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Cited by 2,964Schizophrenia research and treatmentGenetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and Animals

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Open access
Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B., Bryois, Julien, Chen, Chia-Yen +609 more·2022·Nature
DOI 10.1038/s41586-022-04434-5PMC PMC9392466

Published version of a preprint

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Abstract

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies. A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

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Crossref · 10.1038/s41586-022-04434-5

Cites

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Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Fine-mapped candidate genes were also enriched for genes implicated by rare variants in neurodevelopmental disorders.

    “and were also enriched for genes implicated by such variants in neurodevelopmental disorders”
    Quote in the paperSubstantial claim
  • Findingown data

    The two-stage genome-wide association study found common variant associations at 287 separate genomic loci.

    “we report common variant associations at 287 distinct genomic loci”
    • Also stated in: § Association Meta-Analysis · plain
      “identified 342 LD-independent significant SNPS (Supplementary Table 2) located in 287 loci”
    Quote in the paperSubstantial claim
  • Findingcitation

    In the European-ancestry sample, SNP-based heritability was estimated to be 0.24 with SE 0.007.

    “In the EUR sample, the SNP-based heritability (h2SNP) (i.e. proportion of variance in liability attributable to all measured SNPs) was estimated13 to be 0.24 (SE 0.007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Zeng, J. et al. Widespread signatures of natural selection across human complex traits and functional genomic categories. Nat. Commun. 12, 1164 (2021). source

      Not checked in the free run.

  • Findingown data

    The study shows convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders.

    “show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders”
    Quote in the paperSubstantial claim
  • Findingown data

    The Extended GWAS identified 342 LD-independent significant SNPs located in 287 loci.

    “identified 342 LD-independent significant SNPS (Supplementary Table 2) located in 287 loci”
    Quote in the paperSubstantial claim
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingown data

    The primary genome-wide association study identified 313 independent SNPs exceeding genome-wide significance, spanning 263 distinct loci.

    “This primary GWAS identified 313 independent SNPs (linkage disequilibrium (LD) r2 < 0.1) that exceeded genome-wide significance (p<5×10−8) (Extended Data Figure 1; Supplementary Table 1), spanning 263 distinct loci.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The associations were concentrated in genes expressed in central nervous system neurons, both excitatory and inhibitory, and not in other tissues or cell types.

    “Associations were concentrated in genes expressed in CNS neurons, excitatory and inhibitory, but not other tissues or cell types.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All 24 associated gene ontology classifications were relevant to neuronal function, including development, differentiation, and synaptic transmission, and involved multiple cellular components including ion channels, synapses, and axon and dendritic annotations.

    “All were relevant to neuronal function including development, differentiation, and synaptic transmission, and involved multiple cellular components including ion channels, synapses, and both axon and dendritic annotations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Using SynGO, conditionally significant annotations were mainly within postsynaptic terms, although enrichment was also found for genes involved in synaptic organisation and signalling.

    “we further examined the synaptic signal and found that conditionally significant annotations were mainly within postsynaptic terms (Supplementary Tables 8, 9), although enrichment was also found for genes involved in synaptic organisation and signalling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For 33 regions, the 95% credible set contained 5 or fewer SNPs, and for 9 regions it contained only a single SNP.

    “For 33 regions, the 95% credible set contained 5 or fewer SNPs (Supplementary Table 11c) and for 9, only a single SNP.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Using the all-ancestry primary GWAS as discovery, polygenic risk score analysis explained a median of 0.073 of variance in liability for SNPs with GWAS p<0.05, and 0.024 when restricted to genome-wide significant SNPs.

    “Using the all ancestry primary GWAS as the discovery sample, polygenic risk score (PRS) analysis explained a median of 0.073 of variance in liability (SNPs with GWAS p<0.05), and 0.024 when restricted to genome-wide significant SNPs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Compared with the lowest centile of PRS, the highest centile has an odds ratio for schizophrenia of 39 (95% CI 29-53), and 5.6 (CI 4.9-6.5) when the top centile is compared with the remaining 99%.

    “Compared to the lowest centile of PRS, the highest centile of PRS has an OR for schizophrenia of 39 (95% CI=29–53), and 5.6 (CI 4.9–6.5) when the top centile is compared with the remaining 99% of individuals”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Associations were enriched in genes with high expression in excitatory glutamatergic neurons from cerebral cortex and hippocampus, including pyramidal CA1 and CA3 cells and dentate gyrus granule cells, and also in human cortical inhibitory interneurons.

    “we found associations were enriched in genes with high expression in excitatory glutamatergic neurons from cerebral cortex and hippocampus (pyramidal CA1 and CA3 cells, and granule cells of dentate gyrus) and also human cortical inhibitory interneurons”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Using a different dataset of 265 cell types in the mouse central and peripheral nervous system, very strong enrichments were seen for genes expressed in excitatory glutamatergic neurons of the cortex, especially deep layers, and hippocampus, but also amygdala.

    “Very strong enrichments were again seen for genes expressed in excitatory glutamatergic neurons of the cortex (especially the deep layers) and hippocampus but also the amygdala”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    rs4766428 has posterior probability greater than 0.99, is the only credible SNP in a locus containing 25 genes, and is located within ATP2A2.

    “We highlight rs4766428 (PP>0.99) which is the only credible SNP in a locus that contains 25 genes and is located within ATP2A2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    PRS explained most variance in liability in cohorts of European ancestry and in samples likely to include the most severe cases, such as hospitalised patients or those treated with clozapine.

    “PRS explained most variance in liability in cohorts of European ancestry (again a result of the ancestry composition of the GWAS9) and in samples which by ascertainment likely include the most severe cases (hospitalised patients or those treated with clozapine)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Lam, M. et al. Comparative genetic architectures of schizophrenia in East Asian and European populations. Nat. Genet. 51, 1670–1678 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Highly significant enrichments were seen for other neuronal populations, including inhibitory medium spiny neurones in striatum, excitatory and inhibitory neurons from midbrain, thalamus and hindbrain, and inhibitory cells from hippocampus.

    “Highly significant enrichments were also seen for other neuronal populations, including as above, inhibitory medium spiny neurones in striatum, but also both excitatory and inhibitory neurons from the midbrain, thalamus and hindbrain, and inhibitory cells from the hippocampus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among 70 FINEMAP prioritised genes, 64 protein-coding, 16 genes were based on non-synonymous or UTR variants.

    “Among the 70 FINEMAP prioritised genes (64 protein-coding) were 16 genes (protein-coding by definition) based on NS or UTR variants”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    For almost all cohorts, PRS had more explanatory power when based on risk alleles from the larger combined-ancestry GWAS than from the matched-ancestry GWAS, and this effect was strongest for non-European samples.

    “For almost all cohorts, PRS had more explanatory power based on risk alleles derived from the larger combined ancestry GWAS than from the matched ancestry GWAS; given the ancestry specific sample sizes, unsurprisingly9, this effect was strongest for the non-EUR samples”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Lam, M. et al. Comparative genetic architectures of schizophrenia in East Asian and European populations. Nat. Genet. 51, 1670–1678 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    After removing duplicates, there were 55 SMR/SMR-Hi-C prioritised genes, of which 46 were protein-coding.

    “After removing duplicates, there were 55 SMR/SMR-Hi-C prioritised genes (Supplementary Table 12) of which 46 were protein-coding.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Genes where putatively causal eQTLs captured high FINEMAP posterior probability, greater than 95%, include ACE with schizophrenia under-expression, DCLK3 with under-expression, and SNAP91 with over-expression.

    “Genes where putatively causal eQTLs captured a particularly high FINEMAP PP (>95%) (Supplementary Table 17g) include ACE encoding angiotensin converting enzyme, the target of a major class of anti-hypertensive drugs (schizophrenia under-expression), DCLK3 encoding a neuroprotective kinase29(schizophrenia under-expression) and SNAP91 (discussed below; schizophrenia over-expression).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Galvan, L. et al. The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin. Brain 141, 1434–1454 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Multiple prioritised genes encode receptors and ion channels, including voltage-gated calcium and chloride channels CACNA1C and CLCN3, metabotropic receptors GRM1 and GABBR2, and the ligand-gated NMDA receptor subunit GRIN2A.

    “Multiple genes encode receptors and ion channels, including voltage-gated calcium and chloride channels (CACNA1C, CLCN3), metabotropic receptors (glutamate (GRM1) and GABA (GABBR2)), and the ligand-gated NMDA receptor subunit (GRIN2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of the 106 proteins encoded by prioritised genes, 15 have synaptic annotations: 7 postsynaptic, 5 both pre- and post-synaptic, 2 presynaptic, and 1 not mapped to a specific compartment.

    “Of the 106 proteins encoded, 15 have synaptic annotations (Supplementary Table 19); 7 postsynaptic, 5 both pre- and post- synaptic, 2 presynaptic, and 1 gene is not mapped to any specific compartment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Missense and UTR variants prioritised IRF3, while KLF6 was highlighted by three variants in the 3' UTR.

    “Missense and UTR variants prioritised interferon regulatory factor 3 (IRF3 while KLF6, a transcription factor, was highlighted by three variants in the 3’ UTR.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Other prioritised genes involve proteins in endocytosis such as SNAP91, synaptic organisation and differentiation such as DLGAP2, LRRC4B, GPM6A, and PAK6, including PTPRD interacting with postsynaptic cell adhesion molecules such as IL1RAPL1, and modulation of chemical transmission such as MAPK3, DCC, CLCN3, and DLGAP2.

    “Others involve proteins playing a role in endocytosis (SNAP91), synaptic organisation and differentiation (DLGAP2, LRRC4B, GPM6A, PAK6), including PTPRD a receptor protein tyrosine phosphatase presynaptic organizer that trans‐synaptically interacts with multiple postsynaptic cell adhesion molecules (e.g. IL1RAPL1), and modulation of chemical transmission (MAPK3, DCC, CLCN3, DLGAP2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both sets of SCHEMA genes were enriched for common variant associations, as were more weakly associated SCHEMA genes down to uncorrected P<0.001.

    “We found both sets of genes were enriched for common variant associations, as were more weakly associated SCHEMA genes down to uncorrected P<0.001”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    FOXP1 and MYT1L are associated with both developmental disorder and autism spectrum disorder and met the fine-mapping prioritisation criteria in the core PGC dataset.

    “FOXP1 and MYT1L are associated with both DD and ASD and met our fine-mapping prioritisation criteria in the core PGC dataset”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Enrichment of common variant associations was restricted to genes expressed in central nervous system neurons, both excitatory and inhibitory, and to fundamental biological processes related to neuronal function.

    “Enrichment of common variant associations was restricted to genes expressed in CNS neurons, both excitatory and inhibitory, and fundamental biological processes related to neuronal function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study performed the largest GWAS of schizophrenia to date and identified a substantial increase in the number of associated loci.

    “We have performed the largest GWAS of schizophrenia to date and in doing so, identify a substantial increase in the number of associated loci.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    RERE was prioritised by SMR and is associated with developmental disorder.

    “RERE was prioritised by SMR and is associated with DD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SNPs mapping to STAG1 and FAM120A had cumulative FINEMAP posterior probabilities of 0.88 and 0.72 respectively.

    “SNPs mapping to these genes had cumulative FINEMAP PP of 0.88 and 0.72 respectively”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Schizophrenia has an estimated heritability of 60-80%, and a large portion of that heritability is due to common risk alleles.

    “Schizophrenia has a heritability of 60–80%, much of which is attributable to common risk alleles.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A large share of between-person variation in schizophrenia risk is genetic and involves many common alleles, rare copy number variants, and rare coding variants.

    “Much of the between-individual variation in risk is genetic, involving large numbers of common alleles,5 rare copy number variants (CNVs)6, and rare coding variants (RCVs)7,8.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009). source

      Not checked in the free run.

    • cites [6] Pocklington, A. J. et al. Novel findings from CNVs implicate inhibitory and excitatory signaling complexes in schizophrenia. Neuron 86, 1203–1214 (2015). source

      Not checked in the free run.

    • cites [7] 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.

    Premisecitation

    A previous genome-wide association study reported 176 genomic loci containing common alleles associated with schizophrenia.

    “A recent genome-wide association study (GWAS) reported 176 genomic loci containing common alleles associated with schizophrenia9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Lam, M. et al. Comparative genetic architectures of schizophrenia in East Asian and European populations. Nat. Genet. 51, 1670–1678 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in ATP2A2 cause Darier Disease, which co-segregates with bipolar disorder in several multiplex pedigrees and is associated with bipolar disorder and schizophrenia at a population level.

    “Mutations in ATP2A2 cause Darier Disease21, which co-segregates with bipolar disorder in several multiplex pedigrees and is associated with bipolar disorder and schizophrenia at a population level22.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Sakuntabhai, A. et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat. Genet. 21, 271–277 (1999). source

      Not checked in the free run.

    • cites [22] Cederlöf, M. et al. The association between Darier disease, bipolar disorder, and schizophrenia revisited: a population-based family study. Bipolar Disord. 17, 340–344 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ATP2A2 encodes a sarcoplasmic/endoplasmic reticulum calcium pump, suggesting that its role in schizophrenia pathogenesis may involve regulating neuronal cytoplasmic calcium levels.

    “ATP2A2 encodes a sarcoplasmic/endoplasmic reticulum calcium pump, suggesting that its role in schizophrenia pathogenesis may be through regulating neuronal cytoplasmic calcium levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The overall findings across datasets are consistent with schizophrenia being primarily a disorder of neuronal function, but do not suggest that pathology is restricted to a circumscribed brain region.

    “Overall, the findings across all the datasets are consistent with the hypothesis that schizophrenia is primarily a disorder of neuronal function, but do not suggest that pathology is restricted to a circumscribed brain region.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The SCHEMA companion paper identified 32 genes with damaging ultra-rare mutations associated with schizophrenia at FDR<0.05, including 10 at exome-wide significance.

    “The Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) consortium (companion paper) identified 32 genes with damaging ultra-rare mutations associated with schizophrenia (FDR<0.05), including 10 at exome-wide significance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites companion paper

      Not checked in the free run.

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

    Premisecitation

    Convergences between rare variants and fine-mapped GWAS signals have been previously observed in other traits.

    “Convergences between rare variants and fine-mapped GWAS signals have been previously observed in other traits e.g.,34,35”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] 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 [35] Luo, Y. et al. Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7. Nat. Genet. 49, 186–192 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SP4 is a transcription factor highly expressed in brain, is regulated by NMDA transmission, and regulates NMDA receptor abundance.

    “SP4, a transcription factor highly expressed in brain and which is regulated by NMDA transmission, and also regulates NMDA receptor abundance37.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Singh, T., Neale, B. M. & Daly, M. J. Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia. Preprint at https://doi.org/10.1101/2020.09.18.20192815 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Abnormal neuronal function in schizophrenia is not confined to a small number of brain structures, which might explain its diverse psychopathology, broad cognitive impairments, and lack of regional specificity in neuroimaging.

    “This suggests that abnormal neuronal function in schizophrenia is not confined to a small number of brain structures, which in turn might explain its diverse psychopathology, association with a broad range of cognitive impairments, and lack of regional specificity in neuroimaging measures1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Owen, M. J., Sawa, A. & Mortensen, P. B. Schizophrenia. Lancet 388, 86–97 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Disrupted neuronal function in schizophrenia is unlikely to be restricted to the synapse, but the concentration of associations in genes with pre- and post-synaptic locations and functions related to synaptic organisation, differentiation, and transmission points to the pathophysiological importance of these neuronal compartments and functions.

    “Disrupted neuronal function in schizophrenia is unlikely to be restricted to the synapse, but the concentration of associations in genes with pre- and post-synaptic locations, and with functions related to synaptic organisation, differentiation and transmission, point to the pathophysiological importance of these neuronal compartments and their attendant functions.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The authors used the HEIDI test to remove SMR associations likely caused by linkage disequilibrium between schizophrenia-associated variants and eQTLs.

    “We applied the HEIDI test37 to filter out SMR associations (PHEIDI < 0.01) due to linkage disequilibrium between SCZ-associated variants and eQTLs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Singh, T., Neale, B. M. & Daly, M. J. Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia. Preprint at https://doi.org/10.1101/2020.09.18.20192815 (2020). source

      Not checked in the free run.

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

    Study design and conductown data

    The authors used FUSION and EpiXcan to check whether the SMR results were robust.

    “We used FUSION44 and EpiXcan45 as tests of robustness of the SMR results.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Lam, M. et al. RICOPILI: Rapid Imputation for COnsortias PIpeLIne. Bioinformatics 36, 930–933 (2019). source

      Not checked in the free run.

    • cites [45] Purcell, S., Neale, B., Todd-Brown, K., Thomas, L. & Ferreira, M. A. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am. J. Hum. Genet. 81, 559–575 (2007). 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 conductnone given

    Study protocols were approved by the institutional review board at each recruitment centre, and informed consent and permission to share data were obtained from all subjects.

    “The study protocols were approved by the institutional review board at each centre involved with recruitment. Informed consent and permission to share the data were obtained from all subjects”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The authors limited fine-mapping to regions that achieved genome-wide significance in the core PGC GWAS, since the method needs all markers in a region.

    “As fine-mapping requires data from all markers in the region36 we only performed fine-mapping on regions that attained genome-wide significance (GWS) in the core PGC GWAS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Cheng, Y. et al. Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism. Nat. Commun. 12, 964 (2021). source

      Not checked in the free run.

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

    Study design and conductown data

    The authors applied a Bonferroni correction to p-values within each gene set analysis.

    “Within each gene set analysis, p-values were corrected for multiple testing using the Bonferroni procedure.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Quality control parameters were adjusted until lambda GC was between 1.0 and 1.4 before inclusion of principal components and between 1.0 and 1.15 after inclusion of PCA covariates.

    “we evaluated the effectiveness of the primary technical and genomic quality control parameters on the genome-wide inflation of test statistics using the lambda GC (median)5 and as necessary made the QC parameters more stringent until this value was between 1.0 and 1.4 (before inclusion of principal components as covariates) and/or between 1.0 and 1.15 after inclusion of PCA covariates.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The analysis controlled for 10,360 genes with detectable brain expression to distinguish synaptic signals from general brain expression.

    “We controlled for a set of 10,360 genes with detectable expression in brain tissue measured as Fragments Per Kilobase of transcript per Million mapped reads (FPKM)32 to detect synaptic signals above signals simply reflecting the property of brain expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014). source

      Not checked in the free run.

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

    Study design and conductcitation

    Technical quality control was applied to the core PGC cohorts using PGC standards, including thresholds for SNP and subject missingness, heterozygosity, case-control missingness, Hardy-Weinberg equilibrium, and Mendelian errors.

    “Technical Quality control was performed on the core PGC cohorts separately according to standards developed by the PGC3 including SNP missingness < 0.05 (before sample removal); subject missingness < 0.02; autosomal heterozygosity deviation (| Fhet | < 0.2); SNP missingness < 0.02 (after sample removal); difference in SNP missingness between cases and controls < 0.02; and SNP Hardy-Weinberg”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Momen, N. C. et al. Association between mental disorders and subsequent medical conditions. N. Engl. J. Med. 382, 1721–1731 (2020). source

      Not checked in the free run.

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

    Study design and conductown data

    Principal component analysis and relatedness checking were performed, and pairs of subjects with PIHAT greater than 0.2 had one member removed at random.

    “We performed PCA for all 90 cohorts separately using SNPs with high imputation quality (INFO >0.8), low missingness (<1%), MAF>0.05 and in relative linkage equilibrium (LD) after 2 iterations of LD pruning (r2 < 0.2, 200 SNP windows).”
    Quote in the paperSubstantial claim
46 of 46

  • The paper relies on this without support.

    The causal variants driving the reported GWAS associations and the biological consequences of those variants are largely unknown.

    “but the causal variants driving these associations and the biological consequences of these variants are largely unknown”
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?

  • Compared to GWAS of other psychiatric disorders in adults (e.g., major depressive disorder with more than 135,000 cases, or schizophrenia with more than 76,000 cases), the five retained GWAS of child neurodevelopmental disorders are relatively small and underpowered to detect robustly associated common genetic risk factors related to these disorders.

    “Compared to GWAS of other psychiatric disorders in adults (e.g., major depressive disorder with more than 135,000 cases 62 , or schizophrenia with more than 76,000 cases 63 ), the five retained GWAS of child neurodevelopmental disorders are relatively small and underpowered to detect robustly associated common genetic risk factors related to these disorders.”

    From Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review (2023) · cites this paper as [63]

  • Common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes.

    “suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes.”

    From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [3]

  • 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”

    From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [3]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting SNP counts for the deCODE meta-analysis

    Minor

    The methods say 1,249 variants were meta-analysed with deCODE, but the association-analysis section says deCODE results were obtained for 1,228 index SNPs. Both passages describe SNPs selected at the same association threshold for this step, without explaining the difference of 21.

  • Opposite LD thresholds used to describe independent SNPs

    Minor

    One methods passage calls variants LD-independent at r2 > 0.1, whereas the association-analysis definition requires r2 < 0.1. These thresholds describe opposite sides of the same cutoff.

2 of 2

Cites

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Research works printed but not linked: 2

  1. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016). · DOI · Paper page
  2. Võsa, U. et al. Large-scale cis- and trans-eQTL analysis identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat. Genet. 53, 1300–1310 (2021). · DOI · Paper page

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Trubetskoy, V., Pardiñas, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., Bryois, J., Chen, C.-Y., Dennison, C. A., Hall, L. S., Lam, M., Watanabe, K., Frei, O., Ge, T., Harwood, J. C., Koopmans, F., Magnusson, S., Richards, A. L., Sidorenko, J., Wu, Y., Zeng, J., Grove, J., Kim, M., Li, Z., Voloudakis, G., Zhang, W., Adams, M., Agartz, I., Atkinson, E. G., Agerbo, E., Al Eissa, M., Albus, M., Alexander, M., Alizadeh, B. Z., Alptekin, K., Als, T. D., Amin, F., Arolt, V., Arrojo, M., Athanasiu, L., Azevedo, M. H., Bacanu, S. A., Bass, N. J., Begemann, M., Belliveau, R. A., Bene, J., Benyamin, B., Bergen, S. E., Blasi, G., Bobes, J., Bonassi, S., Braun, A., Bressan, R. A., Bromet, E. J., Bruggeman, R., Buckley, P. F., Buckner, R. L., Bybjerg-Grauholm, J., Cahn, W., Cairns, M. J., Calkins, M. E., Carr, V. J., Castle, D., Catts, S. V., Chambert, K. D., Chan, R. C. K., Chaumette, B., Cheng, W., Cheung, E. F. C., Chong, S. A., Cohen, D., Consoli, A., Cordeiro, Q., Costas, J., Curtis, C., Davidson, M., Davis, K. L., de Haan, L., Degenhardt, F., DeLisi, L. E., Demontis, D., Dickerson, F., Dikeos, D., Dinan, T., Djurovic, S., Duan, J., Ducci, G., Dudbridge, F., Eriksson, J. G., Fañanás, L., Faraone, S. V., Fiorentino, A., Forstner, A., Frank, J., Freimer, N. B., Fromer, M., Frustaci, A., Gadelha, A., Genovese, G., Gershon, E. S., Giannitelli, M., Giegling, I., Giusti-Rodríguez, P., Godard, S., Goldstein, J. I., González Peñas, J., González-Pinto, A., Gopal, S., Gratten, J., Green, M. F., Greenwood, T. A., Guillin, O., Gülöksüz, S., Gur, R. E., Gur, R. C., Gutiérrez, B., Hahn, E., Hakonarson, H., Haroutunian, V., Hartmann, A. M., Harvey, C., Hayward, C., Henskens, F. A., Herms, S., Hoffmann, P., Howrigan, D. P., Ikeda, M., Iyegbe, C., Joa, I., Julià, A., Kähler, A. K., Kam-Thong, T., Kamatani, Y., Karachanak-Yankova, S., Kebir, O., Keller, M. C., Kelly, B. J., Khrunin, A., Kim, S.-W., Klovins, J., Kondratiev, N., Konte, B., Kraft, J., Kubo, M., Kučinskas, V., Kučinskiene, Z. A., Kusumawardhani, A., Kuzelova-Ptackova, H., Landi, S., Lazzeroni, L. C., Lee, P. H., Legge, S. E., Lehrer, D. S., Lencer, R., Lerer, B., Li, M., Lieberman, J., Light, G. A., Limborska, S., Liu, C.-M., Lönnqvist, J., Loughland, C. M., Lubinski, J., Luykx, J. J., Lynham, A., Macek, M., Mackinnon, A., Magnusson, P. K. E., Maher, B. S., Maier, W., Malaspina, D., Mallet, J., Marder, S. R., Marsal, S., Martin, A. R., Martorell, L., Mattheisen, M., McCarley, R. W., McDonald, C., McGrath, J. J., Medeiros, H., Meier, S., Melegh, B., Melle, I., Mesholam-Gately, R. I., Metspalu, A., Michie, P. T., Milani, L., Milanova, V., Mitjans, M., Molden, E., Molina, E., Molto, M. D., Mondelli, V., Moreno, C., Morley, C. P., Muntané, G., Murphy, K. C., Myin-Germeys, I., Nenadić, I., Nestadt, G., Nikitina-Zake, L., Noto, C., Nuechterlein, K. H., O’Brien, N. L., O’Neill, F. A., Oh, S.-Y., Olincy, A., Ota, V. K., Pantelis, C., Papadimitriou, G. N., Parellada, M., Paunio, T., Pellegrino, R., Periyasamy, S., Perkins, D. O., Pfuhlmann, B., Pietiläinen, O., Pimm, J., Porteous, D., Powell, J., Quattrone, D., Quested, D., Radant, A. D., Rampino, A., Rapaport, M. H., Rautanen, A., Reichenberg, A., Roe, C., Roffman, J. L., Roth, J., Rothermundt, M., Rutten, B. P. F., Saker-Delye, S., Salomaa, V., Sanjuan, J., Santoro, M. L., Savitz, A., Schall, U., Scott, R. J., Seidman, L. J., Sharp, S. I., Shi, J., Siever, L. J., Sigurdsson, E., Sim, K., Skarabis, N., Slominsky, P., So, H.-C., Sobell, J. L., Söderman, E., Stain, H. J., Steen, N. E., Steixner-Kumar, A. A., Stögmann, E., Stone, W. S., Straub, R. E., Streit, F., Strengman, E., Stroup, T. S., Subramaniam, M., Sugar, C. A., Suvisaari, J., Svrakic, D. M., Swerdlow, N. R., Szatkiewicz, J. P., Ta, T. M. T., Takahashi, A., Terao, C., Thibaut, F., Toncheva, D., Tooney, P. A., Torretta, S., Tosato, S., Tura, G. B., Turetsky, B. I., Üçok, A., Vaaler, A., van Amelsvoort, T., van Winkel, R., Veijola, J., Waddington, J., Walter, H., Waterreus, A., Webb, B. T., Weiser, M., Williams, N. M., Witt, S. H., Wormley, B. K., Wu, J. Q., Xu, Z., Yolken, R., Zai, C. C., Zhou, W., Zhu, F., Zimprich, F., Atbaşoğlu, E. C., Ayub, M., Benner, C., Bertolino, A., Black, D. W., Bray, N. J., Breen, G., Buccola, N. G., Byerley, W. F., Chen, W. J., Cloninger, C. R., Crespo-Facorro, B., Donohoe, G., Freedman, R., Galletly, C., Gandal, M. J., Gennarelli, M., Hougaard, D. M., Hwu, H.-G., Jablensky, A. V., McCarroll, S. A., Moran, J. L., Mors, O., Mortensen, P. B., Müller-Myhsok, B., Neil, A. L., Nordentoft, M., Pato, M. T., Petryshen, T. L., Pirinen, M., Pulver, A. E., Schulze, T. G., Silverman, J. M., Smoller, J. W., Stahl, E. A., Tsuang, D. W., Vilella, E., Wang, S.-H., Xu, S., Indonesia Schizophrenia Consortium, Dai, N., Wenwen, Q., Wildenauer, D. B., Agiananda, F., Amir, N., Antoni, R., Arsianti, T., Asmarahadi, A., Diatri, H., Djatmiko, P., Irmansyah, I., Khalimah, S., Kusumadewi, I., Kusumaningrum, P., Lukman, P. R., Nasrun, M. W., Safyuni, N. S., Prasetyawan, P., Semen, G., Siste, K., Tobing, H., Widiasih, N., Wiguna, T., Wulandari, D., Evalina, N., Hananto, A. J., Ismoyo, J. H., Marini, T. M., Henuhili, S., Reza, M., Yusnadewi, S., PsychENCODE, Abyzov, A., Akbarian, S., Ashley-Koch, A., van Bakel, H., Breen, M., Brown, M., Bryois, J., Carlyle, B., Charney, A., Coetzee, G., Crawford, G., Dracheva, S., Emani, P., Farnham, P., Fromer, M., Galeev, T., Gandal, M., Gerstein, M., Giase, G., Girdhar, K., Goes, F., Grennan, K., Gu, M., Guerra, B., Gursoy, G., Hoffman, G., Hyde, T., Jaffe, A., Jiang, S., Jiang, Y., Kefi, A., Kim, Y., Kitchen, R., Knowles, J. A., Lay, F., Lee, D., Li, M., Liu, C., Liu, S., Mattei, E., Navarro, F., Pan, X., Peters, M. A., Pinto, D., Pochareddy, S., Polioudakis, D., Purcaro, M., Purcell, S., Pratt, H., Reddy, T., Rhie, S., Roussos, P., Rozowsky, J., Sanders, S., Sestan, N., Sethi, A., Shi, X., Shieh, A., Swarup, V., Szekely, A., Wang, D., Warrell, J., Weissman, S., Weng, Z., White, K., Wiseman, J., Witt, H., Won, H., Wood, S., Wu, F., Xu, X., Yao, L., Zandi, P., Psychosis Endophenotypes International Consortium, Arranz, M. J., Bakker, S., Bender, S., Bramon, E., Collier, D. A., Crepo-Facorro, B., Hall, J., Iyegbe, C., Kahn, R., Lawrie, S., Lewis, C., Lin, K., Linszen, D. H., Mata, I., McIntosh, A., Murray, R. M., Ophoff, R. A., van Os, J., Powell, J., Rujescu, D., Walshe, M., Weisbrod, M., The SynGO Consortium, Achsel, T., Andres-Alonso, M., Bagni, C., Bayés, À., Biederer, T., Brose, N., Brown, T. C., Chua, J. J. E., Coba, M. P., Cornelisse, L. N., de Jong, A. P. H., de Juan-Sanz, J., Dieterich, D. C., Feng, G., Goldschmidt, H. L., Gundelfinger, E. D., Hoogenraad, C., Huganir, R. L., Hyman, S. E., Imig, C., Jahn, R., Jung, H., Kaeser, P. S., Kim, E., Koopmans, F., Kreutz, M. R., Lipstein, N., MacGillavry, H. D., Malenka, R., McPherson, P. S., O’Connor, V., Pielot, R., Ryan, T. A., Sahasrabudhe, D., Sala, C., Sheng, M., Smalla, K.-H., Smit, A. B., Südhof, T. C., Thomas, P. D., Toonen, R. F., van Weering, J. R. T., Verhage, M., Verpelli, C., Adolfsson, R., Arango, C., Baune, B. T., Belangero, S. I., Børglum, A. D., Braff, D., Bramon, E., Buxbaum, J. D., Campion, D., Cervilla, J. A., Cichon, S., Collier, D. A., Corvin, A., Curtis, D., Forti, M. D., Domenici, E., Ehrenreich, H., Escott-Price, V., Esko, T., Fanous, A. H., Gareeva, A., Gawlik, M., Gejman, P. V., Gill, M., Glatt, S. J., Golimbet, V., Hong, K. S., Hultman, C. M., Hyman, S. E., Iwata, N., Jönsson, E. G., Kahn, R. S., Kennedy, J. L., Khusnutdinova, E., Kirov, G., Knowles, J. A., Krebs, M.-O., Laurent-Levinson, C., Lee, J., Lencz, T., Levinson, D. F., Li, Q. S., Liu, J., Malhotra, A. K., Malhotra, D., McIntosh, A., McQuillin, A., Menezes, P. R., Morgan, V. A., Morris, D. W., Mowry, B. J., Murray, R. M., Nimgaonkar, V., Nöthen, M. M., Ophoff, R. A., Paciga, S. A., Palotie, A., Pato, C. N., Qin, S., Rietschel, M., Riley, B. P., Rivera, M., Rujescu, D., Saka, M. C., Sanders, A. R., Schwab, S. G., Serretti, A., Sham, P. C., Shi, Y., St Clair, D., Stefánsson, H., Stefansson, K., Tsuang, M. T., van Os, J., Vawter, M. P., Weinberger, D. R., Werge, T., Wildenauer, D. B., Yu, X., Yue, W., Holmans, P. A., Pocklington, A. J., Roussos, P., Vassos, E., Verhage, M., Visscher, P. M., Yang, J., Posthuma, D., Andreassen, O. A., Kendler, K. S., Owen, M. J., Wray, N. R., Daly, M. J., Huang, H., Neale, B. M., Sullivan, P. F., Ripke, S., Walters, J. T. R., O’Donovan, M. C., Schizophrenia Working Group of the Psychiatric Genomics Consortium, de Haan, L., van Amelsvoort, T., van Winkel, R., Gareeva, A., Sham, P. C., Shi, Y., St Clair, D., & van Os, J.
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Corresponding author
  • Ripke, Stephan
  • Walters, James T. R.
  • O’Donovan, Michael C.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2022-04-08
Volume
604
Issue
7906
Pages
502-508
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-022-04434-5
PMC
PMC9392466
OpenAlex
W4223520055
Semantic Scholar
5b68667ad8bf91c7b91a44dfca6564662b85eb17
Cited by
2,964
References
99
Citations by year
2026: 534 · 2025: 701 · 2024: 731 · 2023: 533 · 2022: 331 · 2021: 119 · 2020: 12
FWCI
377.30
Type
journal article
Language
en
Open access
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Funders
  • Johns Hopkins University
  • Fundación Alicia Koplowitz (777394, SAM16PE07CP1, PI19/024, PI16/02012, B2017/BMD-3740 AGES-CM-2)
  • South London and Maudsley NHS Foundation Trust
  • National Alliance for Research on Schizophrenia and Depression (667302, 728018, 602805)
  • Mental Health Research UK (G0901310, G1100583)
  • Wellcome Trust (085475/Z/08/Z, 085475, MR/L010305/1, 777394, 085475/B/08/Z, 223273)
  • Broad Institute
  • National Institute for Health and Care Research (NIHR200756, PDA/02/06/016)
  • Academy of Medical Sciences (AMS-SGCL5-Mondelli)
  • King's College London
  • University College London
  • European Commission (747429, 248828, 2014‐2020, H2020 Program, EU-H2020, CZ.02.1.01, B2017/BMD-3740 AGES-CM-2, HORIZON2020, H2020, 728018, 248778, 667302, 777394, 847776, 115916, 602805, 283798)
  • Cardiff University (MR/L010305/1, G0800509)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2010/08968- 6, 14/07280-1, 2014/, 11/50740-5, 07/58736-1, 2011/, 16/04983-7, Code 001)
  • National Natural Science Foundation of China (XDB38000000, CZ.02, 31525014, 91731303, 32041008, 2017SHZDZX01, 31961130380, 31771388)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ((Code 001), 2011/50740-5)
  • Chinese Academy of Sciences (2017SHZDZX01, XDB38000000, QYZDJ-SSW-SYS009)
  • Lundbeckfonden (R155-2014-1724, R204-2015-4129, R341-2020-222, R248‐2017‐2003, R24-2008-3243, R364-2021-85)
  • Ministerio de Ciencia e Innovación (728018)
  • Shanghai Jiao Tong University
  • Norges Forskningsråd (283798, #248980, 248828, 262656, 223273, 248778, 273 291, B2017/BMD-3740 AGES-CM-2, 777394)
  • Centro de Investigación Biomédica en Red de Salud Mental (B2017/BMD‐3740 AGES‐CM‐2, AGES-CM-2, B2017/BMD-3740)
  • University College London Hospitals NHS Foundation Trust
  • Innovative Medicines Initiative (AIMS-2- TRIALS, 115916, H2020, 777394)
  • Nemzeti Kutatási Fejlesztési és Innovációs Hivatal
  • Qingdao University
  • National Institutes of Health (NMRC/TCR/003/2008, 223273, 2017SHZDZX01, B2017/BMD-3740 AGES-CM-2, 777394, H2020)
  • Horizon 2020 Framework Programme (115916, 667302, 777394, EU‐H2020, # 847776, 728018)
  • Stanley Center for Psychiatric Research, Broad Institute
  • Medical Research Council (G1100583, G0901310, EU H2020, 777394, MR/L010305/1, MC_UU_00007/10, G0800509, MR/W020238/1, NIHR200756)
  • Economic and Social Research Council
  • National Medical Research Council (NMRC/TCR/003/2008, NMRC/TCR/003)
  • Instituto de Salud Carlos III (PI16/, PI16/02012, SAM16PE07CP1, 728018, B2017/BMD-3740 AGES-CM-2, PI19/024, H2020)
  • European Regional Development Fund (02.1.01/0.0/0.0, 2014-2020’, H2020, 667302, CZ.02, CZ.02.1.01, CZ.02.1.01/0.0, CZ.02.1.01/0.0/0.0, B2017/BMD-3740 AGES-CM-2, 728018, B2017/BMD-3740)
  • National Institute of Mental Health (U01MH109514, R01MH119243, K01MH121659, U01MH109536, R01MH116281, R01MH101519, B2017/BMD-3740 AGES-CM-2, NMRC/TCR/003/2008, 777394, R01MH124873, R01MH106575)
  • National Institute of Neurological Disorders and Stroke (R37NS036715)
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 › Genetic Mapping and Diversity in Plants and Animals
Keywords
schizophrenia, genome-wide association study, fine mapping, common genetic variants, GRIN2A, Sp4, neurodevelopmental disorders, excitatory and inhibitory neurons, gene prioritization, synaptic transmission, schizophrenia pathophysiology
MeSH terms
Alleles, Humans, Schizophrenia, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genomics, Genome-Wide Association Study

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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 ›

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