H., Agerbo, E., Als, T. D., Andreassen, O. A., Bækvad-Hansen, M., Mortensen, P. B., Pedersen, C. B., Børglum, A. D., Bybjerg-Grauholm, J., Djurovic, S., Durmishi, N., Pedersen, M. G., Golimbet, V., Grove, J., Hougaard, D. M., Mattheisen, M., Molden, E., Mors, O., Nordentoft, M., Pejovic-Milovancevic, M., Sigurdsson, E., Silagadze, T., Hansen, C. S., Stefansson, K., Stefansson, H., Steinberg, S., Tosato, S., Werge, T., Collier, D. A., Rujescu, D., Kirov, G., Owen, M. J., O’Donovan, M. C., & Walters, J. T. R.
Affiliations
  • Cardiff University (GB)
  • Massachusetts General Hospital (US)
  • King's College London (GB)
  • Broad Institute (US)
  • The University of Adelaide (AU)
  • The University of Queensland (AU)
  • University of Münster (DE)
  • Institute of Genetics and Cancer (GB)
  • University of Edinburgh (GB)
  • Universidade de Vigo (ES)
  • University of California, Los Angeles (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Universidad de Oviedo (ES)
  • Aarhus University (DK)
  • Oslo University Hospital (NO)
  • PHI University Psychiatric Clinic - Skopje (MK)
  • Statens Serum Institut (DK)
  • Diakonhjemmet Hospital (NO)
  • Aarhus University Hospital (DK)
  • University of Copenhagen (DK)
  • University of Belgrade (RS)
  • Tbilisi State Medical University (GE)
  • deCODE Genetics (Iceland) (IS)
  • University of Verona (IT)
  • Martin Luther University Halle-Wittenberg (DE)
Corresponding author
  • Owen, Michael J.
  • O’Donovan, Michael C.
  • Walters, James T. R.
Venue
Nature Genetics
Published
2018-02-26
Volume
50
Issue
3
Pages
381-389
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W2777388159
Cited by
1,552
References
170
Citations by year
2026: 75 · 2025: 109 · 2024: 148 · 2023: 162 · 2022: 233 · 2021: 288 · 2020: 233 · 2019: 207 · 2018: 74 · 2017: 19
FWCI
31.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Consultation of the Doctoral Thesis Database (TESEO) (Ministerio de Educación, Cultura y Deporte) (submittedVersion, cc-by-nc-nd)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • DZNE Pub (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
  • Hirsla (Landspítali University Hospital) (submittedVersion)
Funders
  • Aarhus Universitet
  • NHS Blood and Transplant
  • Wellcome Trust (083270, G0000934, 10436/Z/14/Z, 088262, G0901245, UK10K, 06854/Z/02/Z, 088262/Z/09/Z, MR/L010305/1, WT091310, 076113, 076113/C/04/Z)
  • Scottish Government (CZD/16/6)
  • QIMR Berghofer Medical Research Institute
  • Alzheimer's Society
  • National Institute for Health and Care Research (RP-PG-0310-1002)
  • Scottish Funding Council (HR03006)
  • King's College London
  • European Commission (QLG2-CT-2002-01254, 279227, 201413, 01254, 241909)
  • Cardiff University (MR/L010305/1, G0800509, MR/L011794/1)
  • Deutsche Forschungsgemeinschaft (Dan3/012/17, FOR 2107/ DA1151/5-1, TRR‐58, DA1151/5-1, FOR 2107, SFB TRR 58)
  • Bundesministerium für Bildung und Forschung
  • Lundbeckfonden (R155-2014-1724, R102‐A9118, R248‐2017‐2003)
  • Alfried Krupp von Bohlen und Halbach-Stiftung
  • Xunta de Galicia (ED431C, ED431C 2016-037)
  • H. Lundbeck A/S
  • National Institutes of Health (G0901245, G0000934, 389875, DA12854)
  • Chief Scientist Office, Scottish Government Health and Social Care Directorate (CZD/16/6)
  • Medical Research Council (MR/L023784/2, MR/L011794/1, G0901245, MR/P005748/1, MR/K026992/1, G0500079, G0000934, MR/L010305/1, 1078901, MR/L011794, MC_UU_00007/10, G0800509)
  • Australian Research Council (FT0991360, FT0991022)
  • National Health and Medical Research Council (496739, 613674, 613602, 389927, 1078901, 389891, 552485, 619667, 552498, 442981, 613608, 389938, 241944, 339462, 442915, 389875, 496675, 389892, G0000934)
  • European Regional Development Fund (ED431C2016-037, ED431C, CGL2016)
  • Strategic Research Council
  • Agencia Estatal de Investigación (CGL2016-75904-C2, CGL2016-75904-C2-1-P)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA013321, R01AA013326, R01AA013320, R01AA014041, R01AA007535)
  • National Institute of Mental Health (R01MH110927, R00MH113823, R01MH066206, K99MH113823)
  • National Institute on Drug Abuse (R56DA012854, K08DA019951, R01DA012854)
  • National Human Genome Research Institute
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Child Health and Human Development (HD059215, 389875)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD059215, R01HD044454)
  • FP7 Ideas: European Research Council (294838)
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 › Genomic variations and chromosomal abnormalities
Keywords
schizophrenia, genetic architecture, background selection, positive selection, fine mapping, brain gene expression, chromosome conformation, causal genes
MeSH terms
Alleles, Gene Frequency, Genes, Lethal, Humans, Schizophrenia, Selection, Genetic, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Inheritance Patterns, Genome-Wide Association Study, Genetic Loci

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