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Cited by 983Schizophrenia research and treatmentGenetic Associations and EpidemiologyGenomics and Rare Diseases

Rare coding variants in ten genes confer substantial risk for schizophrenia

Open access
Singh, Tarjinder, Poterba, Timothy, Curtis, David, Akil, Huda, Al Eissa, Mariam, Barchas, Jack D., Bass, Nicholas, Bigdeli, Tim B. +103 more·2022·Nature
DOI 10.1038/s41586-022-04556-wPMC PMC9805802

Published version of a preprint

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Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach. Whole-exome sequencing identifies ten risk genes for schizophrenia implicated by rare protein-coding variants, a subset of which overlap with risk genes in other neurodevelopmental disorders.

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Crossref · 10.1038/s41586-022-04556-w

Cites

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Claims the paper makes

0 of 56 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Genes prioritized from common variant analyses of schizophrenia are enriched for rare variant risk.

    “we demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Trubetskoy, V. et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature https://doi.org/10.1038/s41586-022-04434-5 (2022). source

      Not checked in the free run.

  • Findingnone given

    Most genes identified here are not implicated in neurodevelopment.

    “Most genes described here however are not implicated in neurodevelopment”
    Quote in the paperNot a substantial claim
  • Findingown data

    Even after excluding significantly associated genes, schizophrenia cases carry a substantial excess of URVs.

    “Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.
  • Findingown data

    Combining findings with other sequencing studies reveals shared and distinct genetic signals between schizophrenia and other neurodevelopmental disorders.

    “Combining these findings with other large-scale sequencing studies, we find shared and distinct genetic signals between schizophrenia and other neurodevelopmental disorders.”
    Quote in the paperSubstantial claim
  • Findingown data

    The top associations are supported by complementary variant types including case-control PTVs, damaging missense variants, and de novo mutations.

    “These top associations as a group are supported by complementary types of variation that include case-control PTVs, damaging missense variants, and de novo mutations (Table 1, Table S5).”
    Quote in the paperSubstantial claim
  • May combine two claims. 40
  • Classified as probably not a substantial claim. 20
  • Not yet classified. 1

  • May combine two claims.

    Findingown data

    Meta-analysis of exomes from 24,248 schizophrenia cases and 97,322 controls identified ultra-rare coding variants in ten genes associated with substantial schizophrenia risk (OR 3-50, P<2.14e-6) and 32 genes at FDR<5%.

    “By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 – 50, P < 2.14 × 10−6), and 32 genes at a FDR < 5%.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.

  • May combine two claims.

    Findingown data

    Rare variant risk overlaps between schizophrenia, ASD, epilepsy, and severe neurodevelopmental disorders, although in some shared genes different mutation types are implicated.

    “We observe an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD)1, epilepsy and severe neurodevelopmental disorders (DD/ID)2, though in some shared genes different mutation types are implicated.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Satterstrom, F. K. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180, 568–584 (2020). source

      Not checked in the free run.

    • cites [2] Kaplanis, J. et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 586, 757–762 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The implicated genes show highest expression in central nervous system neurons and have diverse molecular functions including synapse formation, structure, and function.

    “These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Missense variants with MPC>3 have a global signal comparable to PTVs in schizophrenia, ASD, and severe neurodevelopmental disorders, whereas MPC 2-3 variants have a significant but weaker signal and were analyzed separately.

    “We found that missense variants with MPC > 3 have a global signal on par with PTVs in schizophrenia, autism spectrum disorders, and severe neurodevelopmental disorders, while variants with MPC 2 – 3 has a significant but weaker signal than PTVs and were therefore analyzed separately”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    All ten implicated genes are among the most constrained in the genome, showing substantial depletion of PTVs compared to chance expectation.

    “As expected, all ten genes are among the most constrained genes in the genome, with a substantial depletion of PTVs compared to chance expectation24.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] 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

    URVs in the implicated genes confer substantial risk, with odds ratios for PTVs and Class I variants ranging from 3 to 50, though confidence intervals are wide.

    “Although confidence intervals are wide, URVs in these genes appear to confer substantial risk, with odds ratio of PTVs and Class I variants ranging from 3 to 50.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    De novo mutations are enriched in the 244 genes with case-control P<0.01, with limited or no signal in remaining genes.

    “Using Poisson rate tests based on expected mutation rate27, we found these de novo mutations are enriched for the 244 genes with P < 0.01 in our case-control analysis (Figure S13, Table S5), with limited or no signal in the remaining genes in the genome (Figure 1D).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Hu, W., MacDonald, M. L., Elswick, D. E. & Sweet, R. A. The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann. NY Acad. Sci. 1338, 38–57 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Schizophrenia cases show significant excess of URVs compared to controls in 299 DD/ID-associated genes (Pmeta=1.5e-14; ORClass I=1.44, 95% CI 1.3-1.6) and in 102 ASD-associated genes (Pmeta=3.7e-7; ORClass I=1.45, 95% CI 1.23-1.72).

    “We found a significant excess of URVs in schizophrenia cases compared to controls in the 299 DD/ID-associated genes (Pmeta = 1.5 × 10−14; ORClass I = 1.44, 1.3 – 1.6 95% CI), and in the 102 ASD-associated genes (Pmeta = 3.7 × 10−7; ORClass I = 1.45, 1.23 – 1.72 95% CI; Figure 5A; Table S12).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.

  • May combine two claims.

    Findingown data

    This study shows for the first time that common regulatory variants from GWAS and ultra-rare coding variants disrupt an overlapping set of genes, including an allelic series in four genes in which common and rare coding variants increase risk to varying degrees.

    “We show for the first time that common regulatory variants from GWAS and ultra-rare coding variants disrupt an overlapping set of genes, including an allelic series in four genes in which common variants and rare coding variants increase risk to varying degrees.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nine of the ten schizophrenia risk genes showed limited de novo protein-truncating variant signal in developmental delay/intellectual disability, with a combined eight de novo PTVs observed in these genes (expected 4.98; Poisson P = 0.13).

    “Nine of the ten schizophrenia genes showed limited de novo PTV signal in DD/ID, with a combined 8 de novo PTVs observed in these genes (Xexp = 4.98; PPois = 0.13; Figure 5B; Table S13).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 31,058 developmental delay/intellectual disability trios provide sufficient power to evaluate the individual schizophrenia risk genes from this study for a role in broader neurodevelopmental disorders.

  • May combine two claims.

    Findingown data

    Schizophrenia risk genes are involved in the postsynaptic density and broader synaptic function.

    “reaffirm that schizophrenia risk genes are involved in the postsynaptic density and broader synaptic function”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Protein-truncating variants show consistent signals across the different SCHEMA cohorts, and synonymous variants do not deviate from expectation.

    “PTVs show consistent signals across the different cohorts, and synonymous variants do not deviate from expectation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Individual genes such as SETD1A, TRIO, and SP4 exhibited prenatal expression, while GRIN2A and GRIA3 showed postnatal expression.

    “individual genes like SETD1A, TRIO, and SP4 exhibited prenatal expression while GRIN2A and GRIA3 showed postnatal expression (Figure S22).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Protein-truncating variants in 9 of the 10 most confidently associated genes are associated with schizophrenia and not with developmental delay/intellectual disability.

    “PTVs in 9 of the 10 most confidently associated genes are associated with schizophrenia and not for DD/ID”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    De novo missense mutations in GRIN2A cluster at the base of the ion channel, with the most mutations in the exon encoding the pore of the complex.

    “de novo missense mutations in GRIN2A cluster at the base of the ion channel with the most mutations in the exon encoding for the pore of the complex (Figure 5D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    FAM120A and STAG1 reside in complex GWAS-associated regions with multiple genes but were prioritized among their neighbors at FDR<5% in the sequencing study.

    “Furthermore, FAM120A and STAG1 resided in more complex GWAS-associated regions containing multiple genes but were prioritized among their neighbors as FDR < 5% in our sequencing study (Figure 4C, 4D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Fine-mapping prioritized likely underlying protein-coding genes at 64 GWAS associations, and URVs are enriched in these genes in cases versus controls (Pmeta=3.9e-4; ORClass I=1.46, 95% CI 1.2-1.77).

    “Statistical fine-mapping prioritized the likely underlying protein-coding gene at 64 of these associations (Table S11, Figure S18), and we found a case-control enrichment of URVs in these genes (Pmeta = 3.9 × 10−4; ORClass I = 1.46, 1.2 – 1.77 95% CI; Figure 4A, Table S12).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.

  • May combine two claims.

    Findingown data

    Allelic series are observed in GRIN2A, TRIO, and CACNA1G, in which protein-truncating variants increase schizophrenia risk and de novo missense mutations confer strong developmental delay/intellectual disability risk.

    “we observe allelic series in GRIN2A, TRIO, and CACNA1G in which PTVs increase schizophrenia risk and de novo missense mutations confer strong DD/ID risk.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    De novo missense mutations in these genes clustered in specific domains and are associated with more severe neurodevelopmental, syndromic disorders with cognitive impairment.

    “De novo missense mutations in these genes clustered in specific domains and are associated with more severe neurodevelopmental, syndromic disorders with cognitive impairment”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    GRIN2A and SP4, two of the ten significant rare variant genes, have clear associations in schizophrenia GWAS.

    “Beyond the statistical enrichment, GRIN2A and SP4, two of the ten significant rare variant genes, had clear associations in schizophrenia GWAS (Figure 3A, Figure 4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Genes with highest specific expression in brain regions show strongest enrichment of risk URVs, most significantly in human frontal cortex (P=1.63e-8), with limited signal in other tissues.

    “Following earlier reports studying heritability enrichment in GTEx tissues8,31, we found that genes with the highest specific expression in brain regions showed the strongest enrichment of risk URVs, most significantly in the human frontal cortex (P = 1.63 × 10−8) and with limited signal in the other tissue types (Extended Data Figure 4, Table S8, S9).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] 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.

    • cites [31] Koopmans, F. et al. SynGO: an evidence-based, expert-curated knowledge base for the synapse. Neuron 103, 217–234 (2019). source

      Not checked in the free run.

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

    Interpretationreasoning

    More risk genes await discovery using this approach.

    “implying that more risk genes await discovery using this approach.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    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.”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [9] Genovese, G. et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 19, 1433–1441 (2016). source

      Not checked in the free run.

    • cites [11] Singh, T. et al. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat. Genet. 49, 1167–1173 (2017). source

      Not checked in the free run.

    • cites [19] 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 [20] 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 [21] Howrigan, D. P. et al. Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations. Nat. Neurosci. 23, 185–193 (2020). source

      Not checked in the free run.

    • cites [22] Gulsuner, S. et al. Genetics of schizophrenia in the South African Xhosa. Science 367, 569–573 (2020). source

      Not checked in the free run.

    • cites [23] Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020). source

      Not checked in the free run.

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

    Premisecitation

    Several rare recurrent CNVs are robustly associated with schizophrenia, e.g., higher rates in 22q11.2 deletion carriers.

    “Several rare (MAF < 0.1%) recurrent copy number variants (CNVs) have also been robustly associated with schizophrenia, as exemplified by the dramatically higher rates of schizophrenia in 22q11.2 deletion carriers10,15.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Marshall, C. R. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35 (2017). source

      Not checked in the free run.

    • cites [15] Zuk, O. et al. Searching for missing heritability: designing rare variant association studies. Proc. Natl Acad. Sci. USA 111, E455–E464 (2014).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Genovese, G. et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 19, 1433–1441 (2016). source

      Not checked in the free run.

    • cites [11] Singh, T. et al. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat. Genet. 49, 1167–1173 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Because schizophrenia GWAS causal variants are predominantly non-coding, fine-mapping and interpretation challenges limit confident identification of underlying genes, mechanisms, and direction of effect.

    “Because causal variants in schizophrenia GWAS are predominantly non-coding, challenges related to fine-mapping and interpretation of intergenic and intronic elements limit our ability to confidently identify underlying genes, infer the mechanism by which they influence disease risk, and determine the direction of effect.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Quality control steps were performed to ensure high-quality sequence data, exclude contaminated samples, identify related individuals, and infer ancestries.

    “After extracting SCHEMA samples from this callset, we performed quality control steps to ensure high quality of sequence data, exclude contaminated samples, identify parent-proband trios and other related individuals, and infer global ancestries”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Increased scale following this approach will uncover additional risk genes and help complete the genetic architecture of schizophrenia.

    “Finally, we demonstrate that increased scale following this approach will uncover additional risk genes and help complete the genetic architecture of schizophrenia.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Pathway analyses of common variants have prioritized disease-relevant tissues and cell types and sometimes recapitulated known biology.

    “Pathway analyses of common variants have prioritized disease-relevant tissues and cell types, and in some cases, independently recapitulating known biology8,30,31.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] 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.

    • cites [30] Finucane, H. K. et al. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nat. Genet. 50, 621–629 (2018). source

      Not checked in the free run.

    • cites [31] Koopmans, F. et al. SynGO: an evidence-based, expert-curated knowledge base for the synapse. Neuron 103, 217–234 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Technical and methodological batch effects were controlled in variant calling and via permutation testing.

    “We attempted to control for technical and methodological batch effects that may arise from this approach in both variant calling and additionally via permutation testing described below.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The most natural grouping for rare variants is within a gene based on predicted functional consequence or deleteriousness.

    “The most natural grouping for rare variants is within a gene, based on predicted functional consequence or evidence for deleteriousness16,17.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Lee, S., Abecasis, G. R., Boehnke, M. & Lin, X. Rare-variant association analysis: study designs and statistical tests. Am. J. Hum. Genet. 95, 5–23 (2014). source

      Not checked in the free run.

    • cites [17] Rivas, M. A. et al. Effect of predicted protein-truncating genetic variants on the human transcriptome. Science 348, 666–669 (2015). source

      Not checked in the free run.

    • Rests on an assumption: Most rare variants have little or no functional consequence or impact on risk.

  • Classified as probably not a substantial claim.

    Premisecitation

    The glutamatergic hypothesis postulates that hypofunction of NMDA receptor signaling is a possible mechanism of schizophrenia.

    “Developed from neuropharmacological and neuropathological observations, the glutamatergic hypothesis postulates that the hypofunction of glutamatergic signaling through NMDA receptors is a possible mechanism of disease28 (Supplementary Note).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Kang, H. J. et al. Spatio-temporal transcriptome of the human brain. Nature 478, 483–489 (2011). source

      Not checked in the free run.

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

    Interpretationown data

    More genes remain to be discovered.

    “suggesting that more genes remain to be discovered (Figure 2B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Schizophrenia GWAS identified a common variant at GRIN2A (OR=1.057, P=1.57e-10), providing an allelic series where different perturbation of gene function results in severity of disease risk.

    “Schizophrenia GWAS also identified a common variant at GRIN2A (OR = 1.057, P = 1.57 × 10−10), providing an allelic series in which different perturbation of gene function results in severity of disease risk (Figure 3A)8.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] 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.

  • Classified as probably not a substantial claim.

    Premisecitation

    GWAS have identified 270 common risk loci for schizophrenia with individually small effect (median OR <1.05).

    “This has been borne out by genome-wide association studies (GWAS) which have now, in a companion paper, identified 270 common (minor allele frequency [MAF] > 1%) risk loci of individually small effect (median odds ratio [OR] < 1.05)13.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Loh, P.-R. et al. Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis. Nat. Genet. 47, 1385–1392 (2015). source

      Not checked in the free run.

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

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [8] 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.

    • cites [9] Genovese, G. et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 19, 1433–1441 (2016). source

      Not checked in the free run.

    • cites [10] Marshall, C. R. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35 (2017). source

      Not checked in the free run.

    • cites [11] Singh, T. et al. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat. Genet. 49, 1167–1173 (2017). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Site- and genotype-level filters were applied to generate a robust set of coding SNPs and indels for a well-matched case-control analysis.

    “We subsequently applied site- and genotype-level filters to generate a robust set of coding SNPs and indels for a well-matched case-control analysis”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    URV analysis has had limited success in individual gene discovery for schizophrenia due to power limitations, with only SETD1A robustly associated.

    “However, the analysis of URVs has had limited success in delivering individual gene discovery in schizophrenia because of power limitations, with only a single gene, SETD1A, identified as robustly associated16,21.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Lee, S., Abecasis, G. R., Boehnke, M. & Lin, X. Rare-variant association analysis: study designs and statistical tests. Am. J. Hum. Genet. 95, 5–23 (2014). source

      Not checked in the free run.

    • cites [21] Howrigan, D. P. et al. Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations. Nat. Neurosci. 23, 185–193 (2020). source

      Not checked in the free run.

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

    Study design and conductown data

    This enrichment provides additional reassurance of robustness of case-control gene results.

    “which provides additional reassurance of the robustness of our case-control gene results.”
    Quote in the paperNot a substantial claim

  • Not yet classified.

    Premise

    Large-effect CNVs often disrupt many genes simultaneously, limiting functional insights.

    “CNVs of large effect, on the other hand, often disrupt hundreds of kilobases of the genome and multiple genes simultaneously, limiting our ability to derive clear functional insights10.”
    Quote in the paperNot yet classified0 of 1 sources checked
    • cites [10] Marshall, C. R. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35 (2017). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Samples were jointly re-processed and variant-called with a standardized pipeline to ensure calibrated analyses.

    “To ensure calibrated analyses, these samples were included in joint re-processing and variant calling using a standardized BWA-Picard-GATK pipeline as part of the larger Genome Aggregation Database (gnomAD) effort”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NMDA receptor composition changes during neurodevelopment, with GRIN2A predominantly expressed in late childhood and adolescence, matching schizophrenia age-of-onset.

    “The NMDA receptor changes in composition during prenatal to postnatal neurodevelopment with GRIN2A predominantly expressed during late childhood and adolescence, recapitulating expected epidemiological observations on schizophrenia age-of-onset (Supplementary Methods, Figure 3B)29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Network and Pathway Analysis Subgroup of the Psychiatric Genetics Consortium. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat. Neurosci. 18, 199–209 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Common variants explain about 24% of variance in schizophrenia liability.

    “As a class of variation, common variants explain ~24% of the variance in disease liability14.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Karayiorgou, M. et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl Acad. Sci. USA 92, 7612–7616 (1995). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    This suggests that 0.86% of patients are carriers and that approximately 35% of variants are de novo.

    “suggesting that 0.86% of patients are carriers and ~35% of variants are de novo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Because schizophrenia is under strong selection, ultra-rare variants of large effect are expected to be frequently de novo or of very recent origin and to contribute to risk in only a fraction of diagnosed patients.

    “Because schizophrenia as a trait is under strong selection39–41, we expect that URVs of large effect to be frequently de novo or of very recent origin and contribute to risk in only a fraction of diagnosed patients.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [39] Power, R. A. et al. Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. Arch. Gen. Psychiat. 70, 22–30 (2013).

      Not checked in the free run.

    • cites [40] Endele, S. et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat. Genet. 42, 1021–1026 (2010). source

      Not checked in the free run.

    • cites [41] Finn, R. D. et al. Pfam: the protein families database. Nucleic Acids Res. 42, D222–D230 (2014). source

      Not checked in the free run.

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

    Interpretationreasoning

    The vast majority of risk alleles, their direction and magnitude of effect, mode of action, and responsible genes are yet to be discovered.

    “The vast majority of risk alleles, their direction and magnitude of effect, mode of action, and responsible genes are yet to be discovered.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Results suggest at least partial convergence in genes and biological processes implicated by common and ultra-rare genetic variation, and that ultra-rare coding variants can prioritize genes within GWAS loci.

    “Combined, these results suggest there is at least partial convergence in the genes and biological processes implicated by common and ultra-rare genetic variation, and that ultra-rare coding variants can be leveraged to prioritize genes within GWAS loci.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    These observations raise the possibility that certain properties may differentiate genes for adult psychiatric disorders from those for more severe developmental delay/intellectual disability.

    “These observations offer the possibility that certain properties may differentiate genes for adult psychiatric disorders and more severe DD/IDs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These observations suggest that schizophrenia and childhood-onset neurodevelopmental disorders share some genes and biological processes, but that in at least some cases the severity or nature of the functional impairment differs between the disorders.

    “These observations suggest schizophrenia and childhood onset neurodevelopmental disorders share some genes and biological processes, but that at least in some cases, the severity or the nature of the functional impairment differs between disorders.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Exome sequencing studies of ASD and severe neurodevelopmental disorders have identified risk genes, with genetic signals concentrated in constrained genes and shared between the two disorders.

    “These studies have established that the genetic signals were concentrated in constrained genes and shared between the two disorders35,36.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] The Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519, 223–228 (2015). source

      Not checked in the free run.

    • cites [36] Barbosa, S. et al. Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders. Am. J. Hum. Genet. 106, 338–355 (2020). source

      Not checked in the free run.

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

    Premisecitation

    Recent analyses implicated 299 genes from 31,058 DD/ID trios and 102 genes at FDR<10% from 11,986 ASD cases.

    “Most recently, the analysis of de novo mutations from 31,058 DD/ID trios implicated 299 genes, while the analysis of 11,986 ASD cases identified 102 genes at FDR < 10% (Table S11)1,37.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Satterstrom, F. K. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180, 568–584 (2020). source

      Not checked in the free run.

    • cites [37] Haukka, J., Suvisaari, J. & Lönnqvist, J. Fertility of patients with schizophrenia, their siblings, and the general population: a cohort study from 1950 to 1959 in Finland. Am. J. Psychiat. 160, 460–463 (2003). source

      Not checked in the free run.

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

    Premisecitation

    Recent efforts have begun to generate a more comprehensive view of schizophrenia genetic architecture, comprising common variants of small effect, large copy-number variants with elevated frequencies driven by genomic instability, and ultra-rare variants of large effect implicating individual genes.

    “Efforts in the past decade are beginning to generate a more comprehensive view of the genetic architecture for schizophrenia, composed of common variants of small effects, large CNVs with elevated frequencies driven by genomic instability, and now, URVs of large effect implicating individual genes (Figure 6A)8,10.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] 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.

    • cites [10] Marshall, C. R. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35 (2017). source

      Not checked in the free run.

52 of 52

  • The paper relies on this without support.

    The population controls used in the case-control analysis are assumed to be free of schizophrenia.

    “50,437 individuals without a known psychiatric diagnosis”

  • The paper relies on this without support.

    Most rare variants have little or no functional consequence or impact on risk.

    “most rare variants will have little or no functional consequence or impact on risk”

  • The paper relies on this without support.

    Expression patterns in mouse nervous system cell types can be generalized to human schizophrenia risk genes.

    “we investigated which single cell types in the mouse nervous system show the highest specific expression for the 32 (FDR < 5%) schizophrenia risk genes”

  • The paper relies on this without support.

    The 31,058 developmental delay/intellectual disability trios provide sufficient power to evaluate the individual schizophrenia risk genes from this study for a role in broader neurodevelopmental disorders.

    “With 31,058 trios, the scale of gene discovery in severe DD/ID provided sufficient power to evaluate the individual schizophrenia risk genes associated in our study for a role in broader neurodevelopmental disorders.”

  • The paper relies on this without support.

    The NMDA receptor is composed of two GRIN2 units (GRIN2A and/or GRIN2B) along with two constitutive GRIN1 units, and GRIN2A expression increases dramatically later in childhood and adolescence, mimicking the age of onset of schizophrenia.

    “the NMDA receptor is composed of two GRIN2 units (GRIN2A and/or GRIN2B) along with two constitutive GRIN1 units, and GRIN2A increases dramatically in expression later in childhood and adolescence, mimicking the age of onset of disease for schizophrenia.”
5 of 5

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?

  • CACNA1G loss-of-function mutations are associated with schizophrenia and intellectual disability.

    “The thalamus-enriched voltage-dependent calcium channel CaV3.1 encoded by the Wnt target CACNA1G is the key mediator of thalamocortical connectivity, and putative loss-of-function mutations of CACNA1G have been associated with schizophrenia and intellectual disability [65–67].”

    From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [66]

    The Discussion reports that protein-truncating variants (putative loss-of-function variants) in CACNA1G increase schizophrenia risk. It attributes the developmental-disorder and intellectual-disability risk instead to de novo missense mutations, and says the two variant types may have different functional effects. Thus the source does not support attributing both associations to loss-of-function mutations. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Rare variant overlaps exist in liability to schizophrenia, autism spectrum disorder, and developmental disorder.

    “There are rare variant overlaps in liability to schizophrenia, autism spectrum disorder (ASD) and developmental disorder (DD)8,30,31.”

    From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [30]

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Authors
Singh, T., Poterba, T., Curtis, D., Akil, H., Al Eissa, M., Barchas, J. D., Bass, N., Bigdeli, T. B., Breen, G., Bromet, E. J., Buckley, P. F., Bunney, W. E., Bybjerg-Grauholm, J., Byerley, W. F., Chapman, S. B., Chen, W. J., Churchhouse, C., Craddock, N., Cusick, C. M., DeLisi, L., Dodge, S., Escamilla, M. A., Eskelinen, S., Fanous, A. H., Faraone, S. V., Fiorentino, A., Francioli, L., Gabriel, S. B., Gage, D., Gagliano Taliun, S. A., Ganna, A., Genovese, G., Glahn, D. C., Grove, J., Hall, M.-H., Hämäläinen, E., Heyne, H. O., Holi, M., Hougaard, D. M., Howrigan, D. P., Huang, H., Hwu, H.-G., Kahn, R. S., Kang, H. M., Karczewski, K. J., Kirov, G., Knowles, J. A., Lee, F. S., Lehrer, D. S., Lescai, F., Malaspina, D., Marder, S. R., McCarroll, S. A., McIntosh, A. M., Medeiros, H., Milani, L., Morley, C. P., Morris, D. W., Mortensen, P. B., Myers, R. M., Nordentoft, M., O’Brien, N. L., Olivares, A. M., Ongur, D., Ouwehand, W. H., Palmer, D. S., Paunio, T., Quested, D., Rapaport, M. H., Rees, E., Rollins, B., Satterstrom, F. K., Schatzberg, A., Scolnick, E., Scott, L. J., Sharp, S. I., Sklar, P., Smoller, J. W., Sobell, J. L., Solomonson, M., Stahl, E. A., Stevens, C. R., Suvisaari, J., Tiao, G., Watson, S. J., Watts, N. A., Blackwood, D. H., Børglum, A. D., Cohen, B. M., Corvin, A. P., Esko, T., Freimer, N. B., Glatt, S. J., Hultman, C. M., McQuillin, A., Palotie, A., Pato, C. N., Pato, M. T., Pulver, A. E., St. Clair, D., Tsuang, M. T., Vawter, M. P., Walters, J. T., Werge, T. M., Ophoff, R. A., Sullivan, P. F., Owen, M. J., Boehnke, M., O’Donovan, M. C., Neale, B. M., & Daly, M. J.
Affiliations
  • Broad Institute (US)
  • Queen Mary University of London (GB)
  • University of Michigan (US)
  • Weill Cornell Medicine (US)
  • University College London (GB)
  • SUNY Downstate Health Sciences University (US)
  • King's College London (GB)
  • Stony Brook University (US)
  • Virginia Commonwealth University (US)
  • University of California, Irvine (US)
  • University of California, San Francisco (US)
  • National Taiwan University (TW)
  • Cambridge Health Alliance (US)
  • Texas Tech University Health Sciences Center (US)
  • University of Helsinki (FI)
  • SUNY Upstate Medical University (US)
  • Boston Children's Hospital (US)
  • Aarhus University (DK)
  • Harvard University (US)
  • Statens Serum Institut (DK)
  • James J. Peters VA Medical Center (US)
  • Cardiff University (GB)
  • Wright State University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Edinburgh (GB)
  • University of Tartu (EE)
  • Ollscoil na Gaillimhe – University of Galway (IE)
  • HudsonAlpha Institute for Biotechnology (US)
  • University of Copenhagen (DK)
  • University of Cambridge (GB)
  • Oxford Health NHS Foundation Trust (GB)
  • Emory University (US)
  • Massachusetts General Hospital (US)
  • University of Southern California (US)
  • Finnish Institute for Health and Welfare (FI)
  • Trinity College Dublin (IE)
  • Karolinska Institutet (SE)
  • Johns Hopkins University (US)
  • University of California San Diego (US)
  • University of California, Los Angeles (US)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
  • Singh, Tarjinder
  • Neale, Benjamin M.
  • Daly, Mark J.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2022-04-08
Volume
604
Issue
7906
Pages
509-516
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-022-04556-w
PMC
PMC9805802
OpenAlex
W4223433728
Semantic Scholar
c2b5a9c2f887fcdd0127f72ee28d110469c6b366
Cited by
983
References
80
Citations by year
2026: 158 · 2025: 214 · 2024: 220 · 2023: 197 · 2022: 139 · 2021: 53 · 2020: 1 · 2019: 1
FWCI
125.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, other-oa)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
  • STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
Funders
  • GlaxoSmithKline
  • Massachusetts General Hospital
  • Biogen
  • Dalio Foundation
  • Broad Institute (U54HG003067)
  • Stanley Family Foundation
  • National Institute for Health and Care Research
  • King's College London
  • Cardiff University (MR/L010305/1, G0800509)
  • Lundbeckfonden (R155-2014-1724, R204-2015-4129, R341-2020-222, R248‐2017‐2003, R24-2008-3243, R364-2021-85)
  • National Institutes of Health (5u01da024417-02, -0001, 5p30ns069329-02, AA 09367, DA 05147, DA024417)
  • Institute of Psychiatry, Psychology and Neuroscience, King’s College London
  • Canadian Institutes of Health Research
  • Medical Research Council (MR/L010305/1, G0800509)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA009367, R37AA009367)
  • National Institute on Aging (R01AG064955, R01AG035083, P50AG005681, P01AG003991)
  • National Heart, Lung, and Blood Institute (U01HL117626, R01HL117626)
  • National Institute of Mental Health (U01MH109539, R01MH085521, U01MH105641, U01MH105666, U01MH105653, R01MH116037, R01MH085548, R01MH104964, R01MH094145, MH105653, U01MH105578, R01MH124851, R01MH123451, DA05147)
  • National Institute on Drug Abuse (U01-DA024417, R01DA037904, R01DA024417, R01DA005147, R01DA036216, R37DA005147)
  • National Human Genome Research Institute (U54HG003067, R01HG007022)
  • National Institute of Neurological Disorders and Stroke (P30-NS069329)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD105351)
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, risk genes, GRIN2A, GRIA3, NMDA receptor, AMPA receptors, glutamatergic system, synapses, neurodevelopmental disorders, autism spectrum disorder, epilepsy, schizophrenia pathogenesis
MeSH terms
Humans, Mutation, Schizophrenia, Case-Control Studies, Receptors, N-Methyl-D-Aspartate, Genetic Predisposition to Disease, Exome, Neurodevelopmental Disorders

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.

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