A polygenic burden of rare disruptive mutations in schizophrenia
Open accessAbstract
Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.
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CYFIP1 regulation of calcium channel subunits compromises intracellular calcium levels, resulting in delayed axonal development.
“These findings support our model in which CYFIP1 regulation of calcium channel subunits compromise intracellular calcium levels, resulting in delayed axonal development10,84,85 (Fig. 7).”
From CYFIP1 governs the development of cortical axons by modulating calcium availability (2025) · cites this paper as [10]
The Extended Data table lists a disruptive CYFIP1 variant, and the ‘ARC, PSD-95 and calcium ion channel genes’ section reports mutations in calcium-channel subunits. The Discussion proposes altered calcium-dependent signaling as a possibility. Neither passage shows that CYFIP1 regulates those subunits, changes intracellular calcium levels, or delays axonal development; those links are the citing authors’ model, not findings established by this source. (LLM, conf=0.78)
Experimental — accuracy not yet measuredA rare heterozygous disruptive nonsense variant p.Arg624Ter in CYFIP1 was detected in a patient diagnosed with schizophrenia.
“Additionally, a polygenic pattern including a rare heterozygous disruptive nonsense variant, p.Arg624Ter, in CYFIP1 was detected in a patient diagnosed with SCZ115 (Table 2n).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [115]
Extended Data Tables 3 and 8 report one singleton disruptive CYFIP1 variant in a schizophrenia case and none in controls. The passages do not identify it as p.Arg624Ter or establish that it was a heterozygous nonsense variant. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCommon variation dominates heritable risk for schizophrenia and autism spectrum disorder.
“direct comparisons of the contributions of common and rare genetic variation show that common variation dominates heritable risk for SCZ and ASD (Gaugler et al., 2014; Purcell et al., 2014)”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Purcell et al., 2014
When directly examined, polygenic risk combines additively with major mutation burden.
“In the instances where this has been studied directly, polygenic risk acts additively with major mutational burdens (Gaugler et al., 2014; Niemi et al., 2018; Purcell et al., 2014; Weiner et al., 2017).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Purcell et al., 2014
Many severe mutations do not converge on one specific phenotype but instead seem to cause a range of clinical disorders.
“Thus, many severe mutations do not converge on one specific phenotype but instead seem to cause a range of clinical disorders74,76,80,81,84,87,91.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [81]
Whole-exome sequencing studies have found enrichment of FMRP targets among rare mutations in schizophrenia, intellectual disability, and epilepsy.
“Additionally, whole-exome sequencing studies of other neurodevelopmental disorders have found enrichment for FMRP targets in rare mutations in schizophrenia81, intellectual disability68 and epilepsy78.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [81]
Earlier sequencing studies established that ultra-rare and de novo mutations contribute to schizophrenia risk and found enrichment in neuronal genes and synaptic processes.
“Earlier schizophrenia sequencing studies have established that ultra-rare and de novo mutations contribute to risk as a category, and have prioritized disease-relevant tissues and processes, specifically observing an enrichment in neuronal genes and synaptic processes9,11,19–23.”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [19]
Additional ExAC data allowed reclassification of about 66% of variants previously called singletons among 5,092 individuals as segregating variants.
“among 5,092 (of the 12,332) individuals who were also part of an earlier sequencing study9, the additional data allowed us to re-classify ~66% of variants that had been “singletons” as segregating variants (not URVs in the current analysis).”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [9]
A strong and consistent finding in exome-sequencing studies of schizophrenia involves an excess of variants in genes whose mRNAs are bound by FMRP.
“A strong and consistent finding in exome-sequencing studies of schizophrenia involves an excess of variants in genes whose mRNAs are bound by the fragile X mental retardation protein (FMRP)9,12,27.”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [9]
The observed enrichment was consistent across previously analyzed exomes and newly generated data; because previous exomes were sequenced in randomized batches with equal cases and controls, this provides additional evidence the enrichment is not due to technical effects.
“The observed enrichment was consistent across data from previously analyzed exomes9 and newly generated data (Supplementary Fig. 5); as the previously analyzed exomes were sequenced across randomized batches with equal number of cases and controls in each batch, this provides additional evidence that the enrichment is not due to technical effects.”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [9]
The current analysis did not implicate individual genes of large effect in an unbiased exome-wide search while documenting a clear exome-wide elevation of hundreds of pathogenic variants across 4,877 schizophrenia cases relative to controls, lending support to high polygenicity of schizophrenia extending to rare as well as common variants.
“The fact that an analysis of the current scale (4,877 cases, 6,203 controls, and 45,376 other genomes used to help identify ultra-rare variants) did not implicate individual genes of large effect in an unbiased exome-wide search – while documenting a very clear exome-wide elevation of hundreds of pathogenic variants across 4,877 individuals affected with schizophrenia relative to controls – lends”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [9]
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 [9]
Schizophrenia risk is highly polygenic, arising from many genetic variants each with small effects.
“SCZ is truly complex and appears to result from a myriad of genetic variants exerting small effects on disease risk4,5, conforming closely to a classical polygenic model.”
From Gene expression elucidates functional impact of polygenic risk for schizophrenia (2016) · cites this paper as [5]
Schizophrenia results from many genetic variants with small effects, fitting a polygenic model.
“SCZ is truly complex and appears to result from a myriad of genetic variants exerting small effects on disease risk4,5, conforming closely to a classical polygenic model.”
From Gene expression elucidates functional impact of polygenic risk for schizophrenia (2016) · cites this paper as [5]
Available data implicate synaptic components, including calcium channel subunits and post-synaptic elements, in schizophrenia.
“The available data are incomplete but implicate synaptic components, including calcium channel subunits and post-synaptic elements5–7.”
From Gene expression elucidates functional impact of polygenic risk for schizophrenia (2016) · cites this paper as [5]
Strong independent support of our findings comes from the observation that analyses of rare variants have also implicated postsynaptic pathways in schizophrenia etiology, suggesting that both rare and common variants are relevant.
“We note that strong, independent support of our findings comes from the observation that analyses of rare variants have also implicated postsynaptic pathways in SCZ etiology23,24, suggesting that both rare and common variants are relevant.”
From Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways (2015) · cites this paper as [24]
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Huentelman, M. J., Muppana, L., Corneveaux, J. J., Dinu, V., Pruzin, J. J., Reiman, R., Borish, C. N., De Both, M., Ahmed, A., Todorov, A., et al. (2015) · PLOS ONE · doi:10.1371/journal.pone.0135076 · Cited by 52 · see citing works
“And exome sequencing has identified rare disruptive mutations involving proteins that associate with ARC are more prevalent in schizophrenia patients than controls [29].”
Backgroundde Bartolomeis, A., Buonaguro, E. F., Latte, G., Rossi, R., Marmo, F., Iasevoli, F., & Tomasetti, C. (2017) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2017.00240 · Cited by 44 · see citing works
Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders
Schadt, E. E., Buchanan, S., Brennand, K. J., & Merchant, K. M. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00252 · Cited by 39 · see citing works
Torrico, B., Shaw, A. D., Mosca, R., Vivó-Luque, N., Hervás, A., Fernàndez-Castillo, N., Aloy, P., Bayés, M., Fullerton, J. M., Cormand, B., et al. (2019) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.180184 · Cited by 34 · see citing works
- Authors
- Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O’Dushlaine, C., Chambert, K., Bergen, S. E., Kähler, A., Duncan, L., Stahl, E., Genovese, G., Fernández, E., Collins, M. O., Komiyama, N. H., Choudhary, J. S., Magnusson, P. K. E., Banks, E., Shakir, K., Garimella, K., Fennell, T., DePristo, M., Grant, S. G. N., Haggarty, S. J., Gabriel, S., Scolnick, E. M., Lander, E. S., Hultman, C. M., Sullivan, P. F., McCarroll, S. A., & Sklar, P.
- Affiliations
- Broad Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Massachusetts General Hospital (US)
- Karolinska Institutet (SE)
- KU Leuven (BE)
- Wellcome Sanger Institute (GB)
- University of Edinburgh (GB)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Purcell, Shaun M.
- ORCID
- Purcell, Shaun M.
- Moran, Jennifer L.
- Fromer, Menachem
- Ruderfer, Douglas
- Solovieff, Nadia
- Roussos, Panos
- Bergen, Sarah E.
- Kähler, Anna
- Duncan, Laramie
- Genovese, Giulio
- Fernández, Esperanza
- Collins, Mark O.
- Komiyama, Noboru H.
- Choudhary, Jyoti S.
- Magnusson, Patrik K. E.
- Banks, Eric
- Garimella, Kiran
- Fennell, Tim
- Grant, Seth G. N.
- Haggarty, Stephen J.
- Gabriel, Stacey
- Scolnick, Edward M.
- Lander, Eric S.
- Sullivan, Patrick F.
- McCarroll, Steven A.
- Sklar, Pamela
- Venue
- Nature
- Published
- 2014-01-22
- Volume
- 506
- Issue
- 7487
- Pages
- 185-190
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4136494
- OpenAlex
- W2132297623
- Cited by
- 1,385
- References
- 51
- Citations by year
- 2026: 23 · 2025: 39 · 2024: 34 · 2023: 60 · 2022: 96 · 2021: 98 · 2020: 123 · 2019: 145 · 2018: 158 · 2017: 169 · 2016: 169 · 2015: 158 · 2014: 113
- FWCI
- 154.88
- Type
- journal article
- Language
- en
- Open access
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UNC Libraries
- Funders
- U.S. Department of Veterans Affairs (I01BX002395)
- Wellcome Trust
- European Commission (242167, 241995)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (645-000-003)
- Karolinska Institutet
- Vetenskapsrådet (R01 MH077139)
- National Institutes of Health (241995)
- Stanley Center for Psychiatric Research, Broad Institute
- Medical Research Council
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health (R01MH077139, T32MH017119, TT32MH017119, R01MH095088, RC2MH089905, R01MH095034, MH077139, R01MH091115, R01MH099126)
- National Human Genome Research Institute (U54HG003067, R01HG005827)
- 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 › Genomics and Rare Diseases
- Keywords
- schizophrenia, polygenic burden, exome sequencing, activity-regulated cytoskeleton-associated protein, postsynaptic density, FMRP, glutamatergic synapses, autism spectrum disorder
- MeSH terms
- Disks Large Homolog 4 Protein, Autistic Disorder, Cytoskeletal Proteins, Female, Humans, Male, Membrane Proteins, Intellectual Disability, Mutation, Nerve Tissue Proteins, Schizophrenia, Calcium Channels, Receptors, N-Methyl-D-Aspartate, Multifactorial Inheritance, Intracellular Signaling Peptides and Proteins, Fragile X Messenger Ribonucleoprotein 1, Genome-Wide Association Study, DNA Copy Number Variations
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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.
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