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Cited by 1,177Genetic Associations and EpidemiologySchizophrenia research and treatmentGenomic variations and chromosomal abnormalities

Genetic architectures of psychiatric disorders: the emerging picture and its implications

Open access
Sullivan, Patrick F., Daly, Mark J., O'Donovan, Michael·2012·Nature Reviews Genetics
DOI 10.1038/nrg3240PMC PMC4110909
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Abstract

Psychiatric disorders are among the most intractable enigmas in medicine. In the past 5 years, there has been unprecedented progress on the genetics of many of these conditions. In this Review, we discuss the genetics of nine cardinal psychiatric disorders (namely, Alzheimer's disease, attention-deficit hyperactivity disorder, alcohol dependence, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, nicotine dependence and schizophrenia). Empirical approaches have yielded new hypotheses about aetiology and now provide data on the often debated genetic architectures of these conditions, which have implications for future research strategies. Further study using a balanced portfolio of methods to assess multiple forms of genetic variation is likely to yield many additional new findings.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes genetic findings across nine psychiatric disorders and concludes that both rare and common variation contribute across an allelic spectrum, with most disorders being highly polygenic. It argues that larger, balanced genomic studies with statistical rigor are needed to complete the “parts list” and generate biological hypotheses.

Key findings

  • For Alzheimer’s disease, 10 loci identified to date account for ~20% of total variation in risk or ~33% of genetic risk, with APOE the major contributor; pathway analyses implicate cholesterol metabolism and innate immune response.
  • In schizophrenia, a PGC mega-analysis of 9,394 cases and 12,462 controls identified seven genome-wide significant loci; in bipolar disorder, 7,481 cases and 9,250 controls identified two loci. Common polygenic variation in hundreds of loci contributes to schizophrenia and partially overlaps bipolar disorder, with risk profile scores explaining between a quarter and a third of liability variance.
  • In autism spectrum disorder, 5.8% of probands had ≥1 rare de novo structural variant versus 1.7% of unaffected siblings (OR=3.5); exome studies estimate 400–1000 genes, and common variation remains unresolved.
  • A major depressive disorder PGC mega-analysis of 9,240 cases and 9,519 controls found no genome-wide significant findings; ADHD shows increased structural variant burden (OR=2.1; OR=5.7 with mental retardation).

Methods

  • Narrative review of nine psychiatric disorders (Alzheimer’s disease, ADHD, alcohol dependence, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, nicotine dependence, schizophrenia) selected because they have been intensively studied and have published genome-wide results.
  • Synthesizes published genome-wide association, structural variation, linkage, candidate gene, and exome/sequencing studies, emphasizing findings that meet community standards for replication.
  • Uses tables, figures, and an allelic spectrum synthesis; no new primary data or meta-analysis are reported.

Limitations

  • Stated: many published GWAS are small and underpowered (e.g., ASD, ADHD, AN, ALC); MDD null results likely reflect high heterogeneity and lower heritability; no comprehensive “parts list” exists for any psychiatric disorder; pathway analyses have limitations in pathway definition, significance thresholds, and null expectations.
  • Stated: exonic variation studies face background neutral variation and false-positive concerns, requiring large samples and statistical rigor; funding constraints are noted.
  • Evident: as a narrative review, it does not conduct a systematic search or quantitative synthesis, so conclusions depend on the selected literature and available published data.

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

Integrity signals

Registry

Crossref · 10.1038/nrg3240

Cites

207 of 207 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 164 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    The proportion of variance explained by the risk profile score increased with relaxation of the significance thresholds.

    “The proportion of variance explained by the risk profile score increased with relaxation of the significance thresholds.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Yue, W. H. et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nature Genet. 43, 1228–1231 (2011). source

      Not checked in the free run.

  • Findingcitation

    The SCZ risk profile was not predictive of case status for any of six non-psychiatric diseases.

    “As an important test of specificity, the SCZ risk profile was not predictive of case status for any of six non-psychiatric diseases. 177”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007). source

      Not checked in the free run.

  • Findingcitation

    In three independent GWAS, SCZ cases had significantly higher risk profile scores than controls.

    “In three independent GWAS, SCZ cases had significantly higher risk profile scores than controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Yue, W. H. et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nature Genet. 43, 1228–1231 (2011). source

      Not checked in the free run.

  • Findingcitation

    A novel association for SCZ is in Ensembl gene RP11-490G2.1 which encodes the primary transcript for miR-137 (MIR137).

    “A novel association for SCZ is in Ensembl gene RP11-490G2.1 which encodes the primary transcript for miR-137 (MIR137). 62”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Zhong, L., Cherry, T., Bies, C. E., Florence, M. A. & Gerges, N. Z. Neurogranin enhances synaptic strength through its interaction with calmodulin. EMBO J. 28, 3027–3039 (2009). source

      Not checked in the free run.

  • Findingnone given

    For SCZ, the strongest association is in the extended MHC region (chr6:27-33 Mb).

    “For SCZ, the strongest association is in the extended MHC region (chr6:27–33 Mb).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 49
  • Classified as probably not a substantial claim. 20

  • May combine two claims.

    Findingcitation

    One report found more rare SV in SCZ cases (odds ratio, OR=1.15), particularly for large deletions (OR=3.6).

    “One report found more rare SV in SCZ cases (odds ratio, OR=1.15), particularly for large deletions (OR=3.6). 48”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Estimates from two different methods indicated that the risk profile component for SCZ contributes between a quarter and a third of the overall variance in liability to SCZ, a substantial fraction of the 65-81% heritability of SCZ.

    “Finally, estimates from two different methods indicated that the risk profile component for SCZ contributes between a quarter and a third of the overall variance in liability to SCZ, 69,130 a substantial fraction of the 65–81% heritability of SCZ. 179,180”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [69] Yue, W. H. et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nature Genet. 43, 1228–1231 (2011). source

      Not checked in the free run.

    • cites [130] Kim, Y., Zerwas, S., Trace, S. E. & Sullivan, P. F. Schizophrenia genetics: where next? Schizophr. Bull. 37, 456–463 (2011). source

      Not checked in the free run.

    • cites [179] Sullivan, P. F., Kendler, K. S. & Neale, M. C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187–1192 (2003). source

      Not checked in the free run.

    • cites [180] Lichtenstein, P. et al. Common genetic influences for schizophrenia and bipolar disorder: a population-based study of 2 million nuclear families. Lancet 373, 234–239 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    De novo SV may be relevant in BIP (OR=4.8), particularly in cases with earlier ages of onset (OR=6.3).

    “De novo SV may be relevant in BIP (OR=4.8), particularly in cases with earlier ages of onset (OR=6.3). 53”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Malhotra, D. et al. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72, 951–963 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In SCZ, 9,394 cases and 12,462 controls were combined in a single analysis and the top 81 statistically independent loci from that analysis were then tested in over 8,000 cases. The mega-analysis identified seven significant loci.

    “In SCZ, 9,394 cases and 12,462 controls were combined in a single analysis and the top 81 statistically independent loci from that analysis were then tested in over 8,000 cases. The mega-analysis identified seven significant loci (Table 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Need, A. C. et al. Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am. J. Hum. Genet. (in the press). In the largest study yet reported, the authors report exome resequencing of 166 cases with schizophrenia enriched for strong family histories of illness and treatment non-response. No definitive associations were identified: this intriguing finding makes the 'many Mendelians' model of this disorder far less tenable.

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Two small exome sequencing studies reported rates of putatively functional mutations that exceeded null expectations in SCZ cases, although the rate of de novo point mutations was not elevated in cases and specific genes were not identified.

    “Two small exome sequencing studies 56,57 reported rates of putatively functional mutations that exceeded null expectations in SCZ cases (although the rate of de novo point mutations was not elevated in cases and specific genes were not identified).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Girard, S. L. et al. Increased exonic de novo mutation rate in individuals with schizophrenia. Nature Genet. 43, 860–863 (2011). source

      Not checked in the free run.

    • cites [57] Xu, B. et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nature Genet. 43, 864–868 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    For BIP, the discovery phase consisted of 7,481 cases and 9,250 controls with follow-up of 34 statistically independent loci in around 4,500 cases. Two loci exceeded genome-wide significance.

    “For BIP, the discovery phase consisted of 7,481 cases and 9,250 controls with follow-up of 34 statistically independent loci in around 4,500 cases. Two loci exceeded genome-wide significance (Table 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Schizophrenia Psychiatric Genome-Wide Association Study Consortium. Genome-wide association study identifies five new schizophrenia loci. Nature Genet. 43, 969–976 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Large SVs are present in 5-10% of ASD cases, and the number of ASD SVs could total 130-234.

    “Large SVs are present in 5–10% of ASD cases, and the number of ASD SVs could total 130–234. 80”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Betancur, C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42–77 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    There are now replicated data that vulnerability to SCZ is influenced by common genetic variation in hundreds of different loci, and this vulnerability partially overlaps that for BIP.

    “There are now replicated data that vulnerability to SCZ is influenced by common genetic variation in hundreds of different loci, and this vulnerability partially overlaps that for BIP. 69”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Yue, W. H. et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nature Genet. 43, 1228–1231 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Predicted targets of miR-137 were significantly enriched for smaller GWAS p-values (p<0.01), and four of the genes that achieved genome-wide significance contain verified miR-137 binding sites.

    “Supporting the hypothesis that this association implicates MIR137, predicted targets of miR-137 were significantly enriched for smaller GWAS p-values (p<0.01), and four of the genes that achieved genome-wide significance contain verified miR-137 binding sites. 63”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Bemis, L. T. et al. MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines. Cancer Res. 68, 1362–1368 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    There are three instances of ASD cases with de novo deletions of 16p11.2 who also had an affected sibling without this deletion along with similar observations for SV in 1q21.1 and 17p12.

    “Intriguingly, there are three instances of ASD cases with de novo deletions of 16p11.2 who also had an affected sibling without this deletion 157–159 along with similar observations for SV in 1q21.1 and 17p12. 158”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [157] Ott, J. Analysis of Human Genetic Linkage (Johns Hopkins Univ. Press, 1999). source

      Not checked in the free run.

    • cites [158] Weiss, L. A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008). source

      Not checked in the free run.

    • cites [159] Szatmari, P. et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genet. 39, 319–328 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    5.8% of ASD probands had ≥1 rare de novo SV versus 1.7% of their unaffected siblings (OR=3.5), and this difference was more pronounced for SV that intersected genes.

    “For example, 5.8% of ASD probands had ≥1 rare de novo SV versus 1.7% of their unaffected siblings (OR=3.5), and this difference was more pronounced for SV that intersected genes. 80”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Betancur, C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42–77 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The components of the Fagerstrom Test for Nicotine Dependence had heritabilities ranging from relatively high to near zero with important common environmental effects.

    “As part of the TAG consortium, 92 we determined that the components of the Fagerstrom Test for Nicotine Dependence (a measure of NIC) had heritabilities ranging from relatively high to near zero with important common environmental effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994).

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    There are now multiple high-confidence SV, rare exonic variants (currently only for ASD, AD, and ALC), and an increasing number of robustly significant and replicated common variants.

    “Specifically, there are now multiple high-confidence SV (Table 2), rare exonic variants (currently only for ASD, AD, and ALC), and an increasing number of robustly significant and replicated common variants (Table 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    For SCZ, there are no known Mendelian variants, and power analyses can exclude common variants of modest effect (genotypic relative risk > 1.5 for allele frequencies > 0.1).

    “There are no known Mendelian variants, and power analyses can exclude common variants of modest effect (genotypic relative risk > 1.5 for allele frequencies > 0.1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For SCZ, there are multiple SVs that are rare, strong, but non-specific risk factors, and 17 common variant associations of subtle effects.

    “There are multiple SVs that are rare, strong, but non-specific risk factors (Table 2), and 17 common variant associations of subtle effects (Table 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The 10 loci identified to date account for ~20% of the total variation in risk or ~33% of the risk attributable to genetic effects, with the major contribution being from APOE.

    “the 10 loci identified to date account for ~20% of the total variation in risk or ~33% of the risk attributable to genetic effects, with the major contribution being from APOE”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [33] Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genet. 41, 1088–1093 (2009). source

      Not checked in the free run.

    • cites [34] Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genet. 41, 1094–1099 (2009). source

      Not checked in the free run.

    • cites [35] Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nature Genet. 43, 429–435 (2011). source

      Not checked in the free run.

    • cites [36] Naj, A. C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nature Genet. 43, 436–441 (2011). source

      Not checked in the free run.

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

    Premisenone given

    These advances have mostly been via genome-wide association (GWAS) and structural variation (SV) studies.

    “These advances have mostly been via genome-wide association (GWAS) and structural variation (SV) studies”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    None of these SVs is fully penetrant, and nearly all appear to be non-specific as risk is often increased for SCZ, ASD, developmental delay, mental retardation, epilepsy, somatic dysmorphism, and extremes of body mass and head size.

    “None is fully penetrant, and nearly all appear to be non-specific as risk is often increased for SCZ, ASD, developmental delay, mental retardation, epilepsy, somatic dysmorphism, and extremes of body mass and head size.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    A sign test for consistency between the mega-analysis and follow-up stage was highly significant, implying that many of the 81 top loci include true risk loci but that power was insufficient.

    “A sign test for consistency between the mega-analysis and follow-up stage was highly significant, implying that many of the 81 top loci include true risk loci but that power was insufficient.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Need, A. C. et al. Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am. J. Hum. Genet. (in the press). In the largest study yet reported, the authors report exome resequencing of 166 cases with schizophrenia enriched for strong family histories of illness and treatment non-response. No definitive associations were identified: this intriguing finding makes the 'many Mendelians' model of this disorder far less tenable.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    For BIP, there are reports of increased and similar SV burden in cases versus controls.

    “For BIP, there are reports of increased 51–53 and similar SV burden in cases versus controls 54,55”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [51] Zhang, D. et al. Singleton deletions throughout the genome increase risk of bipolar disorder. Mol. Psychiatry 14, 376–380 (2009). source

      Not checked in the free run.

    • cites [52] Priebe, L. et al. Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder. Mol. Psychiatry 17, 421–432 (2011). source

      Not checked in the free run.

    • cites [53] Malhotra, D. et al. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72, 951–963 (2011). source

      Not checked in the free run.

    • cites [54] Grozeva, D. et al. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch. Gen. Psychiatry 67, 318–327 (2010). source

      Not checked in the free run.

    • cites [55] McQuillin, A. et al. Analysis of genetic deletions and duplications in the University College London bipolar disorder case control sample. Eur. J. Hum. Genet. 19, 588–592 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This implies that sample sizes are insufficient and that additional loci can be discovered in larger samples.

    “This implies that sample sizes are insufficient and that additional loci can be discovered in larger samples.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    This suggests the discovery sample was insufficiently large to identify many true risk loci at even nominal levels of significance: adding more SNPs contributed more genetic signal than noise.

    “This suggests the discovery sample was insufficiently large to identify many true risk loci at even nominal levels of significance: adding more SNPs contributed more genetic signal than noise.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The same set of markers also discriminated BIP cases from controls indicating substantial genetic contributions between SCZ and BIP.

    “Remarkably, the same set of markers also discriminated BIP cases from controls indicating substantial genetic contributions between SCZ and BIP.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Yue, W. H. et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nature Genet. 43, 1228–1231 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The evidence for association in the extended MHC region is compelling but high gene density and exceptionally high linkage disequilibrium complicate the identification of specific sequence variation.

    “The evidence for association is compelling but high gene density and exceptionally high linkage disequilibrium complicate the identification of specific sequence variation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ASD mutations with very high penetrance are exceptional (i.e., Rett syndrome mutations in MECP2 and CDKL5), and Mendelian diseases enriched for ASD have far less than complete penetrance (e.g., Fragile X syndrome and tuberous sclerosis).

    “Indeed, ASD mutations with very high penetrance are exceptional (i.e., Rett syndrome mutations in MECP2 and CDKL5), and Mendelian diseases enriched for ASD have far less than complete penetrance (e.g., Fragile X syndrome and tuberous sclerosis). 78”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Stahl, E. A. et al. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nature Genet. 44, 483–489 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ASD has been noted as a comorbid feature of >100 single gene, Mendelian medical genetic syndromes, although the penetrance and confidence of the clinical associations are variable.

    “In addition, ASD has been noted as a comorbid feature of >100 single gene, Mendelian medical genetic syndromes, 79 although the penetrance and confidence of the clinical associations are variable.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Folstein, S. E. & Rosen-Sheidley, B. Genetics of autism: complex aetiology for a heterogeneous disorder. Nature Rev. Genet. 2, 943–955 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Results from SGENE+ implicate NRGN (neurogranin) which may act as a calcium sensor.

    “Further, results from SGENE+ 60 implicate NRGN (neurogranin) which may act as a calcium sensor. 61”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nature Genet. 43, 977–983 (2011). These two papers are the largest and most comprehensive GWAS mega-analyses conducted for psychotic disorders. source

      Not checked in the free run.

    • cites [61] Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 460, 744–747 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    A sign test between the discovery and follow-up results was highly significant, again suggesting insufficient power.

    “Similarly, a sign test between the discovery and follow-up results was highly significant, again suggesting insufficient power. 59”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Schizophrenia Psychiatric Genome-Wide Association Study Consortium. Genome-wide association study identifies five new schizophrenia loci. Nature Genet. 43, 969–976 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    miR-137 is a key regulator of neuronal development with roles in neurogenesis and maturation and is highly expressed at synapses in the cortex and hippocampus.

    “miR-137 is a key regulator of neuronal development with roles in neurogenesis and maturation 64,65 and is highly expressed at synapses in the cortex and hippocampus. 66”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [64] Kwon, E., Wang, W. & Tsai, L. H. Validation of schizophrenia-associated genes CSMD1, C10orf26, CACNA1C and TCF4 as miR-137 targets. Mol. Psychiatry 20 Dec 2011 (doi:10.1038/mp.2011.170). source

      Not checked in the free run.

    • cites [65] Szulwach, K. E. et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J. Cell Biol. 189, 127–141 (2010). source

      Not checked in the free run.

    • cites [66] Smrt, R. D. et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 28, 1060–1070 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Case-control studies are simpler, and most biases can be surmounted by careful study procedures, but cannot delineate rare inherited from de novo variation.

    “Case-control studies are simpler, and most biases can be surmounted by careful study procedures, but cannot delineate rare inherited from de novo variation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    All three studies noted an increased rate of de novo exonic mutations in older parents, with the mutations generally being of paternal origin.

    “Intriguingly, all three studies noted an increased rate of de novo exonic mutations in older parents (with the mutations generally being of paternal origin), 83–85”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [83] Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008). source

      Not checked in the free run.

    • cites [84] Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). source

      Not checked in the free run.

    • cites [85] O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    A focus on multiplex pedigrees has led to the identification of specific mutations underlying hundreds of Mendelian disorders (including ASD and AD).

    “A focus on multiplex pedigrees has led to the identification of specific mutations underlying hundreds of Mendelian disorders (including ASD and AD).”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    The 16p11.2 SV associated with ASD and SCZ has been termed a 'mirror image' SV since the deletion and duplication are associated with increased and reduced head and body size.

    “The 16p11.2 SV associated with ASD and SCZ has been termed a “mirror image” SV since the deletion and duplication are associated with increased and reduced head and body size.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    It is difficult to understand the clinical features of ASD and SCZ as mirror images and, more importantly, ASD is associated with both 16p11.2 deletions and duplications.

    “However, it is difficult to understand the clinical features of ASD and SCZ as mirror images and, more importantly, ASD is associated with both 16p11.2 deletions and duplications.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Simplex-based ascertainment is tailored to evaluate de novo mutations, and predicated on a model in which disorder with dramatically reduced fecundity and a proven role of de novo SV might be explicable as a series of Mendelian disorders attributable to recent high-penetrance mutations in any of a large number of genes.

    “Simplex-based ascertainment is tailored to evaluate de novo mutations, and predicated on a model in which disorder with dramatically reduced fecundity and a proven role of de novo SV might be explicable as a series of Mendelian disorders attributable to recent high-penetrance mutations in any of a large number of genes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    De novo events must confer risk in multiplex families, as such mutations increase the chance that an individual is affected and increase risk in that person's offspring.

    “It has also been pointed out that de novo events must confer risk in multiplex families, as such mutations increase the chance that an individual is affected and increase risk in that person’s offspring.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    For ALC, the published GWAS are small and no large-scale meta-analysis has been conducted.

    “For ALC, the published GWAS are small and no large-scale meta-analysis has been conducted. 93–97”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [93] Tobacco and Genetics Consortium. Meta-analyses of genome-wide association studies implicate multiple loci for smoking behavior. Nature Genet. 42, 441–447 (2010). source

      Not checked in the free run.

    • cites [94] Edenberg, H. J. et al. Genome-wide association study of alcohol dependence implicates a region on chromosome 11. Alcohol. Clin. Exp. Res. 34, 840–852 (2010). source

      Not checked in the free run.

    • cites [95] Bierut, L. J. et al. A genome-wide association study of alcohol dependence. Proc. Natl Acad. Sci. USA 107, 5082–5087 (2010). source

      Not checked in the free run.

    • cites [96] Kendler, K. S. et al. Genomewide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample. Alcohol. Clin. Exp. Res. 35, 963–975 (2011). source

      Not checked in the free run.

    • cites [97] Heath, A. C. et al. A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications. Biol. Psychiatry 70, 513–518 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Voineagu et al. identified a gene expression module that had attenuated expression in post-mortem brain samples of individuals with ASD and which also had enrichment for GWAS signals.

    “Additional support for our recommendation for more GWAS is provided by Voineagu et al. who identified a gene expression module that had attenuated expression in post-mortem brain samples of individuals with ASD and which also had enrichment for GWAS signals. 90”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Ma, D. et al. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann. Hum. Genet. 73, 263–273 (2009). source

      Not checked in the free run.

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

    Premisecitation

    Associations to the nicotinic receptor gene region have also been reported for lung cancer.

    “Associations to this region have also bee reported for lung cancer. 105,106”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [105] Saccone, N. L. et al. Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. PLoS Genet. 6, e1001053 (2010). source

      Not checked in the free run.

    • cites [106] Thorgeirsson, T. E. et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638–642 (2008). source

      Not checked in the free run.

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

    Premisecitation

    A provocative finding from 2003 was that risk for MDD might be influenced by a gene-environment interaction with genetic variation near the serotonin transporter.

    “A provocative finding from 2003 was that risk for MDD might be influenced by a gene-environment interaction with genetic variation near the serotonin transporter. 110”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Rucker, J. J. et al. Genome-wide association analysis of copy number variation in recurrent depressive disorder. Mol. Psychiatry 1 Nov 2011 (doi:10.1038/mp.2011.144). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Almost all other published GWAS with N>11,000 for any disease has found at least one genome-wide significant finding.

    “These null results are intriguing as almost all other published GWAS with N>11,000 for any disease has found at least one genome-wide significant finding.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The most likely reasons for the null MDD GWAS results are particularly high heterogeneity of MDD and insufficient power arising from its lower heritability.

    “The most likely reasons for these results are particularly high heterogeneity of MDD and insufficient power arising from its lower heritability. 108”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] Fowler, C. D., Lu, Q., Johnson, P. M., Marks, M. J. & Kenny, P. J. Habenular α5 nicotinic receptor subunit signalling controls nicotine intake. Nature 471, 597–601 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is an important component arising from common variation in hundreds of different loci for SCZ, and larger sample sizes are likely to convert many of these to genome-wide significance.

    “There is an important component arising from common variation in hundreds of different loci (Box 3), and larger sample sizes are likely to convert many of these to genome-wide significance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The data support multiple novel biological hypotheses (cholesterol metabolism and innate immune response in AD, a network involving miR-137 for SCZ, calcium signaling for BIP and SCZ, and chromatin remodeling for ASD) and reinforce previous hypotheses such as synaptic biology for SCZ and ASD.

    “The data support multiple novel biological hypotheses (for example, cholesterol metabolism and the innate immune response in AD, a network involving miR-137 for SCZ, calcium signaling for BIP and SCZ, and chromatin remodeling for ASD) and reinforce previous hypotheses such as synaptic biology for SCZ and ASD).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    For disorders with sufficient data (AD, BIP, and SCZ), the results are consistent with an allelic spectrum and an etiological role for both rare and common variation.

    “For disorders with sufficient data (AD, BIP, and SCZ), the results are consistent with an allelic spectrum and an etiological role for both rare and common variation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The data support both rare and common variant models for psychiatric disorders.

    “Although we were initially agnostic 123 we now believe that the data support both positions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Common variant SNP effects have been estimated to explain large proportions of the phenotypic heritability for a wide range of diseases: BIP and SCZ; T1DM, T2DM, Crohn's disease, rheumatoid arthritis, celiac disease, and coronary artery disease; and continuous traits (height, intelligence, and body mass).

    “Common variant SNP effects have been estimated to explain large proportions of the phenotypic heritability for a wide range of diseases: BIP and SCZ; 69,130 T1DM, T2DM, Crohn’s disease, rheumatoid arthritis, celiac disease, and coronary artery disease; 70,77 and continuous traits (height, intelligence, and body mass). 70,131,132”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [69] Yue, W. H. et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nature Genet. 43, 1228–1231 (2011). source

      Not checked in the free run.

    • cites [130] Kim, Y., Zerwas, S., Trace, S. E. & Sullivan, P. F. Schizophrenia genetics: where next? Schizophr. Bull. 37, 456–463 (2011). source

      Not checked in the free run.

    • cites [70] International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009). source

      Not checked in the free run.

    • cites [77] Speliotes, E. K. et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nature Genet. 42, 937–948 (2010). source

      Not checked in the free run.

    • cites [131] Lee, S. et al. Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nature Genet. 44, 247–250 (2012). This is a provocative paper showing that liability to SCZ is substantial and distributed among genetic variants across the common variant spectrum and across the genome. The authors suggest that the so-called missing heritability problem is hidden and that the architecture of SCZ is polygenic. source

      Not checked in the free run.

    • cites [132] Davies, G. et al. Genome-wide association studies establish that human intelligence is highly heritable and polygenic. Mol. Psychiatry 16, 996–1005 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    There are statistical hints that ADHD and MDD might also be polygenic.

    “There are statistical hints that ADHD and MDD might also be polygenic.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The knowledge base in psychiatric genetics is vastly greater than five years ago, and the rate of change is unprecedented in the history of the field.

    “the knowledge base in psychiatric genetics is vastly greater than five years ago, and the rate of change is unprecedented in the history of the field.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    SV testing is often part of the clinical evaluation of ASD.

    “For example, SV testing is often part of the clinical evaluation of ASD”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    It is possible to provide realistic estimates of power and to predict the number of new associations for each increment in sample size.

    “It is possible to provide realistic estimates of power and to predict the number of new associations for each increment in sample size 128,129,140”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [128] Orozco, G., Barrett, J. C. & Zeggini, E. Synthetic associations in the context of genome-wide association scan signals. Hum. Mol. Genet. 19, R137–R144 (2010). source

      Not checked in the free run.

    • cites [129] Lander, E. S. Initial impact of the sequencing of the human genome. Nature 470, 187–197 (2011). source

      Not checked in the free run.

    • cites [140] Miller, G. Is pharma running out of brainy ideas? Science 329, 502–504 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    The genomic search space is large but finite and so, in theory, elucidating the parts list for a psychiatric disorder could be achieved.

    “The genomic search space is large but finite and so, in theory, elucidating the parts list for a psychiatric disorder could be achieved.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The genomic search space is large but finite.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    A comprehensive portrait of genetic architecture does not now exist for any psychiatric disorder.

    “A comprehensive portrait of genetic architecture does not now exist for any psychiatric disorder.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    There have been multiple meta-analysis consortia in psychiatric genetics, of which the Psychiatric Genomics Consortium is the largest and most encompassing.

    “there have been multiple meta-analysis 146,147 consortia in psychiatric genetics, of which the Psychiatric Genomics Consortium (http://pgc.unc.edu) is the largest and most encompassing. 123,148,149”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [123] McClellan, J. & King, M. C. Genomic analysis of mental illness: a changing landscape. JAMA 303, 2523–2524 (2010). source

      Not checked in the free run.

    • cites [148] de Bakker, P. I., Neale, B. M. & Daly, M. J. Meta-analysis of genome-wide association studies. Cold Spring Harb. Protoc. 2010, pdb.top81 (2010). source

      Not checked in the free run.

    • cites [149] Psychiatric GWAS Consortium. Genome-wide association studies: history, rationale, and prospects for psychiatric disorders. Am. J. Psychiatry 166, 540–546 (2009). source

      Not checked in the free run.

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

    Premisecitation

    The lifetime cost per person with SCZ is on the order of $US 1.4 million.

    “For example, the lifetime cost per person with SCZ is on the order of $US 1.4 million: 145”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Lamarre-Cliche, M., Castilloux, A. M. & LeLorier, J. Association between the burden of disease and research funding by the Medical Research Council of Canada and the National Institutes of Health. A cross-sectional study. Clin. Invest. Med. 24, 83–89 (2001).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    The successful study of any type of genetic variation in complex biomedical diseases requires very large sample sizes.

    “The successful study of any type of genetic variation in complex biomedical diseases requires very large sample sizes as a means to cut the Gordian knot posed by genetic architecture, etiological complexity, and phenotypic uncertainty.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Genomic technologies routinely posit 105-108 hypotheses, and false positives are a serious concern.

    “Genomic technologies routinely posit 105–108 hypotheses, and false positives are a serious concern.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Humans carry a huge pool of phenotypically-neutral background variation that adds noise to genetic analyses (for example, each person has ~100 loss-of-function variants, most of which are rare in a population).

    “Humans carry a huge pool of phenotypically-neutral background variation that adds noise to genetic analyses (for example, each person has ~100 loss-of-function variants, most of which are rare in a population), 152,153”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [152] Easton, D. F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007). source

      Not checked in the free run.

    • cites [153] MacArthur, D. G. et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012). source

      Not checked in the free run.

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

    Premiseown data

    A GWAS co-authorship network graph demonstrates the high connectedness of researchers in the field.

    “Indeed, a GWAS co-authorship network graph demonstrates the high connectedness of researchers in the field (Figure S2).”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    The published results for ASD and unpublished data on SCZ suggest these issues will be important and underscore the need for sequencing studies to have the same emphasis on statistical rigor and large sample sizes that has enabled GWAS to realize success for multiple psychiatric disorders.

    “The published results for ASD 83–85 and unpublished data on SCZ suggest these issues will be important and underscore the need for sequencing studies to have the same emphasis on statistical rigor and large sample sizes that has enabled GWAS to realize success for multiple psychiatric disorders. 154”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [83] Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008). source

      Not checked in the free run.

    • cites [84] Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). source

      Not checked in the free run.

    • cites [85] O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012). source

      Not checked in the free run.

    • cites [154] Durbin, R. M. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    The genetics knowledge base has advanced considerably during the past five years, and results to date contain clear indications that further study will yield greater insight.

    “the genetics knowledge base has advanced considerably during the past five years, and results to date contain clear indications that further study will yield greater insight.”
    Quote in the paperNot a substantial claim
61 of 61

  • The authors state this as an assumption.

    Pathway analysis is based on the assumption that risk variants for a disease will converge on sets of genes whose functions are more closely related to each other than to random sets of genes.

    “Pathway analysis is based on the assumption that risk variants for a disease will converge on sets of genes whose functions are more closely related to each other than to random sets of genes.”

  • The authors state this as an assumption.

    For rare variants in complex diseases, pathway analysis will by necessity be based on sets of genes whose involvement in disease is unclear (e.g., genes with a single observed de novo exonic deleterious mutation).

    “For rare variants in complex diseases, based on recent empirical results for ASD, it is probably reasonable to assume that pathway analysis will by necessity be based on sets of genes whose involvement in disease is unclear (e.g., genes with a single observed de novo exonic deleterious mutation). 83,84”

  • The paper relies on this without support.

    Common variation plays a clear role in other psychiatric disorders.

    “given that detailed studies of rare variation currently explain a fraction of risk and that common variation plays a clear role in other psychiatric disorders.”

  • The paper relies on this without support.

    The genomic search space is large but finite.

    “The genomic search space is large but finite and so, in theory, elucidating the parts list for a psychiatric disorder could be achieved.”
4 of 4

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?

Self-check

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

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

  • Conflicting conclusions about whether ASD risk can be entirely due to rare variants

    Major

    The paper says the available evidence cannot establish or rule out a role for common genetic variation in ASD, but later says an architecture consisting entirely of rare variants is inconsistent with the ASD data. The latter conclusion rules out what the former says remains possible.

1 of 1

Cites

Flagged first, then by citations

2 of the 209 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. World Health Organization. The Global Burden of Disease: 2004 Update (WHO Press, 2008).

Cited by

Sorted by citations

Related

Authors
Sullivan, P. F., Daly, M. J., & O'Donovan, M.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Harvard University (US)
Corresponding author
Sullivan, Patrick F.
ORCID
Venue
Nature Reviews Genetics
Publisher
Springer Science and Business Media LLC
Published
2012-07-10
Volume
13
Issue
8
Pages
537-551
ISSN
  • 1471-0056 (ISSN-L)
  • 1471-0064
DOI
10.1038/nrg3240
PMC
PMC4110909
OpenAlex
W2017826413
Semantic Scholar
0daf00932712fc6331a171911cea4681ab7a668e
Cited by
1,177
References
209
Citations by year
2026: 35 · 2025: 56 · 2024: 37 · 2023: 41 · 2022: 58 · 2021: 68 · 2020: 84 · 2019: 91 · 2018: 103 · 2017: 107 · 2016: 107 · 2015: 127 · 2014: 150 · 2013: 90 · 2012: 21
FWCI
15.22
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
Funders
  • Wellcome Trust
  • National Institutes of Health
  • Medical Research Council
  • National Institute of Mental Health (R01MH077139, U01MH085520, MH085520, MH077139)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
mental illness, genetic architecture, genome-wide association study, structural variants, exome sequencing, Alzheimer's disease, attention deficit hyperactivity disorder, alcoholism, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, nicotine dependence, schizophrenia, genetic aetiology
MeSH terms
Alcoholism, Alzheimer Disease, Anorexia Nervosa, Attention Deficit Disorder with Hyperactivity, Mental Disorders, Bipolar Disorder, Child, Child Development Disorders, Pervasive, Major Depressive Disorder, Humans, Models, Genetic, Schizophrenia, Tobacco Use Disorder

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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