No Evidence for Widespread Positive Selection Signatures in Common Risk Alleles Associated with Schizophrenia
Open accessAbstract
Schizophrenia poses an evolutionary-genetic paradox as it exhibits strongly negative fitness effects (early mortality and decreased fecundity), yet it persists at a prevalence of approximately 1% worldwide. Evidence from several studies have suggested that schizophrenia is evolved and maintained in part as a maladaptive byproduct of recent positive selection and adaptive evolution in human beings. However, inconsistent results have been also proposed, challenging the recent positive selection theory to explain the high population frequency of schizophrenia-associated alleles. Here, we used public domain data to locate signatures of positive selection based on genetic diversity, derived allele frequency, differentiation between populations, and long haplotypes at schizophrenia-associated single nucleotide polymorphisms (SNPs) and randomly selected SNPs (as negative controls). We found evidence for positive selection at 10 out of the 105 schizophrenia-associated SNPs, while 5 of these SNPs involved positive selection for the protective allele. Taken together, the absence of widespread positive selection signals at the schizophrenia-associated SNPs, along with the fact that half of the positive selection favored the protective allele, provide little evidence supporting the positive selection theory in schizophrenia.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
No SNP-h2 enrichment for positive selection signatures was identified in East Asian and European analyses.
“Similar to other studies conducted in EUR [34, 35], we did not identify SNP-h2 enrichment for positive selection signatures in our EAS and EUR analyses (Additional file 1: Table S4).”
From Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations (2022) · cites this paper as [34]
None of the positive-selection annotations tested was significant in the two populations tested.
“However, similar to previous studies [34, 35], none of the positive-selection annotations tested was significant in the two populations tested.”
From Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations (2022) · cites this paper as [34]
Cites
Biological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577 · see citing works
A Map of Recent Positive Selection in the Human Genome
Voight, B. F., Kudaravalli, S., Wen, X., & Pritchard, J. K. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040072 · Cited by 2,912 · see citing works
Schizophrenia as a Complex Trait: Evidence From a Meta-analysis of Twin Studies
Sullivan, P. F., Kendler, K. S., & Neale, M. C. (2003) · Archives of General Psychiatry · doi:10.1001/archpsyc.60.12.1187 · Cited by 2,356 · see citing works
Lichtenstein, P., Yip, B. H., Björk, C., Pawitan, Y., Cannon, T. D., Sullivan, P. F., & Hultman, C. M. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60072-6 · Cited by 2,125 · see citing works
Detecting recent positive selection in the human genome from haplotype structure
Sabeti, P. C., Reich, D. E., Higgins, J. M., Levine, H. Z. P., Richter, D. J., Schaffner, S. F., Gabriel, S. B., Platko, J. V., Patterson, N. J., McDonald, G. J., et al. (2002) · Nature · doi:10.1038/nature01140 · Cited by 2,106 · see citing works
Molecular Signatures of Natural Selection
Nielsen, R. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.073003.112420 · Cited by 1,644 · see citing works
GERAD1 Consortium, Pardiñas, A. F., CRESTAR Consortium, Holmans, P., Pocklington, A. J., Escott-Price, V., Ripke, S., Carrera, N., Legge, S. E., Bishop, S., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0059-2 · Cited by 1,552 · see citing works
A polygenic burden of rare disruptive mutations in schizophrenia
Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O’Dushlaine, C., Chambert, K., Bergen, S. E., Kähler, A., et al. (2014) · Nature · doi:10.1038/nature12975 · Cited by 1,385 · see citing works
Genetic signatures of strong recent positive selection at the lactase gene.
Bersaglieri, T., Sabeti, P. C., Patterson, N., VanderPloeg, T., Schaffner, S., Drake, J. A., Rhodes, M., Reich, D., & Hirschhorn, J. (2004) · American Journal of Human Genetics · doi:10.1086/421051 · Cited by 1,098 · see citing works
SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans
Lamason, R. L., Mohideen, M.-A. P. K., Mest, J. R., Wong, A. C., Norton, H. L., Aros, M. C., Jurynec, M. J., Mao, X., Humphreville, V. R., Humbert, J. E., et al. (2005) · Science · doi:10.1126/science.1116238 · Cited by 1,043 · see citing works
Detecting Natural Selection in Genomic Data
Vitti, J. J., Grossman, S. R., & Sabeti, P. C. (2013) · Annual Review of Genetics · doi:10.1146/annurev-genet-111212-133526 · Cited by 694 · see citing works
Natural selection has driven population differentiation in modern humans
Barreiro, L. B., Laval, G., Quach, H., Patin, E., & Quintana-Murci, L. (2008) · Nature Genetics · doi:10.1038/ng.78 · Cited by 605 · see citing works
Genomic insights into positive selection
Biswas, S., & Akey, J. M. (2006) · Trends in Genetics · doi:10.1016/j.tig.2006.06.005 · Cited by 471 · see citing works
Adaptation–not by sweeps alone
Pritchard, J. K., & Di Rienzo, A. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2880 · Cited by 445 · see citing works
Crow, T. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(99)00029-6 · Cited by 387 · see citing works
Power, R. A., Kyaga, S., Uher, R., MacCabe, J. H., Långström, N., Landen, M., McGuffin, P., Lewis, C. M., Lichtenstein, P., & Svensson, A. C. (2013) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.268 · Cited by 336 · see citing works
Wilde, S., Timpson, A., Kirsanow, K., Kaiser, E., Kayser, M., Unterländer, M., Hollfelder, N., Potekhina, I. D., Schier, W., Thomas, M. G., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1316513111 · Cited by 257 · see citing works
The role of genetic variation in the causation of mental illness: an evolution-informed framework
Uher, R. (2009) · Molecular Psychiatry · doi:10.1038/mp.2009.85 · Cited by 189 · see citing works
Adaptive evolution of genes underlying schizophrenia
Crespi, B. J., Summers, K., & Dorus, S. (2007) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2007.0876 · Cited by 187 · see citing works
Burns, J. K. (2004) · Behavioral and Brain Sciences · doi:10.1017/s0140525x04000196 · Cited by 164 · see citing works
Aberrant Epigenetic Regulation Could Explain the Relationship of Paternal Age to Schizophrenia
Perrin, M. C., Brown, A. S., & Malaspina, D. (2006) · Schizophrenia Bulletin · doi:10.1093/schbul/sbm093 · Cited by 150 · see citing works
Xu, K., Schadt, E. E., Pollard, K. S., Roussos, P., & Dudley, J. T. (2015) · Molecular Biology and Evolution · doi:10.1093/molbev/msv031 · Cited by 133 · see citing works
Genetic Markers of Human Evolution Are Enriched in Schizophrenia
Srinivasan, S., Bettella, F., Mattingsdal, M., Wang, Y., Witoelar, A., Schork, A. J., Thompson, W. K., Zuber, V., Winsvold, B. S., Zwart, J.-A., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.10.009 · Cited by 129 · see citing works
Selection and Adaptation in the Human Genome
Fu, W., & Akey, J. M. (2013) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-091212-153509 · Cited by 123 · see citing works
Schizophrenia—an evolutionary enigma?
Brüne, M. (2003) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2003.10.002 · Cited by 97 · see citing works
Schizophrenia, Psychiatric Genetics, and Darwinian Psychiatry: An Evolutionary Framework
Pearlson, G. D., & Folley, B. S. (2007) · Schizophrenia Bulletin · doi:10.1093/schbul/sbm130 · Cited by 94 · see citing works
Detecting ancient positive selection in humans using extended lineage sorting
Peyrégne, S., Boyle, M. J., Dannemann, M., & Prüfer, K. (2017) · Genome Research · doi:10.1101/gr.219493.116 · Cited by 93 · see citing works
Polimanti, R. A., & Gelernter, J. E. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006618 · Cited by 91 · see citing works
Schizophrenia as one extreme of a sexually selected fitness indicator
Shaner, A. L., Miller, G. F., & Mintz, J. (2003) · Schizophrenia Research · doi:10.1016/j.schres.2003.09.014 · Cited by 75 · see citing works
Wang, G., & Speakman, J. R. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.014 · Cited by 61 · see citing works
Psychosis: A costly by-product of social brain evolution in Homo sapiens
Burns, J. K. (2006) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2006.01.006 · Cited by 60 · see citing works
Evolutionary Perspectives on Schizophrenia
Polimeni, J. O., & Reiss, J. P. (2003) · The Canadian Journal of Psychiatry · doi:10.1177/070674370304800107 · Cited by 59 · see citing works
Fertility of first-degree relatives of patients with schizophrenia: A three generation perspective
Svensson, A. C., Lichtenstein, P., Sandin, S., & Hultman, C. M. (2007) · Schizophrenia Research · doi:10.1016/j.schres.2006.12.002 · Cited by 53 · see citing works
dbPSHP: a database of recent positive selection across human populations
Li, M. J., Wang, L. Y., Xia, Z., Wong, M. P., Sham, P. C., & Wang, J. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1052 · Cited by 39 · see citing works
Probing the Association between Early Evolutionary Markers and Schizophrenia
Srinivasan, S., Bettella, F., Hassani, S., Wang, Y., Witoelar, A., Schork, A. J., Thompson, W. K., Collier, D. A., Desikan, R. S., Melle, I. S., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0169227 · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Uncovering the extensive trade-off between adaptive evolution and disease susceptibility
Tang, J., Huang, M., He, S., Zeng, J., & Zhu, H. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111351 · Cited by 34 · see citing works
Koller, D., Wendt, F. R., Pathak, G. A., De Lillo, A., De Angelis, F., Cabrera-Mendoza, B., Tucci, S., & Polimanti, R. (2022) · BMC Biology · doi:10.1186/s12915-022-01449-2 · Cited by 27 · see citing works
“However, similar to previous studies [34, 35], none of the positive-selection annotations tested was significant in the two populations tested.”
MethodResultEvidence of positive selection of genetic variants associated with PCOS
Yu, Z., Li, Y., Zhao, S., Liu, F., Zhao, H., & Chen, Z. (2023) · Human Reproduction · doi:10.1093/humrep/dead106 · Cited by 11 · see citing works
Mahadevan, J., Pathak, A. K., Vemula, A., Nadella, R. K., Viswanath, B., Jain, S., Rao, N. P., Narayanaswamy, J. C., Viswanath, B., Sivakumar, P. T., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-00123-x · Cited by 5 · see citing works
Mitterœcker, P., & Merola, G. P. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105636 · Cited by 6 · see citing works
Sandroni, V., & Chaumette, B. (2025) · Genes Brain & Behavior · doi:10.1111/gbb.70013 · Cited by 5 · see citing works
Recent natural selection conferred protection against schizophrenia by non-antagonistic pleiotropy
González‐Peñas, J., de Hoyos, L., Díaz‐Caneja, C. M., Andreu-Bernabeu, Á., Stella, C., Gurriarán, X., Fañanás, L., Bobes, J., González-Pinto, A. M., Crespo‐Facorro, B., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-42578-0 · Cited by 6 · see citing works
Evolutionary Perspectives on Schizophrenia Spectrum Disorders
Brüne, M. (2022) · Cambridge University Press eBooks · doi:10.1017/9781009030564.012 · Cited by 4 · see citing works
Koller, D., Wendt, F., Pathak, G., Lillo, A. D., Angelis, F. D., Cabrera-Mendoza, B., Tucci, S., & Polimanti, R. (2021) · bioRxiv · doi:10.1101/2021.08.12.456138 · Cited by 4 · see citing works
Kasap, M., & Dwyer, D. S. (2022) · Genes · doi:10.3390/genes13061040 · Cited by 3 · see citing works
- Authors
- Yao, Y., Yang, J., Xie, Y., Liao, H., Yang, B., Xu, Q., & Rao, S.
- Affiliations
- Sichuan University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Chengdu University of Traditional Chinese Medicine (CN)
- Southwest Jiaotong University (CN)
- Corresponding author
- Rao, Shuquan
- Venue
- Schizophrenia Bulletin
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-05-31
- Volume
- 46
- Issue
- 3
- Pages
- 603-611
- ISSN
- 0586-7614 (ISSN-L)
- 1745-1701
- PMC
- PMC7147583
- OpenAlex
- W2947992475
- Cited by
- 10
- References
- 35
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 2
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Schizophrenia Bulletin (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sichuan Province Science and Technology Support Program (2019YFH0137)
- Fundamental Research Funds for the Central Universities (2682018CX38)
- 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 › Evolution and Genetic Dynamics
- Keywords
- schizophrenia, positive selection
- MeSH terms
- Gene Frequency, Haplotypes, Humans, Schizophrenia, Selection, Genetic, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
