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Cited by 879Genomic variations and chromosomal abnormalitiesSchizophrenia research and treatmentGenetics and Neurodevelopmental Disorders

De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia

Open access
Kirov, G, Pocklington, A J, Holmans, P, Ivanov, D, Ikeda, M, Ruderfer, D, Moran, J, Chambert, K +22 more·2012·Molecular Psychiatry
DOI 10.1038/mp.2011.154PMC PMC3603134
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Abstract

A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband-parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams-Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10⁻⁶. This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10⁻⁶) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10⁻⁸) postsynaptic signalling complexes. In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia.

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Written from the paper’s full text.

TL;DR

In 662 schizophrenia proband–parent trios, rare de novo CNVs were significantly more frequent in cases (5.1%) than in controls (2.2% Icelandic; 1.6% autism unaffected sibs), supporting a role for de novo CNVs in schizophrenia. Gene-set analyses implicated postsynaptic signalling complexes, especially NMDAR and ARC, with NMDAR enrichment also observed in independent case–control data.

Key findings

  • We identified 34 confirmed de novo CNVs, a rate of 5.1% in all cases and 5.5% in family-history-negative cases, compared with 2.2% in 2623 Icelandic controls (P=0.00015) and 1.6% in autism unaffected sibs (P=0.00008). Eight de novos occurred at known schizophrenia loci: 3q29, 15q11.2, 15q13.3 and 16p11.2.
  • Multiple de novos spanned DLG family MAGUK genes and EHMT1. In case–control data, after excluding known schizophrenia loci, CNVs at loci affected by case de novos occurred in 0.4% of cases (32/7907) versus 0.21% of controls (22/10,585), a twofold enrichment (Fisher one-tailed P=0.012); nominal associations were seen for DLG2 (P=0.02) and MSRA (P=0.03), with EHMT1 just missing threshold (P=0.055).
  • Case de novos were significantly enriched for the PSD proteome (P=1.72 × 10−6), NMDAR complex (P=4.24 × 10−6) and ARC complex (P=3.78 × 10−8). Conditional analyses indicated ARC and NMDAR explained the PSD and PSD-95 enrichments, while ARC and NMDAR enrichments were partially independent of each other.
  • In 18,492 subjects (7907 cases and 10,585 controls), case CNVs were enriched for NMDAR complex members (P=0.0015) but not ARC (P=0.14).

Methods

  • De novo CNV analysis used 662 Bulgarian parent–proband trios from 638 families; all cases met DSM-IV criteria for schizophrenia or schizoaffective disorder. Controls included 2623 Icelandic parent–offspring trios, autism unaffected sibs, and four case–control datasets (ISC, MGS, UK, Japanese) totaling 7907 independent cases and 10,585 controls.
  • Genotyping used Affymetrix 6.0 arrays; CNV calling used Genotyping Console, PennCNV and a modified MeZOD algorithm, with validation of putative de novos on custom Agilent SurePrint G3 CGH microarrays. A CNV was considered de novo if not spanned >50% of its length by a parental CNV.
  • Gene-set enrichment used logistic regression comparing case and control CNVs, adjusting for CNV size and total genes hit outside the gene set, with conditional regression and random-placement analyses; proteomic PSD/synaptic complex sets and Gene Ontology sets were tested.

Limitations

  • The paper states that not every observed case de novo CNV is likely pathogenic, that no individual novel CNV locus survived correction for multiple testing (Bonferroni threshold P=0.0025 for 19 loci), and that it cannot exclude effects across multiple functional sets.
  • The paper notes the case–control design has lower power than the de novo analysis; ARC was not significant in case–control data (P=0.14), and control de novo comparator sets were small (N=59 Icelandic, N=14 autism sibs), reducing power.
  • Evident from the text: Bulgarian cases did not have formal IQ assessments, and control datasets differed in genotyping platforms, although sensitivity analyses were performed to address platform-related bias.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/mp.2011.154

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 81 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2).

    “Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2).”
    Quote in the paperSubstantial claim
  • Findingown data

    Multiple de novos spanned genes encoding members of the DLG family of MAGUKs that are components of the postsynaptic density (PSD).

    “Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD).”
    Quote in the paperSubstantial claim
  • Findingown data

    De novo CNVs of known pathogenic significance in other genomic disorders were observed, including deletion at the TAR region on 1q21.1 and duplication at the WBS region at 7q11.23.

    “De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams–Beuren syndrome) region at 7q11.23.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The PSD enrichment was largely explained by enrichment for members of the NMDAR (P=4.24 × 10−6) and ARC (P=3.78 × 10−8) postsynaptic signalling complexes.

    “This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10−6) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10−8) postsynaptic signalling complexes.”
    Quote in the paperSubstantial claim
  • Findingown data

    Compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10−6).

    “systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10−6).”
    Quote in the paperSubstantial claim
  • May combine two claims. 28
  • Classified as probably not a substantial claim. 39

  • May combine two claims.

    Findingown data

    In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14).

    “In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Parents of probands with de novos were not older at the time of birth of their children than parents of probands without de novos.

    “Parents of probands with de novos were not older at the time of birth of their children than parents of probands without de novos: (27.8 vs 28.7 years, respectively, for fathers and 25.1 vs 25.1 years for mothers).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Probands with de novo CNVs did not differ from the rest of the probands regarding age at onset, average school results, and number of children.

    “Probands with de novo CNVs (Table 1) did not differ from the rest of the probands regarding age at onset (23.9 vs 23.8 years, P=0.9) and average school results (4.5 vs 4.7, P=0.5), and both sets of probands had similar numbers of children (0.52 vs 0.59, P=0.6).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The nonsignificant excess of paternal de novos was largely attributable to CNVs that were not generated by nonallelic homologous recombination.

    “The nonsignificant excess of paternal de novos was largely attributable to CNVs that were not generated by nonallelic homologous recombination, eight such events being observed on chromosomes of paternal origin compared with two on those that were maternally derived, although this is not significantly different from chance (P=0.06).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    More de novos occurred in the paternal than the maternal genome, but this was not statistically significant.

    “In those instances (21) where it was possible to determine the parental origin, more de novos occurred in the paternal (P=14) than the maternal (n=7) genome but this was not statistically significant (P=0.13).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    An excess of CNVs in cases was observed at deletions of the TAR region (P=0.11) and duplications of the WBS region (P=0.11), although not nominally significant.

    “we also observed an excess of CNVs in cases at two other loci known to be implicated in nonpsychiatric genomic disorders: deletions of the TAR (thrombocytopenia absent radius) region (P=0.11) and duplications of the WBS (Williams–Beuren syndrome) region (P=0.11)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Nominally significant associations were observed for deletions at DLG2 (P=0.02) and MSRA (P=0.03), whereas the EHMT1 locus just failed to reach this uncorrected threshold (P=0.055).

    “nominally significant associations (P uncorrected <0.05) were observed for deletions at DLG2 (P=0.02) and MSRA (P=0.03), whereas the EHMT1 locus just failed to reach this uncorrected threshold (P=0.055).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Significant enrichments were also observed in presynaptic vesicle and nuclear gene sets, but not after conditioning on the PSD, whereas the PSD gene set remained significantly enriched for hits after conditioning on the other sets individually or combined.

    “Significant enrichments were also observed in presynaptic vesicle and nuclear gene sets, but not after conditioning on the PSD (Pmin=0.66), whereas the PSD gene set remained significantly enriched for hits after conditioning on the other sets individually (Pmax=5.20 × 10−3) or combined (P=0.016) (Supplementary Section 13).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The de novo mutation rate in cases was higher than in both sets of controls (2.2%, P=0.00015 and 1.6%, P=0.00008), both of which had a similar rate (P=0.28).

    “The de novo mutation rate in our cases was higher than in both sets of controls (2.2%, P=0.00015 and 1.6%, P=0.00008, respectively), both of which had a similar rate (P=0.28) despite differences in the density of markers in the control genotyping platforms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Relative enrichment for de novos among cases was similar for large de novos >500 kb and small de novos <200 kb, and the overall size distribution of case de novos was not shifted towards smaller CNVs compared with control de novos.

    “relative enrichment for de novos among cases was similar for large de novos >500 kb (2.1% vs 0.8%, P=0.0014) as it was for small de novos <200 kb (2.3% vs 0.9%, P=0.0035), and the overall size distribution of case de novos was not shifted towards smaller CNVs (Figure 2 and Supplementary Table S3) compared with the control de novos.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of all GO categories, 'the synapse' (GO: 45202) was by two orders of magnitude the most significantly enriched (P=9.6 × 10−9) but most of this signal was attributable to the PSD gene set.

    “Of all categories, ‘the synapse' (GO: 45202) was by two orders of magnitude the most significantly enriched (P=9.6 × 10−9) (Supplementary Section 11 and Supplementary Table S4) but most of this signal was attributable to the PSD gene set (P=0.049 after removing PSD genes, Supplementary Table S5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    We identified 34 confirmed de novo CNVs, a rate in all cases of 5.1%.

    “We identified 34 confirmed de novo CNVs (Table 1), a rate in all cases of 5.1%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Even after excluding all CNVs at known schizophrenia loci represented among our de novos, we found rates of 0.4% (32/7907) in cases and 0.21% (22/10 585) in controls, a twofold enrichment (Fisher one-tailed P=0.012).

    “Even after an extremely conservative approach of excluding all CNVs (deletions and duplications) at known schizophrenia loci represented among our de novos (3q29, 15q11.2, 15q13.3 and 16p11.2), we found rates of 0.4% (32/7907) in cases and 0.21% (22/10 585) in controls, a twofold enrichment (Fisher one-tailed P=0.012).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The duplication/deletion ratios in the data sets were not significantly different; both sets of controls had a higher proportion of duplications than the cases.

    “These were not significantly different (P>0.35 for each sample), although contrary to the hypothesis of a selective loss of sensitivity to detect duplications, both sets of controls actually had a higher proportion of duplications (Icelandic=0.39, Autism controls=0.36) than the cases (0.29).”
    Quote in the paperSubstantial claim

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

    Findingcitation

    The de novo rate in those with a history of psychosis in a parent was lower (1.6%) than in those without such history (5.5%), although this was not statistically significant.

    “As in an earlier study,24 the de novo rate in those with a history of psychosis in a parent was lower (1.6%) than in those without such history (5.5%), although this was not statistically significant.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M . Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 2008; 40: 880–885. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Two previously documented schizophrenia loci, 15q11.2 and 15q13.3, were each found more than once as de novos.

    “It is notable that two previously documented schizophrenia loci, at 15q11.2 and 15q13.3, were each found more than once as de novos (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    EHMT1 and DLG2 were each represented by two de novo CNVs.

    “Two other loci were represented by two de novo CNVs each: EHMT1 (encoding Eu-HMTase1), a histone H3 Lys 9 (H3-K9) methyltransferase, and DLG2 (encoding discs, large homologue 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of the 34 Agilent-validated de novos, 91% (31) were rated highly suggestive and 9% (3) ambiguous.

    “Of the 34 Agilent-validated de novos, 91% (N=31) had been rated (using MeZOD) as highly suggestive, whereas only 9% (N=3) had been called as ambiguous.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At EHMT1, there were two de novos, three additional exonic CNVs in cases, and one in a control.

    “At EHMT1 we observed a total of two de novos, three additional exonic CNVs in cases and one in a control.”
    Quote in the paperSubstantial claim

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

    Findingcitation

    Our estimate of the de novo rate is comparable with more recent estimates in autism.

    “but is comparable with more recent estimates in autism.25, 29, 30”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] Sanders Stephan J, Ercan-Sencicek AG, Hus V, Luo R, Murtha Michael T, Moreno-De-Luca D et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 2011; 70: 863–885. source

      Not checked in the free run.

    • cites [29] Rujescu D, Ingason A, Cichon S, Pietiläinen OP, Barnes MR, Toulopoulou T et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet 2009; 18: 988–996. source

      Not checked in the free run.

    • cites [30] Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 2010; 466: 368–372. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Defects in NMDAR postsynaptic signalling and, possibly, ARC complexes play a significant role in the pathogenesis of schizophrenia.

    “Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: NMDAR and ARC complexes are important in synaptic plasticity and cognition.

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

    Premisecitation

    Pleiotropic effects are common; the same CNV often confers risk for a range of neurodevelopmental phenotypes including autism, mental retardation, attention deficit hyperactivity disorder and epilepsy.

    “Pleiotropic effects are common, the same CNV often conferring risk for a range of neurodevelopmental phenotypes including autism, mental retardation, attention deficit hyperactivity disorder and epilepsy”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Grozeva D, Kirov G, Ivanov D, Jones IR, Jones L, Green EK et al. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch Gen Psychiatry 2010; 67: 318–327. source

      Not checked in the free run.

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

    Premisecitation

    One large study has reported no overall excess of CNVs in cases at all.

    “indeed, one large study has reported no overall excess of CNVs in cases at all.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Levinson DF, Duan J, Oh S, Wang K, Sanders AR, Shi J et al. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry 2011; 168: 302–316. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Several individual CNV loci have been strongly implicated as risk factors for schizophrenia.

    “several individual CNV loci have been strongly implicated as risk factors for schizophrenia with high degrees of statistical confidence. These include deletions at 1q21.1, NRXN1, 3q29, 15q11.2, 15q13.3, 22q11.2 and duplications at VIPR2, 16p11.2, 16p13.1 and 15q11-q13.2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [4] Levinson DF, Duan J, Oh S, Wang K, Sanders AR, Shi J et al. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry 2011; 168: 302–316. source

      Not checked in the free run.

    • cites [5] Moreno-De-Luca D, Mulle JG, Kaminsky EB, Sanders SJ, Myers SM, Adam MP et al. Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. Am J Hum Genet 2010; 87: 618–630. source

      Not checked in the free run.

    • cites [6] Mulle JG, Dodd AF, McGrath JA, Wolyniec PS, Mitchell AA, Shetty AC et al. Microdeletions of 3q29 confer high risk for schizophrenia. Am J Hum Genet 2010; 87: 229–236. source

      Not checked in the free run.

    • cites [7] Stefansson H, Rujescu D, Cichon S, Pietilainen OPH, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236. source

      Not checked in the free run.

    • cites [8] Vacic V, McCarthy S, Malhotra D, Murray F, Chou H-H, Peoples A et al. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 2011; 471: 499–503. source

      Not checked in the free run.

    • cites [9] Ingason A, Kirov G, Giegling I, Hansen T, Isles AR, Jakobsen KD et al. Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness. Am J Psychiatry 2011; 168: 408–417. source

      Not checked in the free run.

    • cites [10] Ingason A, Rujescu D, Cichon S, Sigurdsson E, Sigmundsson T, Pietilainen OPH et al. Copy number variations of chromosome 16p13.1 region associated with schizophrenia. Mol Psychiatry 2011; 16: 17–25. source

      Not checked in the free run.

    • cites [11] Kirov G, Rujescu D, Ingason A, Collier DA, O'Donovan MC, Owen MJ . Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull 2009; 35: 851–854. source

      Not checked in the free run.

    • cites [12] McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 2009; 41: 1223–1227. source

      Not checked in the free run.

    • cites [13] Sebat J, Levy DL, McCarthy SE . Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet 2009; 25: 528–535. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    Many other risk CNV loci remain to be identified.

    “it is likely that many other risk CNV loci remain to be identified”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: All currently known risk CNVs are rare (control frequencies typically <0.001) and confer substantial effects on risk (odds ratios 3–30).
    • Rests on an assumption: The known risk CNVs occur in 2–3% of cases.

  • May combine two claims.

    Interpretationcitation

    The control rates were similar to those in our experimental group with an affected parent, suggesting that technical variation between our own and other studies does not make a major impact on our conclusions.

    “Finally, we note that the control rates were similar to those in our experimental group with an affected parent (who according to an earlier work24 do not have elevated rates of de novo mutation), suggesting that technical variation between our own and other studies does not make a major impact on our conclusions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M . Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 2008; 40: 880–885. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The marked elevation in the rate of de novo CNVs contrasts with the relatively modest elevation in the rate of CNVs seen in case-control studies, and suggests that sets of de novos might be more informative for gene-set enrichment analyses.

    “This marked elevation in the rate of de novo CNVs contrasts with the relatively modest elevation in the rate of CNVs seen in case–control studies,2, 4 and suggests that sets of de novos might be more informative for gene-set enrichment analyses.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] International Schizophrenia Consortium (ISC). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455: 237–241. source

      Not checked in the free run.

    • cites [4] Levinson DF, Duan J, Oh S, Wang K, Sanders AR, Shi J et al. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry 2011; 168: 302–316. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The most parsimonious interpretation is that our findings specifically implicate the PSD, although we cannot exclude the possibility of effects across multiple functional sets.

    “The most parsimonious interpretation is that our findings specifically implicate the PSD, although we cannot exclude the possibility of effects across multiple functional sets.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Early gene-set studies did not allow for important confounders, in particular the large size of genes implicated in brain function, and the conclusions that can be drawn are consequently unclear.

    “it has been noted that the early gene-set studies did not allow for important confounders, in particular the large size of genes implicated in brain function, and that the conclusions that can be drawn are consequently unclear.19”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Raychaudhuri S, Korn JM, McCarroll SA, Consortium TIS, Altshuler D, Sklar P et al. Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. PLoS Genet 2010; 6: pii: e1001097. source

      Not checked in the free run.

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

    Premisecitation

    There is little evidence that schizophrenia-associated CNVs confer risk for bipolar disorder.

    “there is little evidence that schizophrenia-associated CNVs confer risk for bipolar disorder.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Grozeva D, Kirov G, Ivanov D, Jones IR, Jones L, Green EK et al. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch Gen Psychiatry 2010; 67: 318–327. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The enrichments in the PSD, and the great majority of that in the synapse GO gene set, are because of the enrichments in ARC and NMDAR.

    “These findings suggest enrichments in the PSD, and the great majority of that in the synapse GO gene set, is because of the enrichments in ARC and NMDAR”
    Quote in the paperSubstantial claim

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

    Premisecitation

    There is strong published evidence for deletions at 15q11.2 being relevant to schizophrenia.

    “Although there is strong published evidence for deletions at this locus being relevant to schizophrenia,3, 7”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Kirov G, Grozeva D, Norton N, Ivanov D, Mantripragada KK, Holmans P et al. Support for the involvement of large CNVs in the pathogenesis of schizophrenia. Hum Mol Genet 2009; 18: 1497–1503. source

      Not checked in the free run.

    • cites [7] Stefansson H, Rujescu D, Cichon S, Pietilainen OPH, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    EHMT1 haploinsufficiency has been implicated as the cause of 9qSTDS, characterized by moderate-to-severe mental retardation, childhood hypotonia, facial dysmorphisms, and high prevalence of psychiatric symptoms in adulthood.

    “EHMT1 haploinsufficieny has been implicated as the cause of the 9q subtelomeric deletion syndrome (9qSTDS) characterised by moderate-to-severe mental retardation, childhood hypotonia and facial dysmorphisms, as well as a high prevalence of psychiatric symptoms in adulthood.31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Houge G, Foulds N et al. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet 2009; 46: 598–606. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Deletions at EHMT1 are highly penetrant for phenotypes comprising developmental delay and a range of congenital anomalies.

    “A recent study has also reported strong evidence that deletions at EHMT1 are highly penetrant for phenotypes comprising developmental delay and a range of congenital anomalies.32”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 43: 838–846. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The meta-analysis study term makes the analysis robust to differences between studies in chip, analytic method and other study-specific factors.

    “This makes the analysis robust to differences between studies in chip, analytic method and other study-specific factors.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    The random placement analysis ensures that each random assignment hits at least one gene, and that the probability of a gene being hit was proportional to its length.

    “importantly ensuring that each random assignment hits at least one gene, and that the probability of a gene being hit was proportional to its length (Supplementary Section 12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Supplementary Section 12

      Not checked in the free run.

    • The authors state this as an assumption: The probability of a gene being hit is proportional to its length.

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

    Premisecitation

    In Drosophila, ehmt coordinates epigenetic changes important in regulating cognition.

    “Intriguingly, in Drosophila, ehmt coordinates epigenetic changes important in regulating cognition.33”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Kramer JM, Kochinke K, Oortveld MAW, Marks H, Kramer D, de Jong EK et al. Epigenetic regulation of learning and memory by Drosophila EHMT/G9a. PLoS Biol 2011; 9: e1000569. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The analyses control for different sources of potential bias including array type and the possibility that de novos have fundamentally different characteristics than control CNVs.

    “The analyses control for different sources of potential bias including array type (the Bulgarian controls) and the possibility that de novos have fundamentally different characteristics (other than size that is adjusted for) than control CNVs.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The inclusion of CNV size allows for case de novo CNVs being larger than typical CNVs.

    “The inclusion of CNV size allows for case de novo CNVs being larger than typical CNVs (and thus likely to hit more genes).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The 15q11.2 locus was excluded by the filtering criteria adopted by the ISC.

    “and was excluded by the filtering criteria adopted by the ISC,2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] International Schizophrenia Consortium (ISC). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455: 237–241. source

      Not checked in the free run.

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

    Study design and conductown data

    Exclusion of the single de novo in a proband with a family history of psychosis in a parent made essentially no difference to the results.

    “although we note that exclusion of the single de novo in a proband with a family history of psychosis in a parent made essentially no difference to the results.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The results where the analysis was restricted to CNVs hitting genes were similar to those of the primary analysis.

    “As expected, the results where the analysis was restricted to CNVs hitting genes were similar to those of the primary analysis (data not shown).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: De novo CNVs are more likely to hit genes.

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

    Premisecitation

    The NMDA antagonist model has led to a glutamate hypofunction hypothesis of schizophrenia.

    “This has led to a glutamate hypofunction hypothesis of schizophrenia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Abi-Saab WM, D'Souza DC, Moghaddam B, Krystal JH . The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry 1998; 31 (S 2): 104–109. source

      Not checked in the free run.

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

    Premisecitation

    Local synthesis of ARC is central to synaptic remodelling and the long-term maintenance of synaptic changes.

    “with local synthesis of ARC central to synaptic remodelling and the long-term maintenance of synaptic changes.47”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Bramham C, Alme M, Bittins M, Kuipers S, Nair R, Pai B et al. The Arc of synaptic memory. Exp Brain Res 2010; 200: 125–140. source

      Not checked in the free run.

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

    Premisecitation

    Deletions at the TAR region locus have very recently been strongly implicated in developmental delay.

    “Again, deletions at this locus have very recently been strongly implicated in developmental delay.32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 43: 838–846. source

      Not checked in the free run.

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

    Premisecitation

    A deletion at 1q21.1 has been reported in TAR syndrome.

    “The first is a deletion at 1q21.1 reported in TAR syndrome37”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Klopocki E, Schulze H, Strau G, Ott C-E, Hall J, Trotier F et al. Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet 2007; 80: 232–240. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Gene sets were systematically annotated from individual, high-quality proteomic data sets.

    “Using gene sets that have been systematically annotated from individual, high-quality proteomic data sets”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The TAR syndrome 1q21.1 deletion does not overlap the known 1q21.1 schizophrenia locus.

    “(which does not overlap the known 1q21.1 schizophrenia locus2, 7)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] International Schizophrenia Consortium (ISC). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455: 237–241. source

      Not checked in the free run.

    • cites [7] Stefansson H, Rujescu D, Cichon S, Pietilainen OPH, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Given the close functional relationship between different synaptic components, pathology at a number of different points might play a role.

    “given the close functional relationship between different synaptic components, we might expect pathology at a number of different points to play a role.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Duplications at the WBS region have recently been identified increasing susceptibility for autism and developmental delay.

    “given duplications at this locus have also recently been identified increasing susceptibility for autism25 and developmental delay,32”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Sanders Stephan J, Ercan-Sencicek AG, Hus V, Luo R, Murtha Michael T, Moreno-De-Luca D et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 2011; 70: 863–885. source

      Not checked in the free run.

    • cites [32] Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 43: 838–846. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The results converge in pointing to the involvement of the synapse, the PSD, and more specifically, ARC and NMDAR complexes.

    “the results converge in pointing to the involvement of the synapse, the PSD, and more specifically, ARC and NMDAR complexes.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    DLG3 and DLGAP2 have been implicated in mental retardation and autism.

    “whereas other members of the family (DLG3 and DLGAP2) have been implicated in mental retardation35 and autism.30, 36”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Tarpey P, Parnau J, Blow M, Woffendin H, Bignell G, Cox C et al. Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation. Am J Hum Genet 2004; 75: 318–324. source

      Not checked in the free run.

    • cites [30] Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 2010; 466: 368–372. source

      Not checked in the free run.

    • cites [36] Guilmatre A, Dubourg C, Mosca A-L, Legallic S, Goldenberg A, Drouin-Garraud V et al. Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch Gen Psychiatry 2009; 66: 947–956. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Multiple analytic approaches were carefully controlled for biases.

    “and multiple analytic approaches carefully controlled for biases”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Our set-based analyses allow for size differences.

    “Although our set-based analyses allow for size differences”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Our findings do not exclude a role for mutations in other post- or pre-synaptic complexes.

    “our findings do not exclude a role for mutations in other post- or pre-synaptic complexes”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    We provide novel convergent support for the involvement of NMDAR, and to a lesser extent ARC protein, complexes in the aetiology and pathogenesis of schizophrenia.

    “but also provide novel convergent support for the involvement of NMDAR, and to a lesser extent ARC protein, complexes in the aetiology and pathogenesis of the disorder”
    Quote in the paperSubstantial claim

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

    Premisecitation

    NMDA receptor signalling regulates induction of multiple forms of synaptic plasticity.

    “NMDA receptor signalling regulates induction of multiple forms of synaptic plasticity,46”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Malenka RC, Nicoll RA . NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci 1993; 16: 521–527. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Disruption of a number of synaptic proteins linked to glutamate receptor signalling alters cognitive function in rodents.

    “It is clear that disruption of a number of synaptic proteins linked to glutamate receptor signalling alters cognitive function in rodents.44”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Grant SG, Marshall MC, Page KL, Cumiskey MA, Armstrong JD . Synapse proteomics of multiprotein complexes: en route from genes to nervous system diseases. Hum Mol Genet 2005; 14: R225–R234. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Antagonism of NMDA receptors at glutamatergic synapses can induce a schizophrenia-like psychosis that includes cognitive deficits.

    “it has long been known that antagonism of NMDA receptors at glutamatergic synapses can induce a schizophrenia-like psychosis that includes some of those deficits.42”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Abi-Saab WM, D'Souza DC, Moghaddam B, Krystal JH . The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry 1998; 31 (S 2): 104–109. source

      Not checked in the free run.

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

    Premisecitation

    Duplication at the locus causing 7q11.23 microduplication syndrome (deleted in Williams-Beuren Syndrome) has prominent features including autism and developmental delay.

    “Another region is a duplication at the locus causing the 7q11.23 microduplication syndrome (which is deleted in Williams–Beuren Syndrome), the prominent features of which include autism and developmental delay.38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Van der Aa N, Rooms L, Vandeweyer G, van den Ende J, Reyniers E, Fichera M et al. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. Eur J Med Genet 2009; 52: 94–100. source

      Not checked in the free run.

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

    Interpretationown data

    Our findings delineate a circumscribed set of largely postsynaptic proteins and functions that warrant further functional analysis in model systems.

    “Our findings delineate a circumscribed set of largely postsynaptic proteins and functions that warrant further functional analysis in model systems.”
    Quote in the paperNot a substantial claim
61 of 61

  • The paper relies on this without support.

    EHMT1 is a histone methyl transferase that directly regulates DLG family members.

    “Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members.”

  • The paper relies on this without support.

    NMDAR and ARC complexes are important in synaptic plasticity and cognition.

    “which are known to be important in synaptic plasticity and cognition”

  • The paper relies on this without support.

    None of the risk CNVs identified to date are sufficiently penetrant to fully explain the disorder in carriers.

    “as none of the risk CNVs identified to date are sufficiently penetrant to fully explain the disorder in carriers”

  • The paper relies on this without support.

    Cases were recruited from general adult psychiatric services and were typical of those attending those services.

    “Cases were recruited from general adult psychiatric services and were typical of those attending those services.”

  • The paper relies on this without support.

    Duplications are less easily detected by microarrays than deletions.

    “In general, duplications are less easily detected by microarrays than deletions.”

  • The authors state this as an assumption.

    The probability of a gene being hit is proportional to its length.

    “the probability of a gene being hit was proportional to its length”

  • The paper relies on this without support.

    De novo CNVs are more likely to hit genes.

    “to confirm that the results are not due to the fact that de novo CNVs are more likely to hit genes”

  • The paper relies on this without support.

    All currently known risk CNVs are rare (control frequencies typically <0.001) and confer substantial effects on risk (odds ratios 3–30).

    “All of the currently known risk CNVs are rare (control frequencies typically <0.001) and confer substantial effects on risk (odds ratios 3–30).”

  • The paper relies on this without support.

    The known risk CNVs occur in 2–3% of cases.

    “The known risk CNVs occur in 2–3% of cases”

  • The paper relies on this without support.

    Most schizophrenia-associated CNVs span multiple genes.

    “Most schizophrenia-associated CNVs span multiple genes, limiting our ability to make strong inferences regarding pathogenesis.”

  • The paper relies on this without support.

    Most reported CNVs occurring in cases are too rare to allow clear demonstration of association statistically.

    “most reported CNVs occurring in cases are too rare to allow clear demonstration of association statistically”

  • The paper relies on this without support.

    Predominantly transmitted CNVs have different characteristics from case de novo CNVs, most obviously size.

    “Although those CNVs must have originally occurred as de novo mutations, predominantly transmitted CNVs clearly have different characteristics from the case de novos, most obviously size.”

  • The paper relies on this without support.

    Control CNVs drawn from the same population as the trios must have originally occurred as de novo mutations.

    “Although those CNVs must have originally occurred as de novo mutations, predominantly transmitted CNVs clearly have different characteristics from the case de novos, most obviously size.”

  • The paper relies on this without support.

    DLG family MAGUKs are associated with NMDA receptors and are highly concentrated in synapses.

    “They are associated with NMDA receptors and are highly concentrated in synapses.”
14 of 14

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?

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 2009; 41: 1223–1227. · DOI · Paper page
  2. Sebat J, Levy DL, McCarthy SE . Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet 2009; 25: 528–535. · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Kirov, G., Pocklington, A. J., Holmans, P., Ivanov, D., Ikeda, M., Ruderfer, D., Moran, J., Chambert, K., Toncheva, D., Georgieva, L., Grozeva, D., Fjodorova, M., Wollerton, R., Rees, E., Nikolov, I., van de Lagemaat, L. N., Bayés, À., Fernandez, E., Olason, P. I., Böttcher, Y., Komiyama, N. H., Collins, M. O., Choudhary, J., Stefansson, K., Stefansson, H., Grant, S. G. N., Purcell, S., Sklar, P., O'Donovan, M. C., & Owen, M. J.
Affiliations
  • Cardiff University (GB)
  • Fujita Health University (JP)
  • Broad Institute (US)
  • Maichin Dom (BG)
  • University of Edinburgh (GB)
  • KU Leuven (BE)
  • deCODE Genetics (Iceland) (IS)
  • Wellcome Sanger Institute (GB)
Corresponding author
Kirov, G
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2011-11-15
Volume
17
Issue
2
Pages
142-153
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2011.154
PMC
PMC3603134
OpenAlex
W2117787632
Cited by
844
References
47
Citations by year
2026: 17 · 2025: 28 · 2024: 31 · 2023: 53 · 2022: 50 · 2021: 47 · 2020: 56 · 2019: 66 · 2018: 59 · 2017: 81 · 2016: 88 · 2015: 78 · 2014: 81 · 2013: 58 · 2012: 50
FWCI
37.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
  • Hirsla (Landspítali University Hospital) (submittedVersion, other-oa)
Funders
  • Stanley Medical Research Institute
  • Wellcome Trust (241995, 242167)
  • Broad Institute
  • European Commission (218251, 242167, 241995, 223423)
  • Cardiff University (G0800509)
  • Stanley Center for Psychiatric Research, Broad Institute
  • Medical Research Council (G0800509, MH066392)
  • National Institute of Mental Health (P50MH066392, MH066392-05A1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
de novo copy number variants, schizophrenia, postsynaptic density, NMDA receptor complex, Arc, membrane-associated guanylate kinase, EHMT1, 1q21.1 deletion, 15q11.2, 15q13.3, 16p11.2, schizophrenia pathogenesis
MeSH terms
AIDS-Related Complex, Bulgaria, Family Health, Female, Gene Frequency, Genotype, Humans, Iceland, Japan, Male, Models, Biological, Psychiatric Status Rating Scales, Schizophrenia, Synapses, Meta-Analysis as Topic, Signal Transduction, Case-Control Studies, Receptors, N-Methyl-D-Aspartate, Statistics, Nonparametric, Genetic Predisposition to Disease, Microarray Analysis, DNA Copy Number Variations, Post-Synaptic Density

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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