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Rare coding variants in ten genes confer substantial risk for schizophrenia
Open accessPublished version of a preprint
Abstract
Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach. Whole-exome sequencing identifies ten risk genes for schizophrenia implicated by rare protein-coding variants, a subset of which overlap with risk genes in other neurodevelopmental disorders.
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In the paper
“we demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Abstract
What the sources say
- Not checked yetcites [3] Trubetskoy, V. et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature https://doi.org/10.1038/s41586-022-04434-5 (2022). source
boostedcorrelationaln = 24,248- Asserted: passes — The authors put it forward as true.
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“Most genes described here however are not implicated in neurodevelopment”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Abstract
plainn = 24,248- Asserted: passes — The authors put it forward as true.
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In the paper
“Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Abstract
plaincorrelationaln = 24,248- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.
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In the paper
“Combining these findings with other large-scale sequencing studies, we find shared and distinct genetic signals between schizophrenia and other neurodevelopmental disorders.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
plaincorrelationaln = 24,248- Asserted: passes — The authors put it forward as true.
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In the paper
“These top associations as a group are supported by complementary types of variation that include case-control PTVs, damaging missense variants, and de novo mutations (Table 1, Table S5).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
plaincorrelationaln = 24,248- Asserted: passes — The authors put it forward as true.
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In the paper
“The most striking enrichment was observed for the 52 genes with case-control P < 0.001 (Class I mutations: P = 2.1 × 10−11; Rate ratio = 8.3, 95% CI = 4.9 – 13)”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Analysis approach
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In the paper
“The annotated functions of these genes are diverse and include ion transport (CACNA1G, GRIN2A, and GRIA3), neuronal migration and growth (TRIO), transcriptional regulation (SP4, RB1CC1, and SETD1A), nuclear transport (XPO7), and ubiquitin ligation (CUL1, HERC1).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
plainn = 24,248- Asserted: passes — The authors put it forward as true.
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In the paper
“We additionally find that risk URVs in AMPA receptor subunit GRIA3 confer substantial risk (P = 5.98 × 10−7; Class I [PTV and MPC > 3] OR 20.1 95% CI 4.28 – 188; Table 1).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
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- Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Beyond these ten genes, we identify 22 additional genes at a False Discovery Rate (FDR) < 5% (Figure 2A, Table S5).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
plainn = 24,248- Asserted: passes — The authors put it forward as true.
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In the paper
“We observe notable deviation at the tail of the distribution beyond the associated genes”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
plainn = 24,248- Asserted: passes — The authors put it forward as true.
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In the paper
“In tandem with a companion paper from the Psychiatric Genomics Consortium13, we provide evidence that common and ultra-rare coding variants identify an overlapping set of genes.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [13] Loh, P.-R. et al. Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis. Nat. Genet. 47, 1385–1392 (2015). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“As predicted by apparent rare variant burden in schizophrenia, increasing the sample size has led to the identification of 10 genes with URVs that confer substantial risk at exome-wide significance.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
plaindirectn = 24,248- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we find that PTV and damaging missense variants in NMDA receptor subunit GRIN2A confer substantial risk for schizophrenia (P = 7.37 × 10−7; Class I [PTV and MPC > 3] OR 24.1, 95% CI 5.36 – 221; Class II [MPC > 2] OR 2.37, 95% CI 1.1 – 4.92).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Combined, our meta-analysis of 24,248 cases, 97,322 controls, and de novo mutations from 3,402 trios implicates 10 genes in which ultra-rare coding variants are significantly associated with schizophrenia (P < 2.14 × 10−6 corresponding to 0.05/23,321 tests; Figure 2A, 2B).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
plaincorrelationaln = 24,248- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and enriched in expression in neuronal tissues.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“the genome-wide signal in constrained genes (pLI > 0.9: OR = 1.26, P = 7.6 × 10−35) remains significant even after excluding the 32 FDR < 5% genes (OR = 1.23, P = 4.3 × 10−27; Figure 6B, Table S4)”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“De novo missense mutations in TRIO significantly disrupted the exons preceding or containing the RhoGEF domain (Figure 5C)37,38”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
What the sources say
- Not checked yetcites [37] Haukka, J., Suvisaari, J. & Lönnqvist, J. Fertility of patients with schizophrenia, their siblings, and the general population: a cohort study from 1950 to 1959 in Finland. Am. J. Psychiat. 160, 460–463 (2003). source
- Not checked yetcites [38] Laursen, T. M. & Munk-Olsen, T. Reproductive patterns in psychotic patients. Schizophr. Res. 121, 234–240 (2010). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Among these FDR < 5% genes, ASH1L, KDM6B and NR3C2 were associated with ASD 1 (Table S13).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We observed 0.057 (0.049 – 0.065 95% CI) extra singleton PTV variants per individual in cases compared to controls”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Here, we found widespread enrichments across central nervous system neurons with limited to no signal in glial cells and peripheral nervous system neurons (Table S10, Figure S17).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
What the sources say
- Not checked yetcites [33] Skene, N. G. et al. Genetic identification of brain cell types underlying schizophrenia. Nat. Genet. 50, 825–833 (2018). source
- Not checked yetcites [34] De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Expression patterns in mouse nervous system cell types can be generalized to human schizophrenia risk genes.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the 2,304 trios, 0.0394 (0.014 – 0.065 95% CI; 74%) extra singleton PTV variants were inherited per proband”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
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In the paper
“We also observed a missense signal in SETD1A in our study (Table 1; Figure S19).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
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In the paper
“SETD1A had a significant de novo PTV signal in DD/ID (Xobs = 8, Xexp = 0.41; P = 1.3 × 10−8)”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“STAG1, which had a common and rare variant signal in schizophrenia (Figure 4D), was associated with DD/ID primarily through de novo missense mutations (Figure 5B; Table S13).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“we identify genes in which disruptive coding variants confer substantial risk for schizophrenia at exome--wide significance.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
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In the paper
“they are significantly less constrained than DD/ID-associated genes (M-W U test; P = 3.5 × 10−5).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Joint analysis with genetic data from DD/ID and ASD consortia have provided evidence for shared genes between neuropsychiatric and broader neurodevelopmental disorders.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“DD/ID probands have 0.111 (0.103 – 0.119 95% CI) extra de novo PTV mutations in constrained genes”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Because of the clear synaptic signal, we investigated in the refined synaptic ontology defined by the SynGO consortium32, and found consistent enrichment for postsynaptic components and processes (GO:0098794; P = 3.9 × 10−6; Table S7).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
What the sources say
- Not checked yetcites [32] Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014 (2018). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“seven of the 32 FDR < 5% genes are also associated with DD/ID”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“and 0.0121 (0.0022 – 0.02 95% CI; or 26%) extra de novo PTV mutations in constrained genes were identified in cases compared to controls.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“schizophrenia genes as a group did not show pre- or postnatal bias in brain expression (P = 0.21; Figure S21)”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“We observed significant enrichment of URVs in 33 gene sets (P < 2.9 × 10−5) that recapitulated consistent and overlapping cellular compartments and biological processes, including definitions of the postsynaptic density (human cortex biopsy post-synaptic density; P = 1.2 × 10−12), chromatin modification (GO:0016568; P = 1.8 × 10−12), regulation of ion transmembrane transport (GO:0034765; P = 6.7×”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“three of the ten risk genes for schizophrenia (TRIO, GRIN2A, and CACNA1G) were associated with risk of severe DD/IDs exclusively through de novo missense mutations that cluster within each gene (Figure 5B; Table S13)”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
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In the paper
“while the schizophrenia signal was largely driven by PTVs.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“While schizophrenia genes (FDR < 5%) were under substantial genic constraint compared to expectation (Figure S20; M-W U test; P = 2.9 × 10−7; Supplementary Methods)”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
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In the paper
“Genome-wide analyses recapitulated known biological processes”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
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In the paper
“ASD individuals have 0.0478 (0.0387 – 0.0568 95% CI) extra de novo PTV mutations”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In the ten schizophrenia-associated genes, 7 de novo mutations and 13 transmitted variants are observed in 2,304 trios”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“while DD/ID-associated genes were overwhelmingly prenatal in expression (P = 7.5 × 10−20).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“we found that six genes (STAG1, ASH1L, ZMYM2, KDM6B, SRRM2, and HIST1H1E) were significantly associated with DD/ID in addition to schizophrenia (Figure 5B; Table S13).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Abstract
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In the paper
“suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Abstract
What the sources say
- Not checked yetcites [3] Trubetskoy, V. et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature https://doi.org/10.1038/s41586-022-04434-5 (2022). source
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In the paper
“To ensure the robustness of the results generated by this approach, we observed the expected null distribution of P values in gene-based tests of synonymous variants in each strata and in the meta-analysis”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Analysis approach
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In the paper
“Although the variants we have been able to implicate have large effects on risk in the individual, because they are rare they make only a small contribution to overall heritability in the population.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
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In the paper
“Protein-truncating variants (PTVs) are among the most interpretable associations as they suggest that the effect on disease most commonly tracks with decreasing expression of the gene18.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [18] Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014). source
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In the paper
“Theory predicts that the forces of natural selection will tend to keep large effect risk variants at much lower frequencies in the population, especially in disorders such as schizophrenia that are associated with reduced fecundity16.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [16] Lee, S., Abecasis, G. R., Boehnke, M. & Lin, X. Rare-variant association analysis: study designs and statistical tests. Am. J. Hum. Genet. 95, 5–23 (2014). source
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In the paper
“Importantly, we restricted our analysis to coding exons with high-quality data across all major exome capture technologies, reducing any artifacts that may arise from coverage differences”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Analysis approach
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In the paper
“Additionally, we observed no inflation of synonymous P values using the Mantel-Haenszel test even after limiting our analysis to genes with larger total numbers of alleles”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Analysis approach
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In the paper
“This suggests a role for rare gene-disrupting mutations with much larger effects on individual risk (OR 2 – 60).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
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In the paper
“The identification of individual genes provides support for more specific mechanistic hypotheses underlying schizophrenia pathogenesis.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
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In the paper
“All samples in gnomAD and SCHEMA consortia were re-processed and joint called using the same pipeline, and the same variant filters were applied to arrive high-quality calls.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Analysis approach
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In the paper
“suggesting ~5.7% of cases carried a PTV relevant to disease risk.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“suggesting an alternate or gain-of-function effect.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“supporting an earlier report that described SETD1A as a gene associated with both schizophrenia and broader neurodevelopmental disorders21.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
What the sources say
- Not checked yetcites [21] Howrigan, D. P. et al. Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations. Nat. Neurosci. 23, 185–193 (2020). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“A natural dose-response curve occurs at this gene in which common regulatory variants modestly influence disease risk and PTV and predicted damaging missense variants increase risk more substantially.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
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In the paper
“reaffirming the genetic heterogeneity underlying schizophrenia risk”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
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In the paper
“Combined, these results suggest that exome sequencing identifies some common, shared underlying biology that is dysregulated across the allele frequency spectrum, rather than syndromic forms of disease with unrelated biology regulated by common variation.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“De novo mutations in GRIN2B conversely are associated with more severe disorders of neurodevelopment that manifest in childhood, including intellectual disability and autism42.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
What the sources say
- Not checked yetcites [42]
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“To evaluate the overlap of schizophrenia associations from common variants and ultra-rare coding variant analyses, we jointly analyzed our results with the largest GWAS of schizophrenia to date, which identified common variant associations at 270 distinct loci from the analysis of 69,369 cases and 236,642 controls13.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
What the sources say
- Not checked yetcites [13] Loh, P.-R. et al. Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis. Nat. Genet. 47, 1385–1392 (2015). source
plaincorrelationaln = 69,369- Asserted: passes — The authors put it forward as true.
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In the paper
“suggesting that the majority of schizophrenia risk genes in which rare variants confer risk remain to be discovered.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
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In the paper
“These global observations are consistent with the known functions of the individual risk genes now implicated by rare variation (Supplementary Note).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, some schizophrenia rare variant risk appears to be shared with other neurodevelopmental disorders.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Thus, at a high level, global analysis of ultra-rare protein-coding variation independently recapitulated known biology related to schizophrenia pathogenesis, including processes, cellular components, and tissues previously implicated by common variant analyses.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
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In the paper
“The shared genes suggest that there is at least some contribution from early brain developmental processes that predisposes to schizophrenia.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“because of this sharing, coding variants can help refine and fine-map common variant associations like at the STAG1 and FAM120A loci.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the majority of schizophrenia associations reported here appear to have little or no role in DD/ID despite the enormous power of published DD/ID studies to date.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
hedged- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The 31,058 developmental delay/intellectual disability trios provide sufficient power to evaluate the individual schizophrenia risk genes from this study for a role in broader neurodevelopmental disorders.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The association of PTVs in the NMDA receptor subunit GRIN2A to schizophrenia risk provides genetic support for the dysregulation of glutamatergic signaling as a possible mechanism of disease.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 40
- Probably not a substantial claim. 20
- Not yet classified. 1
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 – 50, P < 2.14 × 10−6), and 32 genes at a FDR < 5%.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Abstract
plaincorrelationaln = 24,248- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.
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In the paper
“We observe an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD)1, epilepsy and severe neurodevelopmental disorders (DD/ID)2, though in some shared genes different mutation types are implicated.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Abstract
What the sources say
- Not checked yetcites [1] Satterstrom, F. K. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180, 568–584 (2020). source
- Not checked yetcites [2] Kaplanis, J. et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 586, 757–762 (2020). source
plaincorrelationaln = 24,248- Asserted: passes — The authors put it forward as true.
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In the paper
“These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Abstract
plainn = 24,248- Asserted: passes — The authors put it forward as true.
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In the paper
“We found that missense variants with MPC > 3 have a global signal on par with PTVs in schizophrenia, autism spectrum disorders, and severe neurodevelopmental disorders, while variants with MPC 2 – 3 has a significant but weaker signal than PTVs and were therefore analyzed separately”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Analysis approach
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“As expected, all ten genes are among the most constrained genes in the genome, with a substantial depletion of PTVs compared to chance expectation24.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
What the sources say
- Not checked yetcites [24] Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016). source
plaincorrelationaln = 24,248- Asserted: passes — The authors put it forward as true.
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In the paper
“Although confidence intervals are wide, URVs in these genes appear to confer substantial risk, with odds ratio of PTVs and Class I variants ranging from 3 to 50.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
hedgeddirectn = 24,248- Asserted: passes — The authors put it forward as true.
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In the paper
“Using Poisson rate tests based on expected mutation rate27, we found these de novo mutations are enriched for the 244 genes with P < 0.01 in our case-control analysis (Figure S13, Table S5), with limited or no signal in the remaining genes in the genome (Figure 1D).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Analysis approach
What the sources say
- Not checked yetcites [27] Hu, W., MacDonald, M. L., Elswick, D. E. & Sweet, R. A. The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann. NY Acad. Sci. 1338, 38–57 (2015). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We found a significant excess of URVs in schizophrenia cases compared to controls in the 299 DD/ID-associated genes (Pmeta = 1.5 × 10−14; ORClass I = 1.44, 1.3 – 1.6 95% CI), and in the 102 ASD-associated genes (Pmeta = 3.7 × 10−7; ORClass I = 1.45, 1.23 – 1.72 95% CI; Figure 5A; Table S12).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We show for the first time that common regulatory variants from GWAS and ultra-rare coding variants disrupt an overlapping set of genes, including an allelic series in four genes in which common variants and rare coding variants increase risk to varying degrees.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Nine of the ten schizophrenia genes showed limited de novo PTV signal in DD/ID, with a combined 8 de novo PTVs observed in these genes (Xexp = 4.98; PPois = 0.13; Figure 5B; Table S13).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The 31,058 developmental delay/intellectual disability trios provide sufficient power to evaluate the individual schizophrenia risk genes from this study for a role in broader neurodevelopmental disorders.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“reaffirm that schizophrenia risk genes are involved in the postsynaptic density and broader synaptic function”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“PTVs show consistent signals across the different cohorts, and synonymous variants do not deviate from expectation.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Extended Data
plainn = 22,444- Asserted: passes — The authors put it forward as true.
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In the paper
“individual genes like SETD1A, TRIO, and SP4 exhibited prenatal expression while GRIN2A and GRIA3 showed postnatal expression (Figure S22).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“PTVs in 9 of the 10 most confidently associated genes are associated with schizophrenia and not for DD/ID”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“de novo missense mutations in GRIN2A cluster at the base of the ion channel with the most mutations in the exon encoding for the pore of the complex (Figure 5D).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Furthermore, FAM120A and STAG1 resided in more complex GWAS-associated regions containing multiple genes but were prioritized among their neighbors as FDR < 5% in our sequencing study (Figure 4C, 4D).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Statistical fine-mapping prioritized the likely underlying protein-coding gene at 64 of these associations (Table S11, Figure S18), and we found a case-control enrichment of URVs in these genes (Pmeta = 3.9 × 10−4; ORClass I = 1.46, 1.2 – 1.77 95% CI; Figure 4A, Table S12).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The population controls used in the case-control analysis are assumed to be free of schizophrenia.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we observe allelic series in GRIN2A, TRIO, and CACNA1G in which PTVs increase schizophrenia risk and de novo missense mutations confer strong DD/ID risk.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“De novo missense mutations in these genes clustered in specific domains and are associated with more severe neurodevelopmental, syndromic disorders with cognitive impairment”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Beyond the statistical enrichment, GRIN2A and SP4, two of the ten significant rare variant genes, had clear associations in schizophrenia GWAS (Figure 3A, Figure 4B).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Following earlier reports studying heritability enrichment in GTEx tissues8,31, we found that genes with the highest specific expression in brain regions showed the strongest enrichment of risk URVs, most significantly in the human frontal cortex (P = 1.63 × 10−8) and with limited signal in the other tissue types (Extended Data Figure 4, Table S8, S9).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
What the sources say
- Not checked yetcites [8] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). source
- Not checked yetcites [31] Koopmans, F. et al. SynGO: an evidence-based, expert-curated knowledge base for the synapse. Neuron 103, 217–234 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“implying that more risk genes await discovery using this approach.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Abstract
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence.
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In the paper
“Earlier schizophrenia sequencing studies have established that ultra-rare and de novo mutations contribute to risk as a category, and have prioritized disease-relevant tissues and processes, specifically observing an enrichment in neuronal genes and synaptic processes9,11,19–23.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [9] Genovese, G. et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 19, 1433–1441 (2016). source
- Not checked yetcites [11] Singh, T. et al. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat. Genet. 49, 1167–1173 (2017). source
- Not checked yetcites [19] Purcell, S. M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014). source
- Not checked yetcites [20] Singh, T. et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat. Neurosci. 19, 571–577 (2016). source
- Not checked yetcites [21] Howrigan, D. P. et al. Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations. Nat. Neurosci. 23, 185–193 (2020). source
- Not checked yetcites [22] Gulsuner, S. et al. Genetics of schizophrenia in the South African Xhosa. Science 367, 569–573 (2020). source
- Not checked yetcites [23] Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Several rare (MAF < 0.1%) recurrent copy number variants (CNVs) have also been robustly associated with schizophrenia, as exemplified by the dramatically higher rates of schizophrenia in 22q11.2 deletion carriers10,15.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [10] Marshall, C. R. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35 (2017). source
- Not checked yetcites [15] Zuk, O. et al. Searching for missing heritability: designing rare variant association studies. Proc. Natl Acad. Sci. USA 111, E455–E464 (2014).
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, these risk alleles are concentrated in genes with a near-complete depletion of protein-truncating variants in population studies, a result shared with other neurodevelopmental disorders9,11 and suggesting strong direct selection against such mutations.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [9] Genovese, G. et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 19, 1433–1441 (2016). source
- Not checked yetcites [11] Singh, T. et al. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat. Genet. 49, 1167–1173 (2017). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Because causal variants in schizophrenia GWAS are predominantly non-coding, challenges related to fine-mapping and interpretation of intergenic and intronic elements limit our ability to confidently identify underlying genes, infer the mechanism by which they influence disease risk, and determine the direction of effect.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“After extracting SCHEMA samples from this callset, we performed quality control steps to ensure high quality of sequence data, exclude contaminated samples, identify parent-proband trios and other related individuals, and infer global ancestries”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Data description and quality control
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, we demonstrate that increased scale following this approach will uncover additional risk genes and help complete the genetic architecture of schizophrenia.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
boosteddirectn = 24,248- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Pathway analyses of common variants have prioritized disease-relevant tissues and cell types, and in some cases, independently recapitulating known biology8,30,31.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
What the sources say
- Not checked yetcites [8] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). source
- Not checked yetcites [30] Finucane, H. K. et al. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nat. Genet. 50, 621–629 (2018). source
- Not checked yetcites [31] Koopmans, F. et al. SynGO: an evidence-based, expert-curated knowledge base for the synapse. Neuron 103, 217–234 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We attempted to control for technical and methodological batch effects that may arise from this approach in both variant calling and additionally via permutation testing described below.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Analysis approach
hedgedn = 24,248- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The most natural grouping for rare variants is within a gene, based on predicted functional consequence or evidence for deleteriousness16,17.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [16] Lee, S., Abecasis, G. R., Boehnke, M. & Lin, X. Rare-variant association analysis: study designs and statistical tests. Am. J. Hum. Genet. 95, 5–23 (2014). source
- Not checked yetcites [17] Rivas, M. A. et al. Effect of predicted protein-truncating genetic variants on the human transcriptome. Science 348, 666–669 (2015). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. It may be too vague to check against evidence.
- Rests on an assumption: Most rare variants have little or no functional consequence or impact on risk.
In the paper
“Developed from neuropharmacological and neuropathological observations, the glutamatergic hypothesis postulates that the hypofunction of glutamatergic signaling through NMDA receptors is a possible mechanism of disease28 (Supplementary Note).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
What the sources say
- Not checked yetcites [28] Kang, H. J. et al. Spatio-temporal transcriptome of the human brain. Nature 478, 483–489 (2011). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that more genes remain to be discovered (Figure 2B).”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
hedgedn = 24,248- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Schizophrenia GWAS also identified a common variant at GRIN2A (OR = 1.057, P = 1.57 × 10−10), providing an allelic series in which different perturbation of gene function results in severity of disease risk (Figure 3A)8.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
What the sources say
- Not checked yetcites [8] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“This has been borne out by genome-wide association studies (GWAS) which have now, in a companion paper, identified 270 common (minor allele frequency [MAF] > 1%) risk loci of individually small effect (median odds ratio [OR] < 1.05)13.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [13] Loh, P.-R. et al. Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis. Nat. Genet. 47, 1385–1392 (2015). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“It is well-established that schizophrenia has a substantial genetic component with contributions from across the allele frequency spectrum8–11.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [8] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). source
- Not checked yetcites [9] Genovese, G. et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 19, 1433–1441 (2016). source
- Not checked yetcites [10] Marshall, C. R. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35 (2017). source
- Not checked yetcites [11] Singh, T. et al. The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability. Nat. Genet. 49, 1167–1173 (2017). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We subsequently applied site- and genotype-level filters to generate a robust set of coding SNPs and indels for a well-matched case-control analysis”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Data description and quality control
plainn = 24,248- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“However, the analysis of URVs has had limited success in delivering individual gene discovery in schizophrenia because of power limitations, with only a single gene, SETD1A, identified as robustly associated16,21.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [16] Lee, S., Abecasis, G. R., Boehnke, M. & Lin, X. Rare-variant association analysis: study designs and statistical tests. Am. J. Hum. Genet. 95, 5–23 (2014). source
- Not checked yetcites [21] Howrigan, D. P. et al. Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations. Nat. Neurosci. 23, 185–193 (2020). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“which provides additional reassurance of the robustness of our case-control gene results.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Analysis approach
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“CNVs of large effect, on the other hand, often disrupt hundreds of kilobases of the genome and multiple genes simultaneously, limiting our ability to derive clear functional insights10.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [10] Marshall, C. R. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35 (2017). source
Not yet classified.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To ensure calibrated analyses, these samples were included in joint re-processing and variant calling using a standardized BWA-Picard-GATK pipeline as part of the larger Genome Aggregation Database (gnomAD) effort”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Data description and quality control
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“The NMDA receptor changes in composition during prenatal to postnatal neurodevelopment with GRIN2A predominantly expressed during late childhood and adolescence, recapitulating expected epidemiological observations on schizophrenia age-of-onset (Supplementary Methods, Figure 3B)29.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Individual genes implicated by URVs
What the sources say
- Not checked yetcites [29] Network and Pathway Analysis Subgroup of the Psychiatric Genetics Consortium. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nat. Neurosci. 18, 199–209 (2015). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“As a class of variation, common variants explain ~24% of the variance in disease liability14.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Introduction
What the sources say
- Not checked yetcites [14] Karayiorgou, M. et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl Acad. Sci. USA 92, 7612–7616 (1995). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that 0.86% of patients are carriers and ~35% of variants are de novo.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Because schizophrenia as a trait is under strong selection39–41, we expect that URVs of large effect to be frequently de novo or of very recent origin and contribute to risk in only a fraction of diagnosed patients.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
What the sources say
- Not checked yetcites [39] Power, R. A. et al. Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. Arch. Gen. Psychiat. 70, 22–30 (2013).
- Not checked yetcites [40] Endele, S. et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat. Genet. 42, 1021–1026 (2010). source
- Not checked yetcites [41] Finn, R. D. et al. Pfam: the protein families database. Nucleic Acids Res. 42, D222–D230 (2014). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The vast majority of risk alleles, their direction and magnitude of effect, mode of action, and responsible genes are yet to be discovered.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Discussion
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Combined, these results suggest there is at least partial convergence in the genes and biological processes implicated by common and ultra-rare genetic variation, and that ultra-rare coding variants can be leveraged to prioritize genes within GWAS loci.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared genes with GWAS loci
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These observations offer the possibility that certain properties may differentiate genes for adult psychiatric disorders and more severe DD/IDs.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These observations suggest schizophrenia and childhood onset neurodevelopmental disorders share some genes and biological processes, but that at least in some cases, the severity or the nature of the functional impairment differs between disorders.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“These studies have established that the genetic signals were concentrated in constrained genes and shared between the two disorders35,36.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
What the sources say
- Not checked yetcites [35] The Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519, 223–228 (2015). source
- Not checked yetcites [36] Barbosa, S. et al. Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders. Am. J. Hum. Genet. 106, 338–355 (2020). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Most recently, the analysis of de novo mutations from 31,058 DD/ID trios implicated 299 genes, while the analysis of 11,986 ASD cases identified 102 genes at FDR < 10% (Table S11)1,37.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Shared and distinct genes with DD/IDs
What the sources say
- Not checked yetcites [1] Satterstrom, F. K. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180, 568–584 (2020). source
- Not checked yetcites [37] Haukka, J., Suvisaari, J. & Lönnqvist, J. Fertility of patients with schizophrenia, their siblings, and the general population: a cohort study from 1950 to 1959 in Finland. Am. J. Psychiat. 160, 460–463 (2003). source
plaincorrelationaln = 11,986- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Efforts in the past decade are beginning to generate a more comprehensive view of the genetic architecture for schizophrenia, composed of common variants of small effects, large CNVs with elevated frequencies driven by genomic instability, and now, URVs of large effect implicating individual genes (Figure 6A)8,10.”
§ Rare coding variants in 10 genes confer substantial risk for schizophrenia > Results > Contribution of ultra-rare PTVs to risk
What the sources say
- Not checked yetcites [8] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). source
- Not checked yetcites [10] Marshall, C. R. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 49, 27–35 (2017). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The population controls used in the case-control analysis are assumed to be free of schizophrenia.
“50,437 individuals without a known psychiatric diagnosis”
The paper relies on this without support.
Most rare variants have little or no functional consequence or impact on risk.
“most rare variants will have little or no functional consequence or impact on risk”
The paper relies on this without support.
Expression patterns in mouse nervous system cell types can be generalized to human schizophrenia risk genes.
“we investigated which single cell types in the mouse nervous system show the highest specific expression for the 32 (FDR < 5%) schizophrenia risk genes”
The paper relies on this without support.
The 31,058 developmental delay/intellectual disability trios provide sufficient power to evaluate the individual schizophrenia risk genes from this study for a role in broader neurodevelopmental disorders.
“With 31,058 trios, the scale of gene discovery in severe DD/ID provided sufficient power to evaluate the individual schizophrenia risk genes associated in our study for a role in broader neurodevelopmental disorders.”
The paper relies on this without support.
The NMDA receptor is composed of two GRIN2 units (GRIN2A and/or GRIN2B) along with two constitutive GRIN1 units, and GRIN2A expression increases dramatically later in childhood and adolescence, mimicking the age of onset of schizophrenia.
“the NMDA receptor is composed of two GRIN2 units (GRIN2A and/or GRIN2B) along with two constitutive GRIN1 units, and GRIN2A increases dramatically in expression later in childhood and adolescence, mimicking the age of onset of disease for schizophrenia.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The thalamus-enriched voltage-dependent calcium channel CaV3.1 encoded by the Wnt target CACNA1G is the key mediator of thalamocortical connectivity, and putative loss-of-function mutations of CACNA1G have been associated with schizophrenia and intellectual disability [65–67].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [66]
Experimental — accuracy not yet measuredIn the citing paper
“There are rare variant overlaps in liability to schizophrenia, autism spectrum disorder (ASD) and developmental disorder (DD)8,30,31.”
From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [30]
Citations
Cites
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587
Self-citationThe mutational constraint spectrum quantified from variation in 141,456 humans
Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., et al. (2020) · Nature · doi:10.1038/s41586-020-2308-7 · Cited by 9,434
Self-citationBiological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577
Self-citationPfam: the protein families database
Finn, R. D., Bateman, A., Clements, J., Coggill, P., Eberhardt, R. Y., Eddy, S. R., Heger, A., Hetherington, K., Holm, L., Mistry, J., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gkt1223 · Cited by 6,148
Krystal, J. H. (1994) · Archives of General Psychiatry · doi:10.1001/archpsyc.1994.03950030035004 · Cited by 3,330
Mapping genomic loci implicates genes and synaptic biology in schizophrenia
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., et al. (2022) · Nature · doi:10.1038/s41586-022-04434-5 · Cited by 2,964
Self-citationRecent advances in the phencyclidine model of schizophrenia
(1991) · American Journal of Psychiatry · doi:10.1176/ajp.148.10.1301 · Cited by 2,904
Systematic review and meta-analysis
Gillies, A. (2019) · CRC Press eBooks · doi:10.1201/9781315377315-19 · Cited by 2,876
Synaptic, transcriptional and chromatin genes disrupted in autism
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Self-citationAMPA Receptor Trafficking and Synaptic Plasticity
Malinow, R., & Malenka, R. C. (2002) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.25.112701.142758 · Cited by 2,588
Cited by
Sorted by citations
Mapping genomic loci implicates genes and synaptic biology in schizophrenia
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., et al. (2022) · Nature · doi:10.1038/s41586-022-04434-5 · Cited by 2,964
Self-citationJauhar, S., Johnstone, M., & McKenna, P. J. (2022) · The Lancet · doi:10.1016/s0140-6736(21)01730-x · Cited by 1,116
Demontis, D., Walters, G. B., Athanasiadis, G., Walters, R., Therrien, K., Nielsen, T. T., Farajzadeh, L., Voloudakis, G., Bendl, J., Zeng, B., et al. (2022) · Nature Genetics · doi:10.1016/j.euroneuro.2022.07.018 · Cited by 863
Self-citationFu, J. M., Satterstrom, F. K., Peng, M., Brand, H., Collins, R. L., Dong, S., Wamsley, B., Klei, L., Wang, L., Hao, S. P., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01104-0 · Cited by 640
Self-citation15 years of GWAS discovery: Realizing the promise
Abdellaoui, A., Yengo, L., Verweij, K. J. H., & Visscher, P. M. (2023) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2022.12.011 · Cited by 570
Metadata
- Authors
- Singh, T., Poterba, T., Curtis, D., Akil, H., Al Eissa, M., Barchas, J. D., Bass, N., Bigdeli, T. B., Breen, G., Bromet, E. J., Buckley, P. F., Bunney, W. E., Bybjerg-Grauholm, J., Byerley, W. F., Chapman, S. B., Chen, W. J., Churchhouse, C., Craddock, N., Cusick, C. M., DeLisi, L., Dodge, S., Escamilla, M. A., Eskelinen, S., Fanous, A. H., Faraone, S. V., Fiorentino, A., Francioli, L., Gabriel, S. B., Gage, D., Gagliano Taliun, S. A., Ganna, A., Genovese, G., Glahn, D. C., Grove, J., Hall, M.-H., Hämäläinen, E., Heyne, H. O., Holi, M., Hougaard, D. M., Howrigan, D. P., Huang, H., Hwu, H.-G., Kahn, R. S., Kang, H. M., Karczewski, K. J., Kirov, G., Knowles, J. A., Lee, F. S., Lehrer, D. S., Lescai, F., Malaspina, D., Marder, S. R., McCarroll, S. A., McIntosh, A. M., Medeiros, H., Milani, L., Morley, C. P., Morris, D. W., Mortensen, P. B., Myers, R. M., Nordentoft, M., O’Brien, N. L., Olivares, A. M., Ongur, D., Ouwehand, W. H., Palmer, D. S., Paunio, T., Quested, D., Rapaport, M. H., Rees, E., Rollins, B., Satterstrom, F. K., Schatzberg, A., Scolnick, E., Scott, L. J., Sharp, S. I., Sklar, P., Smoller, J. W., Sobell, J. L., Solomonson, M., Stahl, E. A., Stevens, C. R., Suvisaari, J., Tiao, G., Watson, S. J., Watts, N. A., Blackwood, D. H., Børglum, A. D., Cohen, B. M., Corvin, A. P., Esko, T., Freimer, N. B., Glatt, S. J., Hultman, C. M., McQuillin, A., Palotie, A., Pato, C. N., Pato, M. T., Pulver, A. E., St. Clair, D., Tsuang, M. T., Vawter, M. P., Walters, J. T., Werge, T. M., Ophoff, R. A., Sullivan, P. F., Owen, M. J., Boehnke, M., O’Donovan, M. C., Neale, B. M., & Daly, M. J.
- Affiliations
- Broad Institute (US)
- Queen Mary University of London (GB)
- University of Michigan (US)
- Weill Cornell Medicine (US)
- University College London (GB)
- SUNY Downstate Health Sciences University (US)
- King's College London (GB)
- Stony Brook University (US)
- Virginia Commonwealth University (US)
- University of California, Irvine (US)
- University of California, San Francisco (US)
- National Taiwan University (TW)
- Cambridge Health Alliance (US)
- Texas Tech University Health Sciences Center (US)
- University of Helsinki (FI)
- SUNY Upstate Medical University (US)
- Boston Children's Hospital (US)
- Aarhus University (DK)
- Harvard University (US)
- Statens Serum Institut (DK)
- James J. Peters VA Medical Center (US)
- Cardiff University (GB)
- Wright State University (US)
- Icahn School of Medicine at Mount Sinai (US)
- University of Edinburgh (GB)
- University of Tartu (EE)
- Ollscoil na Gaillimhe – University of Galway (IE)
- HudsonAlpha Institute for Biotechnology (US)
- University of Copenhagen (DK)
- University of Cambridge (GB)
- Oxford Health NHS Foundation Trust (GB)
- Emory University (US)
- Massachusetts General Hospital (US)
- University of Southern California (US)
- Finnish Institute for Health and Welfare (FI)
- Trinity College Dublin (IE)
- Karolinska Institutet (SE)
- Johns Hopkins University (US)
- University of California San Diego (US)
- University of California, Los Angeles (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Singh, Tarjinder
- Neale, Benjamin M.
- Daly, Mark J.
- ORCID
- Singh, Tarjinder
- Poterba, Timothy
- Curtis, David
- Akil, Huda
- Barchas, Jack D.
- Bass, Nicholas
- Bigdeli, Tim B.
- Breen, Gerome
- Bromet, Evelyn J.
- Buckley, Peter F.
- Bunney, William E.
- Byerley, William F.
- Chapman, Sinéad B.
- Chen, Wei J.
- Churchhouse, Claire
- Cusick, Caroline M.
- DeLisi, Lynn
- Escamilla, Michael A.
- Eskelinen, Saana
- Fanous, Ayman H.
- Faraone, Stephen V.
- Fiorentino, Alessia
- Francioli, Laurent
- Gabriel, Stacey B.
- Ganna, Andrea
- Genovese, Giulio
- Glahn, David C.
- Grove, Jakob
- Hall, Mei-Hua
- Heyne, Henrike O.
- Holi, Matti
- Hougaard, David M.
- Howrigan, Daniel P.
- Huang, Hailiang
- Hwu, Hai-Gwo
- Kahn, René S.
- Kang, Hyun Min
- Karczewski, Konrad J.
- Kirov, George
- Knowles, James A.
- Lee, Francis S.
- Lehrer, Douglas S.
- Lescai, Francesco
- Malaspina, Dolores
- Marder, Stephen R.
- McCarroll, Steven A.
- McIntosh, Andrew M.
- Medeiros, Helena
- Milani, Lili
- Morley, Christopher P.
- Morris, Derek W.
- Mortensen, Preben Bo
- Myers, Richard M.
- Nordentoft, Merete
- O’Brien, Niamh L.
- Olivares, Ana Maria
- Ouwehand, Willem H.
- Palmer, Duncan S.
- Paunio, Tiina
- Quested, Digby
- Rapaport, Mark H.
- Rees, Elliott
- Rollins, Brandi
- Satterstrom, F. Kyle
- Schatzberg, Alan
- Scolnick, Edward
- Scott, Laura J.
- Sharp, Sally I.
- Sklar, Pamela
- Smoller, Jordan W.
- Sobell, Janet L.
- Solomonson, Matthew
- Stahl, Eli A.
- Stevens, Christine R.
- Suvisaari, Jaana
- Tiao, Grace
- Watson, Stanley J.
- Blackwood, Douglas H.
- Børglum, Anders D.
- Cohen, Bruce M.
- Corvin, Aiden P.
- Esko, Tõnu
- Freimer, Nelson B.
- Glatt, Stephen J.
- McQuillin, Andrew
- Palotie, Aarno
- Pato, Carlos N.
- Pato, Michele T.
- Tsuang, Ming T.
- Vawter, Marquis P.
- Walters, James T.
- Werge, Thomas M.
- Ophoff, Roel A.
- Sullivan, Patrick F.
- Owen, Michael J.
- Boehnke, Michael
- O’Donovan, Michael C.
- Neale, Benjamin M.
- Daly, Mark J.
- Venue
- Nature
- Published
- 2022-04-08
- Volume
- 604
- Issue
- 7906
- Pages
- 509-516
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9805802
- OpenAlex
- W4223433728
- Semantic Scholar
- c2b5a9c2f887fcdd0127f72ee28d110469c6b366
- Cited by
- 983
- References
- 80
- Citations by year
- 2026: 158 · 2025: 214 · 2024: 220 · 2023: 197 · 2022: 139
- FWCI
- 125.23
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- medRxiv (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- GlaxoSmithKline
- Massachusetts General Hospital
- Biogen
- Dalio Foundation
- Broad Institute (U54HG003067)
- Stanley Family Foundation
- National Institute for Health and Care Research
- King's College London
- Cardiff University (MR/L010305/1, G0800509)
- Lundbeckfonden (R155-2014-1724, R204-2015-4129, R341-2020-222, R248‐2017‐2003, R24-2008-3243, R364-2021-85)
- National Institutes of Health (5u01da024417-02, -0001, 5p30ns069329-02, AA 09367, DA 05147, DA024417)
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Canadian Institutes of Health Research
- Medical Research Council (MR/L010305/1, G0800509)
- National Institute on Alcohol Abuse and Alcoholism (R01AA009367, R37AA009367)
- National Institute on Aging (R01AG064955, R01AG035083, P50AG005681, P01AG003991)
- National Heart, Lung, and Blood Institute (U01HL117626, R01HL117626)
- National Institute of Mental Health (U01MH109539, R01MH085521, U01MH105641, U01MH105666, U01MH105653, R01MH116037, R01MH085548, R01MH104964, R01MH094145, MH105653, U01MH105578, R01MH124851, R01MH123451, DA05147)
- National Institute on Drug Abuse (U01-DA024417, R01DA037904, R01DA024417, R01DA005147, R01DA036216, R37DA005147)
- National Human Genome Research Institute (U54HG003067, R01HG007022)
- National Institute of Neurological Disorders and Stroke (P30-NS069329)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD105351)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- schizophrenia, risk genes, GRIN2A, GRIA3, NMDA receptor, AMPA receptors, glutamatergic system, synapses, neurodevelopmental disorders, autism spectrum disorder, epilepsy, schizophrenia pathogenesis
- MeSH terms
- Humans, Mutation, Schizophrenia, Case-Control Studies, Receptors, N-Methyl-D-Aspartate, Genetic Predisposition to Disease, Exome, Neurodevelopmental Disorders
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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