CoChat
Sign Up
Cited by 444Schizophrenia research and treatmentGenomics and Rare DiseasesGenetic Associations and Epidemiology

Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia

Open access
Genovese, Giulio, Fromer, Menachem, Stahl, Eli A, Ruderfer, Douglas M, Chambert, Kimberly, Landén, Mikael, Moran, Jennifer L, Purcell, Shaun M +4 more·2016·Nature Neuroscience
DOI 10.1038/nn.4402PMC PMC5104192
Open this paper in CoChat — free account

Abstract

By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 × 10−10). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.

Integrity signals

Registry

Crossref · 10.1038/nn.4402

Cites

111 of 111 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 62 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The elevation of protein-compromising URVs in schizophrenia cases was several times larger than the analogous elevation for de novo mutations.

    “This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations”
    • Also stated in: § Exome-wide enrichment of ultra-rare variants · plain
      “This estimate (0.03 per exome) was several times smaller than the elevation of dURVs in affected individuals in our population-based study (0.25 per exome).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014). source

      Not checked in the free run.

    • cites [13] Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014). source

      Not checked in the free run.

    • The authors state this as an assumption: The comparison between the schizophrenia-associated dURV elevation and the de novo mutation elevation assumes uniform technical ascertainment across the sequencing studies.
  • Findingown data

    Most of the genetic signal for elevated protein-compromising URVs arose from large sets of genes whose RNAs interact with synaptically localized proteins.

    “most of this genetic signal arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins.”
    Quote in the paperSubstantial claim
  • Findingown data

    The authors identified 244,246 coding-sequence and splice-site ultra-rare variants that each occurred in only one of 12,332 unrelated Swedish exomes and were absent from the ExAC cohort.

    “we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes.”
    • Also stated in: § Exome-wide enrichment of ultra-rare variants · plain
      “we identified 244,246 coding-sequence and splice-site URVs (among 4,877 schizophrenia cases and 6,203 controls) that were present in only one of the 12,332 unrelated Swedish exomes analyzed and never seen in the Exome Aggregation Consortium (ExAC) cohort”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016). source

      Not checked in the free run.

  • Findingown data

    Among schizophrenia cases, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly neuronally expressed genes.

    “Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes”
    Quote in the paperSubstantial claim
  • Findingown data

    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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Purcell, S.M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014). source

      Not checked in the free run.

  • May combine two claims. 42
  • Classified as probably not a substantial claim. 26
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingown data

    Gene-disruptive and putatively protein-damaging URVs were more abundant in schizophrenia cases than controls, while synonymous URVs were not.

    “We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant in schizophrenia cases than controls (P = 1.3 × 10−10).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The authors observed significant enrichment of dURVs in missense constrained genes (OR=1.28; 95% CI=1.20-1.37; P=3.2e-8) and loss-of-function intolerant genes (OR=1.17; 95% CI=1.12-1.21; P=1.7e-8).

    “we observed a significant enrichment (in cases relative to controls) of dURVs in missense constrained genes22 (OR=1.28; 95% CI=1.20–1.37; P = 3.2 × 10−8) and loss-of-function intolerant genes8 (OR=1.17; 95% CI=1.12-1.21; P = 1.7 × 10−8) (Fig. 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Samocha, K.E. et al. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46, 944–950 (2014). source

      Not checked in the free run.

    • cites [8] Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    A set of 3,388 neuron-specific genes had strong enrichment of dURVs in schizophrenia cases (OR=1.17; 95% CI=1.12-1.22; P=1.9e-7), comparable to brain tissue genes; genes specific to astrocytes and oligodendrocytes were no more enriched than average.

    “A set of 3,388 neuron-specific genes had a strong enrichment of mutations in schizophrenia cases (OR=1.17; 95% CI=1.12–1.22; P = 1.9 × 10−7), comparable to that observed for genes specific to brain tissue itself. Genes specifically expressed in other brain cell types, such as astrocytes and oligodendrocytes, were no more enriched than the average gene (Fig. 3b and Supplementary Fig. 8a).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Missense damaging URVs accounted for approximately 15% of all missense URVs.

    “Missense damaging URVs accounted for approximately 15% of all missense URVs (Supplementary Fig. 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The individual gene with strongest enrichment was KL (klotho), with eight different dURVs in cases and none in controls (P=3.7e-4), but this was not significant given the number of genes tested.

    “The individual gene with the strongest enrichment was KL (klotho) (Supplementary Table 2), in which we found eight different dURVs in cases and none in controls (P = 3.7 × 10−4), but this result was not significant given the number of genes tested.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Significant case-control differences were observed in rates of disruptive URVs (difference 0.12 variants/person; 95% CI 0.07-0.17; P=1.8e-6) and damaging URVs (0.12; 95% CI 0.07-0.18; P=3.4e-5).

    “we observed significant case-control differences in the rates of disruptive URVs (a difference of 0.12 variants/person; 95% confidence interval [CI]=0.07–0.17; P = 1.8 × 10−6) and damaging URVs (0.12 variants/person; 95% CI=0.07–0.18; P = 3.4 × 10−5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adjusting for covariates, there were 7% more dURVs in affected individuals than controls (OR=1.07; 95% CI=1.05-1.09; P=1.5e-10), an elevation of about 0.25 variants/patient on a background of about 4 dURVs per patient.

    “Adjusting for covariates, there were 7% more dURVs in affected individuals than in controls (odds ratios [OR]=1.07; 95% CI=1.05-1.09; P = 1.5 × 10−10), as the case-associated elevation in dURVs (of about 0.25 variants/patient; 95% CI=0.17-0.32) occurred on a background of about 4 dURVs per patient.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The case-control excess of dURVs showed similar concentration into genes expressed in excitatory and inhibitory neurons; the small number of genes specific to either class were insufficient to concentrate the signal, which appeared to reside primarily in genes expressed in both neuronal classes.

    “The case-control excess of dURVs showed a similar degree of concentration into genes expressed in excitatory and inhibitory neurons (Supplementary Fig. 8b). The small number of genes that were specific to excitatory or inhibitory neurons (relative to the other class) were insufficient to concentrate this genetic signal, which appeared to reside primarily in genes that were expressed in both”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There were 63,230 synonymous URVs.

    “synonymous: exonic variants not predicted to change the encoded protein (63,230 URVs);”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There were 27,390 damaging URVs.

    “damaging: missense variants predicted to compromise protein function per an algorithm (Online Methods), in-frame indels, or variants affecting protein-protein-contact domains (27,390 URVs); and”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The authors did not find evidence of dURV enrichment in DPYD (two dURVs in cases, six in controls) or DISC1 (one in cases, two in controls).

    “We did not find any evidence of enrichment of dURVs in DPYD19 (in which we found two dURVs in cases and six in controls), nor in DISC120 (one dURV among cases and two in controls) (Supplementary Table 3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Xu, B. et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat. Genet. 44, 1365–1369 (2012). source

      Not checked in the free run.

    • cites [20] Millar, J.K. et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet. 9, 1415–1423 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Genes encoding CELF4-bound mRNAs also showed enrichment of dURVs in schizophrenia cases (OR=1.14; 95% CI=1.09-1.19; P=6.6e-4), greater than average but less than FMRP-bound genes.

    “The genes encoding CELF4-bound mRNAs also showed an enrichment of dURVs in schizophrenia cases; this enrichment (OR=1.14; 95% CI=1.09–1.19; P = 6.6 × 10−4) was greater than that of the average gene though less strong than that of genes encoding FMRP-bound RNAs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Wagnon, J.L. et al. CELF4 regulates translation and local abundance of a vast set of mRNAs, including genes associated with regulation of synaptic function. PLoS Genet. 8, e1003067 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Among genes previously reported to have potential connections between rare variants and schizophrenia, the authors identified an ultra-rare splice donor variant in TAF13, an ultra-rare nonsense variant in SETD1A, and a single ultra-rare nonsense variant in NRXN1.

    “we identified an ultra-rare splice donor variant in TAF1312, an ultra-rare nonsense variant in SETD1A16,17, and a single ultra-rare nonsense variant in NRXN1, a gene in which exonic deletions associate with schizophrenia18.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [12] Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014). source

      Not checked in the free run.

    • cites [16] Takata, A. et al. Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron 82, 773–780 (2014). source

      Not checked in the free run.

    • cites [17] Singh, T. et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat. Neurosci. 19, 571–577 (2016). source

      Not checked in the free run.

    • cites [18] Rujescu, D. et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet. 18, 988–996 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The elevated frequency of dURVs among affected individuals was statistically significant (P=1.4e-10) but modest, an increase of 0.25 dURVs on a background of about 4 dURVs per individual.

    “Although the elevated frequency of dURVs among affected individuals was statistically significant (P = 1.4 × 10−10), it was still only a modest increase of 0.25 dURVs on a background of about 4 dURVs per individual.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A set of 2,647 genes expressed specifically in brain tissue was strongly enriched for dURVs (OR=1.17; 95% CI=1.11-1.23; P=1.2e-4), whereas sets of genes specific to other tissues, including immune cells, were not.

    “We found that a set of 2,647 genes expressed specifically in brain tissue23 was strongly enriched for dURVs (OR=1.17; 95% CI=1.11–1.23; P = 1.2 × 10−4), whereas sets of genes with expression specific to other tissues (including immune cells) were not (Fig. 3a and Supplementary Fig. 7).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Fagerberg, L. et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol. Cell. Proteomics 13, 397–406 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There were 19,526 disruptive URVs.

    “disruptive: variants that truncate or abrogate the encoded protein in a way that is readily classified as loss-of-function10 or as triggering nonsense mediated decay (NMD)11. These included nonsense, frameshift, splice-site, and very rarely, read-through variants. (19,526 URVs).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] MacArthur, D.G. et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012). source

      Not checked in the free run.

    • cites [11] Maquat, L.E. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat. Rev. Mol. Cell Biol. 5, 89–99 (2004). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There were 134,100 missense non-damaging URVs.

    “missense non-damaging: missense variants not predicted to damage protein function (by the criteria below) (134,100 URVs);”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Damaging and disruptive URVs showed similarly elevated frequencies in cases and were combined into dURVs.

    “Damaging and disruptive URVs showed similarly elevated frequencies in cases and were thus combined into a single category termed dURVs (disruptive and damaging ultra-rare variants) for subsequent analyses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The authors observed case-control enrichment of dURVs among genes encoding interactors with PSD-95 (OR=1.52; 95% CI 1.21-1.90; P=0.0017) and ARC and NMDAR (OR=1.55; 95% CI=1.21-1.98; P=0.0028).

    “We observed case-control enrichment of dURVs among genes thus defined as encoding interactors with PSD-95 (OR=1.52; 95% CI 1.21–1.90; P = 0.0017), ARC and N-methyl-D-aspartate receptors (NMDAR)35 (OR=1.55; 95% CI=1.21–1.98; P = 0.0028) (Fig. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Bayés, A. et al. Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nat. Neurosci. 14, 19–21 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Synaptic genes as defined by SynaptomeDB were enriched (OR=1.14; 95% CI=1.09-1.20; P=0.0022), though this smaller set explained a smaller fraction of the case-control difference.

    “We also observed enrichment in synaptic genes as defined by the SynaptomeDB32 (OR=1.14; 95% CI=1.09–1.20; P = 0.0022), though this smaller set of genes explained a smaller fraction of the case-control difference in dURVs (Fig. 3c).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Pirooznia, M. et al. SynaptomeDB: an ontology-based knowledgebase for synaptic genes. Bioinformatics 28, 897–899 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The authors observed significant enrichment across intellectual disability genes on the X chromosome and in developmental disorder genes.

    “We also observed a significant enrichment across intellectual disability genes on the X chromosome and in developmental disorder genes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The first, second, and fourth principal components corresponded to the three main principal components in the 1000 Genomes project phase 1 distinguishing African, East Asian, and Native American ancestry.

    “while 1st, 2nd, and 4th principal components corresponded to the three main principal components in the 1000 Genomes project phase 1 distinguishing African, East Asian, and Native American ancestry.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Principal components correlated with overall amounts of URVs.

    “While principal components did correlate with overall amounts of URVs (Supplementary Fig. 12e-f)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    The third and fifth principal components corresponded to previously observed Finnish and Northern-Southern Sweden clines.

    “Estimated 3rd and 5th principal components corresponded to previously observed Finnish and Northern-Southern Sweden clines12 (Supplementary Fig. 12d)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    When neuronally expressed gene sets were stratified by whether genes were potentially synaptic (in FMRP, CELF4, RBFOX2, or SynaptomeDB sets), potentially synaptic genes showed elevated dURVs in schizophrenia cases while other neuronally expressed genes did not.

    “No matter how we defined neuronally expressed genes, we observed that this tendency to contain an excess of dURVs in schizophrenia cases distinguished the potentially synaptic genes (which showed elevated rates of dURVs in schizophrenia) from other neuronally expressed genes (which did not) (Fig. 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The dURV elevation was concentrated in X-linked intellectual disability genes (OR=1.88; 95% CI=1.34-2.64; P=9.5e-4) and developmental disorder genes (OR=1.67; 95% CI=1.31-2.13; P=1.6e-4).

    “We did observe the dURV elevation to be concentrated in X-linked intellectual disability (XLID) genes41,42 (OR=1.88; 95% CI=1.34–2.64; P = 9.5 × 10−4) and in developmental disorder (DD) genes43 (OR=1.67; 95% CI=1.31-2.13; P = 1.6 × 10−4) (Online Methods).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [41] Moeschler, J.B. Genetic evaluation of intellectual disabilities. Semin. Pediatr. Neurol. 15, 2–9 (2008). source

      Not checked in the free run.

    • cites [42] Gécz, J., Shoubridge, C. & Corbett, M. The genetic landscape of intellectual disability arising from chromosome X. Trends Genet. 25, 308–316 (2009). source

      Not checked in the free run.

    • cites [43] McRae, J.F. et al. Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation. bioRxiv http://dx.doi.org/10.1101/049056 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The authors identified four dURVs in schizophrenia cases and none in controls in KDM5C, 11 in cases and 2 in controls in KDM5B, and 11 in cases and 3 in controls in ITPR1.

    “we identified four dURVs in schizophrenia cases (and none in controls) in XLID gene KDM5C, an H3K4 methylation eraser gene44, 11 dURVs in cases (and 2 in controls) in DD gene KDM5B, another H3K4 methylation eraser gene45, and 11 dURVs in cases (and 3 in controls) in DD gene ITPR1, which encodes an inositol triphosphate receptor46 (Supplementary Tables 2 and 3).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [44] Jensen, L.R. et al. Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Am. J. Hum. Genet. 76, 227–236 (2005). source

      Not checked in the free run.

    • cites [45] Xiang, Y. et al. JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer. Proc. Natl. Acad. Sci. USA 104, 19226–19231 (2007). source

      Not checked in the free run.

    • cites [46] Matsumoto, M. et al. Ataxia and epileptic seizures in mice lacking type 1 inositol 1,4,5-trisphosphate receptor. Nature 379, 168–171 (1996). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The identified common variant associations replicate previously observed associations for this cohort.

    “replicating a couple of common variants associations previously observed for this cohort50”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Ripke, S. et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45, 1150–1159 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Common variants associated with schizophrenia are localized near XLID genes CNKSR2 and NLGN4X, both of which escape X inactivation, as well as non-XLID gene PJA1.

    “Similarly to rare variants enrichment, common variants associated with schizophrenia are localized near XLID genes CNKSR2 and NLGN4X, both of which escape X inactivation, as well as non-XLID gene PJA124.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). source

      Not checked in the free run.

  • The quote only partly states this claim.

    Findingown data

    XLID genes that escape X-inactivation were more enriched for dURVs than other XLID genes.

    “We also observed that XLID genes which escape X-inactivation were more enriched than other XLID genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    XLID genes and developmental disorder genes were strongly enriched for dURVs in schizophrenia cases.

    “While XLID genes and developmental disorders genes were strongly enriched in schizophrenia cases”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Schizophrenia has a lifetime risk of about 0.7% and heritability of 60-80% despite reduced reproductive fecundity.

    “Schizophrenia is a psychiatric disorder with a lifetime risk of about 0.7%1 and a heritability of 60–80%2,3 despite greatly reduced reproductive fecundity4,5.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [1] McGrath, J., Saha, S., Chant, D. & Welham, J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol. Rev. 30, 67–76 (2008). source

      Not checked in the free run.

    • cites [2] Sullivan, P.F., Kendler, K.S. & Neale, M.C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187–1192 (2003). source

      Not checked in the free run.

    • cites [3] Lichtenstein, P. et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234–239 (2009). source

      Not checked in the free run.

    • cites [4] Bundy, H., Stahl, D. & MacCabe, J.H. A systematic review and meta-analysis of the fertility of patients with schizophrenia and their unaffected relatives. Acta Psychiatr. Scand. 123, 98–106 (2011). source

      Not checked in the free run.

    • cites [5] Power, R.A. et al. Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. JAMA Psychiatry 70, 22–30 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    These results nominate neurons as the CNS cell type in which genetic perturbations most affect schizophrenia risk, though they do not exclude more-modest contributions from other CNS cell types.

    “These results nominate neurons as the central nervous system (CNS) cell type in which genetic perturbations most affect schizophrenia risk, though they do not exclude more-modest contributions from other CNS cell types.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Subsets of human genes have been previously identified as missense constrained or loss-of-function intolerant.

    “Subsets of human genes have been previously identified as “missense constrained” (based on a lack of functional coding variation in controls) or “loss-of-function intolerant” (based on a smaller-than-expected number of loss-of-function mutations in population-scale data)13,21.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014). source

      Not checked in the free run.

    • cites [21] Pinto, D. et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am. J. Hum. Genet. 94, 677–694 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The authors focused on URVs because they are enriched for recent mutations and have been exposed to fewer generations of purifying selection.

    “We focused on URVs in most analyses because such variants – although comprising a tiny fraction (less than 0.2%) of the heterozygous sites in an individual – will be greatly enriched for recent mutations and thus have been exposed to fewer generations of purifying selection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Both missense constrained and loss-of-function intolerant gene sets were enriched for disruptive variants relative to damaging variants; for the latter this may reflect ascertainment for intolerance to disruptive mutations.

    “Both missense constrained and loss-of-function intolerant genes were enriched for disruptive variants relative to damaging variants (Supplementary Fig. 5); for the latter set, this may reflect these genes having been ascertained specifically for intolerance to disruptive mutations.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The authors used a linear regression model controlling for total URVs, sex, birth year, exome enrichment kit, and first 20 principal components.

    “we used a linear regression model to control for possible confounding variables, including each individual’s overall number of detected URVs (including non-coding URVs), sex, birth year, the hybrid selection kit used for exome enrichment, and the first 20 principal components estimated from exome-wide SNP and indel genotypes (Supplementary Table 1).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    The authors tested gene sets for enrichment of dURVs in cases relative to controls by comparing each gene set's enrichment to that of the average gene, a stringent correction that deflates P values.

    “We tested gene sets for an enrichment of dURVs (in cases relative to controls) by comparing each gene set’s enrichment level to that of the average gene (Online Methods). We made this stringent correction to account for the fact that any large gene set is more likely to encompass the exome-wide excess of dURVs we see in schizophrenia cases. Our practice greatly deflates the resulting P values.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Permutation P values agreed with linear regression P values, suggesting the regression P values are well-calibrated.

    “(P values determined by permuting the phenotype data 10 million times agreed with P values from the linear regression analysis, and were: P = 0.81 for synonymous, P = 0.045 for missense non-damaging, P = 3.5 × 10−5 for damaging, and P = 1.8 × 10−6 for disruptive; this suggests that the P values from the regression model are well-calibrated)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Variants with large effect on schizophrenia risk are likely to be rare in populations, requiring sequencing to find them.

    “variants with a large effect on schizophrenia risk are likely to be rare in populations, requiring sequencing to find them.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Purcell, S.M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    In a model where a hypothetical gene is affected in 0.1% of schizophrenia cases, the study had only ~4% power to find this effect at exome-wide significance, and a far-larger sample would be required.

    “in a model in which a hypothetical gene is affected in 0.1% of schizophrenia cases, we would have only ~4% power to conclusively find this effect at exome-wide significance, and a far-larger sample would be required.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Brain-specific genes explained only part of the signal, while a larger set of brain-expressed genes explained most of it, suggesting much of the signal may come from genes expressed in brain and other tissues.

    “(At the same time, the “brain-specific” genes explained only part of this signal, while a larger set of brain-expressed genes explained most of it, suggesting that much of the signal may come from genes that are expressed in brain as well as other tissues, Fig. 3a).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The authors performed a burden test using SKAT adjusting for previously defined covariates to find individual genes with more rare variants in cases or controls.

    “we performed a burden test using SKAT14 adjusting for previously defined covariates (Online Methods).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Ionita-Laza, I., Lee, S., Makarov, V., Buxbaum, J.D. & Lin, X. Sequence kernel association tests for the combined effect of rare and common variants. Am. J. Hum. Genet. 92, 841–853 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The great majority of dURVs driving elevated rates in schizophrenia were inherited rather than de novo, though their very low allele frequency suggests they are on average just a few generations old.

    “We conclude that the great majority of the dURVs driving the elevated rates in schizophrenia were inherited rather than de novo, though the very-low allele frequency of these variants suggests that they are on average just a few generations old.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The comparison between the schizophrenia-associated dURV elevation and the de novo mutation elevation assumes uniform technical ascertainment across the sequencing studies.

  • May combine two claims.

    Study design and conductown data

    Rates of synonymous and non-damaging DNMs were similar in affected (0.475) and unaffected (0.459) individuals, suggesting the DNM analysis is well-calibrated.

    “when estimated by this same approach, rates of synonymous and non-damaging DNMs were similar – 0.475 in affected and 0.459 in unaffected individuals – suggesting that the analysis is well-calibrated.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All subjects provided informed consent; institutional human subject committees approved the research.

    “All subjects provided informed consent; institutional human subject committees approved the research (UNC IRB # 04-1465). All procedures were approved by the ethical committees in Sweden and in the United States.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Because of the rareness of these variants and the infrequency with which any individual gene is affected, sequencing much larger cohorts will be needed to identify specific individual genes in which rare variants shape schizophrenia risk.

    “Because of the rareness of these variants and the infrequency with which any individual gene is affected by them – even among schizophrenia cases – the sequencing of much larger cohorts will be needed to identify the specific individual genes in which rare variants shape risk for schizophrenia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Purcell, S.M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014). source

      Not checked in the free run.

    • cites [50] Ripke, S. et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45, 1150–1159 (2013). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    After removing 119 individuals for quality control reasons, mostly divergent ancestry, the analysis included 4,877 schizophrenia cases and 6,203 controls.

    “After removing 119 individuals for quality control reasons (mostly due to divergent ancestry, Online Methods), we identified 244,246 coding-sequence and splice-site URVs (among 4,877 schizophrenia cases and 6,203 controls)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The final variant predictor was not overfit as the best predictor for this cohort.

    “but it was not overfit as to be the best predictor for this cohort (Supplementary Fig. 15).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The excess of dURVs in schizophrenia cases largely resided in brain-expressed genes, and more specifically in genes expressed in neurons rather than other CNS cell types.

    “The excess of dURVs in schizophrenia cases largely resided in brain-expressed genes, and more specifically in genes that are expressed in neurons, rather than in other CNS cell types (Fig. 6).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Association between single variants and schizophrenia was estimated using logistic regression with sex and the first five principal components as covariates.

    “A logistic regression model was used to estimate association between single variants and schizophrenia phenotype correcting for sex and the first five principal components using plink59,60.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [59] Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007). source

      Not checked in the free run.

    • cites [60] Chang, C.C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The enrichment in ID/DD genes is compatible with observations of the role of intellectual disability genes in some cases of autism and schizophrenia, though penetrance for schizophrenia may be much less than for intellectual disability and may reside primarily in syndromic cases.

    “This enrichment is compatible with observations of the role of intellectual disability genes in some cases of autism38–40 and schizophrenia17, though the penetrance of such mutations for schizophrenia may be much less than their penetrance for intellectual disability, and they may reside primarily in syndromic cases in which schizophrenia is preceded by other developmental disorders17.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [38] Robinson, E.B. et al. Autism spectrum disorder severity reflects the average contribution of de novo and familial influences. Proc. Natl. Acad. Sci. USA 111, 15161–15165 (2014). source

      Not checked in the free run.

    • cites [39] Robinson, E.B., Neale, B.M. & Hyman, S.E. Genetic research in autism spectrum disorders. Curr. Opin. Pediatr. 27, 685–691 (2015). source

      Not checked in the free run.

    • cites [40] Robinson, E.B. et al. Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population. Nat. Genet. 48, 552–555 (2016). source

      Not checked in the free run.

    • cites [17] Singh, T. et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat. Neurosci. 19, 571–577 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Purcell, S.M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014). source

      Not checked in the free run.

    • cites [16] Takata, A. et al. Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron 82, 773–780 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Fifteen individuals with discordant reported and inferred sex (including seven with 47,XXY) and 94 individuals with more than 100 URVs were excluded from the analysis.

    “removed 15 individuals for whom the reported sex and the inferred sex from inbreeding coefficients on the X chromosome mismatched (Supplementary Fig. 13), including 7 individuals with 47, XXY karyotype (Klinefelter syndrome), and 94 individuals with more than 100 URVs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The final variant predictor outperformed all other individual predictors.

    “The final predictor performed better than all other individual predictors (Supplementary Fig. 3b)”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    For each gene set, excess of dURVs in schizophrenia cases was estimated using linear or logistic regression correcting for sex, overall URV count, birth year, hybrid selection kit, and the first twenty principal components.

    “For each gene set, to estimate the excess of dURVs in cases with schizophrenia (or the odds ratios for schizophrenia phenotype) we used a linear (or logistic) regression model correcting for: (i) sex; (ii) overall URV count; (iii) birth year; (iv) the hybrid selection kit used to enrich for exome sequence; and (v) the first twenty principal components estimated from exome-wide SNP genotypes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Unusual associations with batches were estimated using logistic regression including sex and the first 20 principal components as covariates.

    “Due to prevalent population stratification within batches, we estimated unusual associations with a logistic regression model including sex and the first 20 principal components loadings as covariates.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Sex, year of birth, exome capturing kit, the first 20 principal component loadings, and total number of URVs were included as covariates in all statistical analyses involving URVs and dURVs.

    “we included sex, year of birth (Supplementary Fig. 12b), exome capturing kit, the first 20 principal component loadings, and the total number of URVs for each individual as covariates in all statistical analysis involving URVs and dURVs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    When estimating P values, further correction for exome-wide dURV count was applied to estimate the importance of each gene set with respect to observed exome-wide enrichment.

    “When estimating P values, to estimate the importance of each gene set with respect to the observed exome-wide enrichment, we further corrected for exome-wide dURV count.”
    Quote in the paperNot a substantial claim
61 of 61

  • The authors state this as an assumption.

    The comparison between the schizophrenia-associated dURV elevation and the de novo mutation elevation assumes uniform technical ascertainment across the sequencing studies.

    “(We note that such a comparison requires the imperfect assumption of uniform technical ascertainment across the sequencing studies; even under plausible relaxations of this assumption, the dURV excess greatly exceeds the dDNM excess.”
1 of 1

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?

  • isoM13 is enriched for genes harboring ultra-rare variants identified in SCZ.

    “Further, this module is enriched for genes harboring ultra-rare variants identified in SCZ (55) (Fig S13).”

    From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [55]

  • Risk alleles are concentrated in genes with a near-complete depletion of protein-truncating variants in population studies, a result shared with other neurodevelopmental disorders and suggesting strong direct selection against such mutations.

    “Furthermore, these risk alleles are concentrated in genes with a near-complete depletion of protein-truncating variants in population studies, a result shared with other neurodevelopmental disorders 6,8 and suggesting strong direct selection against such mutations.”

    From Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia (2020) · cites this paper as [6]

  • Schizophrenia has a substantial genetic component with contributions across the allele frequency spectrum.

    “It is well-established that schizophrenia has a substantial genetic component with contributions from across the allele frequency spectrum8–11.”

    From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [9]

  • Schizophrenia risk alleles are concentrated in genes nearly depleted of PTVs in population studies, as in other neurodevelopmental disorders, suggesting strong selection against such mutations.

    “Furthermore, these risk alleles are concentrated in genes with a near-complete depletion of protein-truncating variants in population studies, a result shared with other neurodevelopmental disorders9,11 and suggesting strong direct selection against such mutations.”

    From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [9]

  • 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 [9]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Genovese, G., Fromer, M., Stahl, E. A., Ruderfer, D. M., Chambert, K., Landén, M., Moran, J. L., Purcell, S. M., Sklar, P., Sullivan, P. F., Hultman, C. M., & McCarroll, S. A.
Affiliations
  • Broad Institute (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Gothenburg (SE)
  • University of North Carolina at Chapel Hill (US)
  • Karolinska Institutet (SE)
Corresponding author
  • Genovese, Giulio
  • McCarroll, Steven A
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2016-10-03
Volume
19
Issue
11
Pages
1433-1441
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.4402
PMC
PMC5104192
OpenAlex
W2529263373
Semantic Scholar
b6ac8021a27cb5edef700bc04d89da7e17253e69
Cited by
444
References
111
Citations by year
2026: 12 · 2025: 27 · 2024: 27 · 2023: 37 · 2022: 55 · 2021: 52 · 2020: 56 · 2019: 59 · 2018: 71 · 2017: 44 · 2016: 3
FWCI
52.43
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • UNC Libraries
Funders
  • Alexander and Margaret Stewart Trust
  • Sylvan C. Herman Foundation
  • Stanley Center for Psychiatric Research, Broad Institute
  • National Institute of Mental Health (R01MH077139, U01MH109528, RC2MH089905, R01MH105554, R01MH095034, MH077139)
  • National Human Genome Research Institute (R01HG006855, U54HG003067)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
schizophrenia, ultra-rare variants, protein-altering variants, splice site mutation, rare variants, synaptic dysfunction, brain-expressed genes, de novo mutations, genetic risk
MeSH terms
Female, Humans, Male, Mutation, Nerve Tissue Proteins, Risk, Schizophrenia, Sweden, Genetic Predisposition to Disease, Genome-Wide Association Study, Exome

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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