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Cited by 476Genetic Associations and EpidemiologySchizophrenia research and treatmentAutism Spectrum Disorder Research

Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders

Open access
Sullivan, Patrick F., Geschwind, Daniel H.·2019·Cell
DOI 10.1016/j.cell.2019.01.015PMC PMC6432948
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Abstract

Studies of the genetics of psychiatric disorders have become one of the most exciting and fast-moving areas in human genetics. A decade ago, there were few reproducible findings, and now there are hundreds. In this review, we focus on the findings that have illuminated the genetic architecture of psychiatric disorders and the challenges of using these findings to inform our understanding of pathophysiology. The evidence is now overwhelming that psychiatric disorders are "polygenic"-that many genetic loci contribute to risk. With the exception of a subset of those with ASD, few individuals with a psychiatric disorder have a single, deterministic genetic cause; rather, developing a psychiatric disorder is influenced by hundreds of different genetic variants, consistent with a polygenic model. As progressively larger studies have uncovered more about their genetic architecture, the need to elucidate additional architectures has become clear. Even if we were to have complete knowledge of the genetic architecture of a psychiatric disorder, full understanding requires deep knowledge of the functional genomic architecture-the implicated loci impact regulatory processes that influence gene expression and the functional coordination of genes that control biological processes. Following from this is cellular architecture: of all brain regions, cell types, and developmental stages, where and when are the functional architectures operative? Given that the genetic architectures of different psychiatric disorders often strongly overlap, we are challenged to re-evaluate and refine the diagnostic architectures of psychiatric disorders using fundamental genetic and neurobiological data.

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Crossref · 10.1016/j.cell.2019.01.015

Cites

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Statistics

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Claims the paper makes

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  • Findingnone given

    Around 400 protein-coding genes lie in these loci.

    “Around 400 protein-coding genes lie in these loci.”
    Quote in the paperNot a substantial claim
  • Findingreasoning

    These loci together implicate about 76 Mb of the genome as containing common genetic variants involved in the etiology of these disorders.

    “These loci together implicate ~76 Mb of the genome as containing common genetic variants involved in the etiology of these disorders.”
    Quote in the paperNot a substantial claim
  • Findingnone given

    When functional genomic data from human brain are overlaid, about 50% of the time genes located in loci are also implicated by functional data.

    “If we overlay functional genomic data from human brain (e.g., eQTL or regulatory chromatin interactions), about 50% of the time genes located in loci are also implicated by functional data.”
    Quote in the paperNot a substantial claim
  • Findingown data

    SNP-heritability estimates tend to follow traditional heritability.

    “Table 1 shows SNP-heritability estimates, and these tend to follow traditional heritability.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    In SCZ GRS data, cases in the top decile have 15-fold increased risk compared with the lowest decile.

    “Cases in the top decile have 15 fold increased risk for schizophrenia compared to the lowest decile (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014).”
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    • cites Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014

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  • May combine two claims. 38
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    Findingown data

    There are many controls in the top GRS decile and many cases in the lowest decile.

    “Intriguingly, there are many controls in the top decile and many cases in the lowest decile.”
    Quote in the paperNot a substantial claim

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    Findingown data

    Across the ten psychiatric disorders, 241 loci have a significant association, and 22 loci are associated with at least two disorders.

    “Across all disorders, 241 loci have a significant association with the 10 psychiatric disorders in Table 1 with 22 loci associated with ≥2 psychiatric disorders.”
    Quote in the paperSubstantial claim

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    Findingown data

    Most associated loci are disease specific, but many loci increase risk for multiple disorders.

    “Although most loci are disease specific, many loci increase risk for multiple disorders.”
    Quote in the paperSubstantial claim

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    Findingcitation

    Rare protein-truncating variants in mutation-intolerant genes occurred with equal frequency in autism spectrum disorder and ADHD, and the genes impacted significantly overlapped.

    “rare PTV in mutation intolerant genes occurred with equal frequency in both ASD and ADHD and that the genes impacted significantly overlapped”
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    • cites Satterstrom et al., 2018a

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    Findingcitation

    Studying families with multiple children with autism spectrum disorder significantly reduced the signal from de novo variation compared with singleton families, while enhancing the signal from inherited variation for identifying risk genes.

    “studying families having multiple children with ASD significantly reduced the signal from de novo variation compared to singleton families, while enhancing that from inherited variation to identify risk genes (Ruzzo et al., 2018)”
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    Interpretationreasoning

    Complete knowledge of genetic architecture is insufficient for full understanding; functional genomic architecture is also required, involving regulatory effects on gene expression and coordination of genes in biological processes.

    “Even if we were to have complete knowledge of the genetic architecture of a psychiatric disorder, full understanding requires deep knowledge of the functional genomic architecture – the implicated loci impact regulatory processes that influence gene expression and the functional coordination of genes that control biological processes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    SNP-heritability methods calculate heritability from SNP array data and provide assessments based on genome-wide genotypes, improving on traditional heritability measurements.

    “Second, several methods can calculate the heritability of a trait using SNP array data (Bulik-Sullivan et al., 2015; Yang et al., 2011). These provide assessments of heritability based on genome-wide genotypes, and improves upon traditional heritability measurements given their basis in direct genetic measurements.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bulik-Sullivan et al., 2015 source

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    • cites Yang et al., 2011 source

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    Premisecitation

    A large-effect genetic variant is present in about 15% of ASD cases, with smaller proportions in TS, ADHD, and SCZ.

    “This is particularly salient for ASD where a large effect variant is present in ~15% of cases along with smaller proportions of individuals with TS, ADHD, and SCZ (Iossifov et al., 2012; Sanders et al., 2012; Satterstrom et al., 2018c; Singh et al., 2016; Willsey et al., 2017).”
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    • cites Sanders et al., 2012 source

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    • cites Satterstrom et al., 2018c

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    Premisecitation

    Genetic architecture can inform prospects for clinical utility, but for most psychiatric disorders application is probabilistic rather than deterministic.

    “Genetic architecture can inform prospects for clinical utility: although many deterministic monogenetic conditions are predicted or diagnosed using genetic testing, application to most psychiatric disorders traverses far more murky, probabilistic terrain (Timpson et al., 2018).”
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    Premisecitation

    Results to date indicate that psychiatric disorder risk is imparted by many common variants of individually small effects, and several disorders also have contributions from rarer variants with larger impact on risk.

    “The results to date indicate that psychiatric disorder risk is imparted by many common variants of individually small effects, and several disorders also have contributions from rarer variants with larger impact on risk (Geschwind and Flint, 2015; Sullivan et al., 2018).”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    • cites Sullivan et al., 2018 source

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    Premisecitation

    Common genetic variants generally have small effects on disease risk (OR <1.15), while rare variants typically have larger effect sizes (>2.0), are more likely deleterious, and tend to be removed by natural selection.

    “Given what we know now, common variants generally have small effects on disease risk (OR <1.15), and rare variants typically have larger effect sizes (>2.0), are more likely to be deleterious, and tend to be removed by natural selection (Fu et al., 2013; Nelson et al., 2012; Zeng et al., 2018).”
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    • cites Nelson et al., 2012 source

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    • cites Zeng et al., 2018 source

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    Premisecitation

    SNP-heritability estimates are available for thousands of traits.

    “Indeed, SNP-heritability estimates are available for thousands of traits (Zheng et al., 2017).”
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  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based).

    Interpretationreasoning

    Cellular architecture is required to know where and when functional architectures operate across brain regions, cell types, and developmental stages.

    “Following from this is cellular architecture: of all brain regions, cell types, and developmental stages, where and when are the functional architectures operative?”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    SNP-heritability provides strong indications that common genetic variation is important for all complex psychiatric disorders, and more will be discovered with increasing sample sizes.

    “These provide exceptionally strong indications that common variation genetic variation is important for all complex psychiatric disorders, and more will be discovered with increasing sample sizes.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The number of cases is the crucial determinant of the number of loci discovered; increasing sample sizes will identify more loci.

    “The crucial determinant of the number of loci discovered is the number of cases; as sample sizes increase, more loci will be identified (Geschwind and Flint, 2015; Sullivan et al., 2018).”
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    • cites Geschwind and Flint, 2015 source

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    • cites Sullivan et al., 2018 source

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    Premisecitation

    Rare variants can have a continuum of risk, and a fraction of common variants have large effects, such as APOE in Alzheimer's disease.

    “This is not an invariant rule, as rare variants may have a continuum of risk (Marouli et al., 2017), and a fraction of common variants have large effects (e.g., APOE and Alzheimer’s disease).”
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    Premisecitation

    MDD has had notable difficulties with genetic discovery due to relatively low twin-heritability, but focusing on severe cases and increasing sample sizes has been fruitful.

    “As a common disorder with relatively low twin-heritability (Levinson et al., 2014), MDD has had notable difficulties with genetic discovery, but focusing on severe cases (CONVERGE Consortium, 2015) and increasing sample sizes has been particularly fruitful (Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 2018).”
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    • cites CONVERGE Consortium, 2015

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    • cites Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 2018

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    Premisecitation

    The past decade has seen remarkable progress in elucidating the genetic underpinnings of psychiatric disorders, with numerous findings meeting modern criteria for significance and reproducibility.

    “Despite these challenges, there has been remarkable progress in the past decade in elucidating the genetic underpinnings of psychiatric disorders with numerous findings that meet modern criteria for significance and reproducibility (Geschwind and Flint, 2015; Sullivan et al., 2018).”
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    • cites Sullivan et al., 2018 source

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    Premisenone given

    Common variant association studies have identified more than 100 loci for SCZ and MDD, 53 loci for BIP, and 5-12 loci for ADHD, AN, and ASD.

    “Studies in SCZ and MDD have yielded >100 loci, BIP has 53 loci, and ADHD, AN, and ASD have from 5–12 loci.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Most of these ASD mutations also decrease IQ, and intellectual disability is an important comorbidity of ASD.

    “Most of these mutations also decrease IQ and ID is an important comorbidity of ASD (Buja et al., 2018; Iossifov et al., 2014), which is consistent with previous work identifying dozens of known severe, rare medical genetic syndromes associated with ASD (reviewed in (Abrahams and Geschwind, 2008; Geschwind, 2009)).”
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    Premisecitation

    Comparison of SCZ results between European and East Asian samples indicated a genetic correlation indistinguishable from one, strongly indicating that the common variant genetic basis of SCZ is highly similar across these populations.

    “Importantly, comparison of SCZ results between European and East Asian samples indicated that the genetic correlation was indistinguishable from one, strongly indicating that the common variant genetic basis of SCZ is highly similar across these global populations (Lam et al., Submitted).”
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    Interpretationreasoning

    Indirect twin or pedigree heritability estimates are often upwardly biased, and the degree to which SNP-heritability differs from indirect measures is unclear.

    “If reviewed critically, indirect twin/pedigree heritability estimates are often upwardly biased, and the degree to which SNP-heritability is different from indirect measures is unclear.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Previous work has identified dozens of known severe, rare medical genetic syndromes associated with ASD.

    “which is consistent with previous work identifying dozens of known severe, rare medical genetic syndromes associated with ASD (reviewed in (Abrahams and Geschwind, 2008; Geschwind, 2009)).”
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    • cites Abrahams and Geschwind, 2008 source

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    • cites Geschwind, 2009

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    Premisecitation

    Both rare missense and inherited mutations contribute to autism spectrum disorder, with smaller effect sizes than de novo variants.

    “both rare missense and inherited mutations have been shown to contribute to ASD, simply with smaller effect sizes than de novo variants (Ruzzo et al., 2018; Sanders et al., 2015)”
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    Premisecitation

    Several dozen rare copy number variants confer relatively strong risks for psychiatric disorders, most commonly in autism spectrum disorder and schizophrenia and less frequently in bipolar disorder, Tourette syndrome, and ADHD.

    “Several dozen rare CNVs are known to confer relatively strong risks for psychiatric disorders, most commonly in ASD and SCZ and less frequently in BIP, TS, and ADHD.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    A comprehensive effort of 25 psychiatric and neurological disorders showed that most psychiatric disorders had significant genetic inter-correlations, but there were far fewer for neurological conditions.

    “A more comprehensive effort of 25 psychiatric and neurological disorders showed that most psychiatric disorders had significant genetic inter-correlations, but there were far fewer for neurological conditions (Brainstorm Consortium, 2018).”
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    Premisecitation

    Rare de novo variation is predicted to account for about 15% of ASD cases, with each gene accounting for only a small fraction of cases.

    “Although each gene accounts for only a small fraction of cases, rare de novo variation is predicted to account for ~15% of ASD cases (Iossifov et al., 2014).”
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    • cites Iossifov et al., 2014 source

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    Premisenone given

    Recurrent copy number variants usually arise de novo, mainly through non-allelic homologous recombination in regions flanked by low-copy-number repeats.

    “These recurrent CNVs usually arise de novo, mainly via non-allelic homologous recombination in regions flanked by low copy number repeats.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The major pathogenic mechanism of copy number variants is presumed to be dosage sensitivity of genes within the variant, although distal regulatory effects on genes outside the variant are also plausible.

    “the major pathogenic mechanism is presumed to be dosage-sensitivity of genes in the CNV although distal regulatory effects on genes outside of the CNV are also plausible (de la Torre-Ubieta et al., 2018)”
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    Premisecitation

    Under specific assumptions, Mendelian Randomization can suggest causality; lower educational attainment and higher body mass were putatively causal for MDD.

    “Under a set of specific assumptions, we can also apply Mendelian Randomization (MR) to suggest causality; for two traits with sufficient numbers of significant associations, MR can assess the plausibility of whether one trait has a causal relation with another (e.g., lower educational attainment and higher body mass were putatively causal for MDD) (Major Depressive Disorder Working Group of the P”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 2018

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    • The authors state this as an assumption: The specific assumptions required for Mendelian Randomization hold for the analyzed traits.

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

    Premisenone given

    Psychiatric disorders are not generally associated with brain pathology on gross or microscopic examination.

    “Psychiatric disorders are not generally associated with brain pathology on gross or microscopic examination.”
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    Interpretationreasoning

    Integration of functional genomic data from brain yields empirically based hypotheses about regulatory relationships, but experimental validation is required.

    “Although integration of functional genomic data from brain yields empirically-based hypotheses about regulatory relationships, experimental validation is required.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Around half of non-coding regions have regulatory functions shared across tissues, meaning that half of the regulatory elements in a given tissue may be relatively specific to a tissue, cell type, or developmental stage.

    “around half of non-coding regions have regulatory functions that are shared across tissues meaning that half of the regulatory elements in a given tissue may be relatively specific to a tissue, cell type, or developmental stage (Liu et al., 2017a; Roadmap Epigenomics Consortium, 2015; Won et al., 2016)”
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    Network analysis provides an organizing framework that can divide large gene sets into biologically coherent modules for prioritization or add power to genome-wide association studies.

    “network analysis provides an organizing framework that can divide large gene sets into biologically coherent modules for prioritization (Parikshak et al., 2015; Parikshak et al., 2013), or add power to GWAS (Horn et al., 2018)”
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  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Rare variants that disrupt genes provide a clear starting point for mechanistic studies.

    “rare variants that disrupt genes provide a clear starting point for mechanistic studies”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Genome-wide association study results integrated with regulatory chromatin interactions and gene expression show enrichment of enhancer marks in fetal brain and higher expression of autism spectrum disorder target genes during fetal corticogenesis.

    “GWAS results integrated with regulatory chromatin interactions and gene expression, which show enrichment of enhancer marks in the fetal brain and higher expression of ASD target genes during fetal corticogenesis (Grove et al., In press)”
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    • cites Grove et al., In press

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    Premisecitation

    Curated pathway-based studies using combinations of multiple methods and data sources are more convincing than those using single sources, have yielded evidence for common pathways across psychiatric disorders, but still do not fully overcome biases inherent in literature curation.

    “Curated pathway-based studies using combinations of multiple methods and data sources are far more convincing than those using single sources, and have yielded evidence for common pathways across psychiatric disorders (Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium, 2015), but still do not fully overcome biases inherent in literature curation.”
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    Premisenone given

    Published brain eQTL data have fewer than 1000 samples and contain only a fraction of presumed regulatory relationships.

    “Published brain eQTL data have N<1000 and contain only a fraction of presumed regulatory relationships.”
    Quote in the paperNot a substantial claim

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    Premiseown data

    Rare genetic variation plays a role in some psychiatric disorders, particularly autism spectrum disorder and schizophrenia, and also Tourette syndrome and ADHD.

    “Empirical data show that rare genetic variation plays a role in some of these psychiatric disorders (ASD and SCZ in particular but also for TS and ADHD).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    How common variants influence gene expression within biological networks is generally unknown.

    “Exactly how these variants influence gene expression in the context of biological networks is generally unknown”
    Quote in the paperSubstantial claim

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

    Premisenone given

    There are abundant examples of genetic tests now used clinically that have minimal or no scientific basis.

    “there are abundant examples of genetic tests that are now being used clinically that have minimal or no scientific basis”
    Quote in the paperNot a substantial claim

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    Interpretationnone given

    Genetic approaches to psychiatric disorders have yielded more reproducible insights into etiology than any other prior approach.

    “genetic approaches to psychiatric disorders have yielded more reproducible insights into etiology than any other prior approach”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Wilson's disease and Huntington's disease can present with psychotic or mood symptoms.

    “Classic examples include Wilson’s disease and Huntington’s disease which can present with psychotic or mood symptoms.”
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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Inexpensive SNP arrays can measure the contributions of the vast majority of common variation and be efficiently assessed in large populations now.

    “Inexpensive SNP arrays can measure the contributions of the vast majority of common variation and be efficiently assessed in large populations now.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    In many countries, genetic tests can be used by consumers without rigorous evaluation of analytical validity, clinical validity, and clinical utility.

    “In many countries, genetic tests can be used by consumers without having rigorous evaluation of analytical validity, clinical validity, and clinical utility”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Individuals with a wide range of single-gene disorders can initially present with prominent psychiatric features.

    “individuals with a wide range of single-gene disorders can initially present with prominent psychiatric features”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning

    An individual's phenotype results from environmental influences and/or the combined effects of other rare variants and polygenic risk.

    “The resultant phenotype in an individual is dependent on the impact of environmental factors, and/or the additive effects of other rare variation and polygenic risk.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Many de novo or Mendelian mutations affect brain development and function so strongly that they are not specific to one disorder.

  • May combine two claims.

    Interpretationreasoning

    It remains unclear what drives sex differences, and the drivers probably vary by diagnosis.

    “Whether sex differences are due to differential vulnerability, diverging behavioral/cognitive manifestations, and/or observer bias is not known with clarity but is likely to differ across diagnoses.”
    Quote in the paperNot a substantial claim

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    Premisenone given

    The fundamental database is not sufficiently complete to draw unambiguous conclusions.

    “The fundamental database is not sufficiently complete to draw unambiguous conclusions”
    Quote in the paperSubstantial claim
49 of 49

  • The paper relies on this without support.

    Psychiatric disorders are defined by self-report and observation of cognition and behavior rather than by direct measurement of an etiological factor, making them syndromes rather than single diseases.

    “In addition, psychiatric disorders are defined based on self-report and observation of cognition and behavior rather than on direct measurement of an etiological factor, making them syndromes rather than single diseases.”

  • The paper relies on this without support.

    Few diagnostic features from laboratory testing, brain imaging, or pathology have acceptable positive and negative predictive values for routine clinical use.

    “Many diagnostic features from laboratory testing, brain imaging, or pathology have been evaluated but few have acceptable positive and negative predictive values to support routine clinical use.”

  • The paper relies on this without support.

    The internationally accepted definitions of psychiatric disorders were crafted by experts and influenced by traditions dating back a century or more.

    “Furthermore, the internationally accepted definitions of psychiatric disorders were crafted by experts and influenced by traditions dating back a century or more.”

  • The authors state this as an assumption.

    The specific assumptions required for Mendelian Randomization hold for the analyzed traits.

    “Under a set of specific assumptions, we can also apply Mendelian Randomization (MR) to suggest causality; for two traits with sufficient numbers of significant associations, MR can assess the plausibility of whether one trait has a causal relation with another (e.g., lower educational attainment and higher body mass were putatively causal for MDD) (Major Depressive Disorder Working Group of the P”

  • The paper relies on this without support.

    Genetic correlations between psychiatric disorders reflect shared biological processes rather than diagnostic overlap or other confounds.

    “cross-disorder transcriptome correlations parallel genetic correlations, consistent with common biology processes (Gandal et al., 2018a)”

  • The authors state this as an assumption.

    Genetic variants are not caused by the psychiatric disease (absence of reverse causation).

    “given the plausible absence of reverse causation”

  • The paper relies on this without support.

    Current psychiatric diagnostic categories are valid enough to study genetic overlap and clinical utility.

    “the definitions of psychiatric disorders are necessarily based on descriptive data collected via human interactions and organized by expert panels”

  • The paper relies on this without support.

    Few large-effect mutations are specific to a single disorder, suggesting additional genetic, environmental, and stochastic factors.

    “For instance, few large effect mutations are specific to a disorder suggesting a possible role for additional genetic, environmental, and stochastic factors.”

  • The paper relies on this without support.

    Many de novo or Mendelian mutations affect brain development and function so strongly that they are not specific to one disorder.

    “However, the effects on brain development and function of many de novo or Mendelian mutations are so large as to be non-specific with respect to any single disorder (e.g. epilepsy, ASD, SCZ, ID).”

  • The paper relies on this without support.

    Some rare large-effect mutations show clear preferential effects toward a disorder, as with some CNVs and rare protein-altering mutations.

    “We recognize that there are rare large effect mutations that show clear preferential effects towards a disorder as is the case for some CNVs and rare protein altering mutations.”

  • The paper relies on this without support.

    The causes of melanoma remain incompletely understood, yet checkpoint inhibitors developed from partial insights have greatly improved outcomes in disseminated disease.

    “For instance, the causes of melanoma are not fully worked out but the advent of checkpoint inhibitors – based on several key pieces of the melanoma puzzle — has markedly improved outcomes for disseminated disease.”

  • The paper relies on this without support.

    Almost every prototypic psychiatric medication was found by chance rather than design.

    “as with virtually all prototypic medications used in clinical psychiatry”
12 of 12

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?

  • Pathogenic variants in the same genes are identified in individuals with a variety of different clinically defined brain disorders, including ASD, ID, epilepsy, schizophrenia, and other neurodevelopmental and neuropsychiatric conditions.

    “It has also become clear that pathogenic variants in the same genes are identified in individuals with a variety of different clinically defined brain disorders, including ASD, intellectual disability (ID), epilepsy, schizophrenia, and other neurodevelopmental and neuropsychiatric conditions.”

    From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [7]

Cites

Flagged first, then by citations

11 of the 201 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Hook, 2018, Heritability enrichment in open chromatin reveals cortical layer contributions to schizophrenia, bioRxiv
  2. Satterstrom, 2018, Novel genes for autism implicate both excitatory and inhibitory cell lineages in risk, bioRxiv

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Authors
Sullivan, P. F., & Geschwind, D. H.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • University of California, Los Angeles (US)
Corresponding author
  • Sullivan, Patrick F.
  • Geschwind, Daniel H.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2019-03
Volume
177
Issue
1
Pages
162-183
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2019.01.015
PMC
PMC6432948
OpenAlex
W2923203084
Cited by
452
References
201
Citations by year
2026: 48 · 2025: 37 · 2024: 63 · 2023: 69 · 2022: 69 · 2021: 70 · 2020: 69 · 2019: 26 · 2018: 1
FWCI
7.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Swedish Research Council (D0886501)
  • Horizon 2020 Program of the European Union (610307)
  • NIMH (U01 MH109528, R01 MH077139, R01 MH100027, R01 MH081754, U01 MH115746U01, MH105991, R01 MH109912, R01 MH110927)
  • National Institute on Drug Abuse
  • National Institute of Mental Health (U01 MH109532)
  • Hartwell Foundation
  • Simons Foundation (206744, 239766)
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 › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
mental illness, genetic architecture, polygenic risk, genetic loci, functional genomics, gene expression regulation, gene expression, brain cell types, brain development, pathophysiology, autism spectrum disorder
MeSH terms
Alleles, Mental Disorders, Gene Frequency, Humans, Mental Health, Genetic Variation, Genetic Predisposition to Disease, Multifactorial Inheritance, Genomics, Genome-Wide Association Study

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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

What counts as a claim ›How we measure confidence ›How we check this ›

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