CoChat
Sign Up
Cited by 2,565Genetic Associations and EpidemiologyNeurotransmitter Receptor Influence on BehaviorTreatment of Major Depression

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

Open access
Howard, David M., Adams, Mark J., Clarke, Toni-Kim, Hafferty, Jonathan D., Gibson, Jude, Shirali, Masoud, Coleman, Jonathan R. I., Hagenaars, Saskia P. +32 more·2019·Nature Neuroscience
DOI 10.1038/s41593-018-0326-7PMC PMC6522363

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches. The authors conducted a genetic meta-analysis of depression and found 269 associated genes. These genes highlight several potential drug repositioning opportunities, and relationships with depression were found for neuroticism and smoking.

Integrity signals

Registry

Crossref · 10.1038/s41593-018-0326-7

Cites

114 of 114 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 50 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The neuroticism-to-depression effect remained consistent in leave-one-variant-out IVW (P = 1.58 × 10−21).

    “This putative causal effect remained consistent (P = 1.58 × 10-21) in the ‘leave one variant out’, IVW analysis indicating that the observed effect was not driven by a single variant.”
    Quote in the paperNot a substantial claim
  • Findingown data

    A gene-set for somatosensory pyramidal neurons was significant (P = 3.87 × 10−5) using Skene et al. brain cell-type data.

    “We also identified a significant gene-set (P = 3.87 × 10-5) containing somatosensory pyramidal neurons using brain cell-type data from Skene, et al. 15 (Table 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Skene, N. G. et al. Genetic identification of brain cell types underlying schizophrenia. Nat. Genet. 50, 825–833 (2018). source

      Not checked in the free run.

  • Findingown data

    Overlap with neuroticism studies highlighted putative depression associations for DRD2, CELF4, and ELAVL2.

    “Examining significant genes that overlap between the current meta-analysis of depression and the neuroticism studies of both Luciano, et al. 18 and Okbay, et al. 19 revealed putative associations with DRD2, CUGBP Elav-like family member 4 (CELF4) and ELAV like RNA binding protein 2 (ELAVL2).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Luciano, M. et al. Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism. Nat. Genet. 50, 6–11 (2018). source

      Not checked in the free run.

    • cites [19] Okbay, A. et al. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nat. Genet. 48, 624–633 (2016). source

      Not checked in the free run.

  • Findingown data

    Cell-type heritability partitioning showed enrichment for central nervous system and skeletal muscle tissues.

    “Partitioning the heritability estimate by cell type enrichment (Figure 2A, and Supplementary Table 6) revealed that central nervous system (CNS) and skeletal muscle tissues were enriched (Pcorrected < 0.05) for genetic variants contributing to the heritability of depression.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The remaining six gene-sets were biological processes: GO_BEHAVIOR, CO_COGNITION, GO_MODULATION_OF_SYNAPTIC_TRANSMISSION, GO_REGULATION_OF_SYNAPSE_STRUCTURE_OR_ACTIVITY, GO_MODULATION_OF_SYNAPTIC_PLASTICITY, and GO_SINGLE_ORGANISM_BEHAVIOR.

    “The other six associated gene-sets were biological processes: GO_BEHAVIOR, CO_COGNITION, GO_MODULATION_OF_SYNAPTIC_TRANSMISSION, GO_REGULATION_OF_SYNAPSE_STRUCTURE_OR_ACTIVITY, GO_MODULATION_OF_SYNAPTIC_PLASTICITY, and GO_SINGLE_ORGANISM_BEHAVIOR.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 38
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Findingown data

    The three contributing cohorts showed strong pairwise genetic correlations: PGC_139k-23andMe_307k rG = 0.85, UK Biobank-PGC_139k rG = 0.87, and UK Biobank-23andMe_307k rG = 0.85.

    “There was a strong genetic correlation between each of these cohorts. The rG between PGC_139k and 23andMe_307k was 0.85 (s.e = 0.03). The UK Biobank had a rG of 0.87 (s.e = 0.04) with PGC_139k. A similar rG was also found between UK Biobank and 23andMe_307k (0.85, s.e = 0.03).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Bulik-Sullivan, B. K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    DRD2 appeared in all 14 GO gene-sets and in prior depression studies.

    “DRD2 was included in all 14 of the putative Gene Ontology Consortium gene-sets identified (but not the somatosensory pyramidal neurons gene-set) and has been identified in previous studies of depression5, 9, 22.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5] Howard, D. M. et al. Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways. Nat. Commun. 9, 1470 (2018). source

      Not checked in the free run.

    • cites [9] Wray, N. R. et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat. Genet. 50, 668–681 (2018). source

      Not checked in the free run.

    • cites [22] Whitmer, A. J. & Gotlib, I. H. Depressive rumination and the C957T polymorphism of the DRD2 gene. Cogn. Affect. Behav. Neurosci. 12, 741–747 (2012). source

      Not checked in the free run.

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

    Findingown data

    ATC classifications were available for 220 drugs, spanning 54 second-level classes and interacting with 37 genes.

    “Anatomical Therapeutic Chemical (ATC) classifications were available for 220 of these drugs which belonged to 54 different second level ATC classes and which interacted with 37 genes, Figure 3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the replication sample, 97 of 102 variants were nominally significant and 87 survived Bonferroni correction.

    “In the replication sample, 97 out of the 102 associated variants were nominally significant (P < 0.05) and 87 were significant after Bonferroni correction (α = 0.05 / 102; P < 4.90 × 10-4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Enrichment was 1.16× for intronic, 1.41× for H3K4me1, and 17.49× for conserved regions.

    “However, the estimates of enrichment for intronic (1.16×, s.e. = 0.05) and H3K4me1 (1.41×, s.e. = 0.13) regions were much smaller compared to the conserved regions (17.49×, s.e. = 1.68) of the genome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The meta-analysis found significant genetic correlations between depression and neuroticism, anorexia nervosa, ADHD, schizophrenia, and bipolar disorder.

    “Using the meta-analysed results in the current study this was evidenced by significant genetic correlations for depression with neuroticism, anorexia nervosa, attention deficit hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LDSC regression estimated a genomic inflation factor of 1.63 and an intercept of 1.015 (s.e. 0.011) before inflation correction.

    “Linkage Disequilibrium Score (LDSC) regression 10 produced a genomic inflation factor (λGC) estimate of 1.63 with an intercept of 1.015 (0.011) prior to inflation correction”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Bulik-Sullivan, B. K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Leave-one-variant-out IVW analyses showed the depression-to-neuroticism and depression-to-smoking effects were not driven by a single variant.

    “Both the putative causal effects of depression on neuroticism and depression on ever vs. never smoked remained consistent (P < 6.46 × 10-4) in the ‘leave one variant out’ IVW analysis indicating that the observed effect was not driven by a single outlying variant.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IVW MR found a putative causal effect of depression on ever versus never smoking (beta = 0.285, s.e. = 0.077; PFDR = 2.29 × 10−3), without variant heterogeneity.

    “There was also evidence of a putative causal effect of depression on ever vs. never smoked (beta = 0.285, s.e. = 0.077; PFDR = 2.29 × 10-3; Supplementary Figure 5), with no evidence of variant heterogeneity (P = 0.14).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Brain-region and cell-type analyses found significant enrichment for anterior cingulate cortex, frontal cortex, cortex, and neurons.

    “There was significant enrichment (Pcorrected < 0.05) of the anterior cingulate cortex, frontal cortex and cortex brain regions and neuron brain cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Depression was genetically correlated with schizophrenia (rG = 0.32), bipolar disorder (0.33), college completion (−0.19), coronary artery disease (0.13), triglycerides (0.14), body fat (0.16), and waist-to-hip ratio (0.12).

    “Significant genetic correlations with depression included schizophrenia (rG = 0.32, s.e = 0.02), bipolar disorder (rG = 0.33, s.e = 0.03), college completion (rG = -0.19, s.e = 0.03), coronary artery disease (rG = 0.13, s.e = 0.02), triglycerides (rG = 0.14, s.e = 0.02), body fat (rG = 0.16, s.e = 0.03), and waist-to-hip ratio (rG = 0.12, s.e = 0.02).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For neuroticism on depression, weighted median was similar to IVW (beta = 0.337; P = 1.94 × 10−18), while MR Egger was opposite and imprecise (beta = −0.128; P = 0.64).

    “The weighted median test produced similar effect size and P-value to the IVW test (beta = 0.337, s.e. = 0.038; P = 1.94 × 10-18), but the MR Egger test had a large standard error and was in the opposite direction (beta = -0.128, s.e. = 0.271; P = 0.64).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The meta-analysis tested 8,098,588 variants and found 9,744 associated at P < 5 × 10−8, with 102 independently segregating across 101 loci.

    “We tested the effects of 8,098,588 genetic variants on depression and identified 9,744 associated variants (P < 5 × 10-8) of which 102 variants in 101 loci were independently segregating (Supplementary Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Removing 15 LD-overlapping instruments attenuated the depression-to-neuroticism effect from 0.146 to 0.112, and it lost significance after FDR correction (PFDR = 0.037).

    “The effect size for the IVW regression analysis MR test for depression on neuroticism was attenuated from 0.146 (s.e. = 0.039) to 0.112 (s.e. = 0.042) and the P-value was no longer significant after false discovery rate correction (PFDR = 0.037).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both the current meta-analysis PRS and the Wray PRS were significantly associated with MDD in all three target cohorts.

    “Both the meta-analysis PRS and the Wray PRS were significantly associated with MDD in each of the three cohorts”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Novel genetic correlations were observed for depression with Crohn's disease (rG = 0.09) and earlier smoking initiation (rG = −0.21).

    “Additionally, novel genetic correlations were observed between depression and Crohn’s disease (rG = 0.09, s.e. 0.03) and depression and an earlier age of smoking initiation (rG = -0.21, s.e. 0.06).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    After removing 15 LD-overlapping instruments, the neuroticism-to-depression effect fell from 0.366 to 0.289 but stayed significant after FDR correction (PFDR = 1.34 × 10−10).

    “The effect size for the IVW regression analysis MR test for neuroticism on depression was attenuated from 0.366 (s.e. = 0.037) to 0.289 (s.e. = 0.042) and the P-value remained significant after false discovery rate correction (PFDR = 1.34 × 10-10).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    NEGR1 was associated with depression (P = 3.55 × 10−15), with nearby independent variants rs2568958 and rs10890020 in separate loci.

    “The Neuronal Growth Regulator 1 (NEGR1) gene was associated with depression (P = 3.55 × 10-15) and there were two nearby independently-associated variants (rs2568958 and rs10890020) located in separate loci”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LIN28B was significant in the meta-analysis and has been linked to age at menarche.

    “The lin-28 homolog b (LIN28B) gene was significant in our meta-analysis and has been associated with age of menarche 37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Ong, K. K. et al. Genetic variation in LIN28B is associated with the timing of puberty. Nat. Genet. 41, 729–733 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Both heritability enrichment and gene-set analyses supported a role for prefrontal brain regions in depression.

    “The heritability enrichments and gene-set analysis both provided evidence for the role of prefrontal brain regions in depression”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    CDH13 was putatively associated with depression and has been implicated in ADHD.

    “The cadherin 13 (CDH13) gene, which codes for cell adhesion molecules, was found to be putatively associated with depression and has also been implicated in ADHD 32.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Lesch, K.-P. et al. Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J. Neural Transm. (Vienna) 115, 1573–1585 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The meta-analysis found a significant genetic correlation between age at menarche and depression, plus nominal evidence of a bidirectional causal effect.

    “The current meta-analysis identified a significant genetic correlation between age of menarche and depression, and nominal evidence of a bi-directional causal effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    NRG1 is one such candidate, found here in depression and in a recent meta-analysis of antidepressant response.

    “One such candidate is NRG1, identified here in depression, and also in a recent meta-analysis of antidepressant response 50.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Biernacka, J. M. et al. The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response. Transl. Psychiatry 5, e553 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The TCF4 coding region contained two independent depression-associated variants and has been reported in earlier depression studies.

    “The TCF4 gene coding region (Supplementary Figure 12) is also noteworthy as it contained two independently-associated variants for depression and has been identified in previous studies of depression 5, 9, 29.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5] Howard, D. M. et al. Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways. Nat. Commun. 9, 1470 (2018). source

      Not checked in the free run.

    • cites [9] Wray, N. R. et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat. Genet. 50, 668–681 (2018). source

      Not checked in the free run.

    • cites [29] Mossakowska-Wójcik, J., Orzechowska, A., Talarowska, M., Szemraj, J. & Gałecki, P. The importance of TCF4 gene in the etiology of recurrent depressive disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 80, 304–308 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Effect directions were consistent in a large replication sample (1,306,354 individuals; 414,055 cases and 892,299 controls) and across the three contributing studies, increasing confidence in the results.

    “demonstrated a consistency of effect directionality in a large replication sample (total n = 1,306,354, with 414,055 cases and 892,299 controls) and across the three contributing studies allowing greater confidence in the findings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    ASTN2 was putatively associated with depression and is involved in ADHD aetiology and neuronal development.

    “A further gene involved in cell adhesion, astrotactin 2 (ASTN2), which we found to be putatively associated with depression is also involved in ADHD aetiology 32 and plays a role in neuronal development in the brain 33.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Lesch, K.-P. et al. Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J. Neural Transm. (Vienna) 115, 1573–1585 (2008). source

      Not checked in the free run.

    • cites [33] Wilson, P. M., Fryer, R. H., Fang, Y. & Hatten, M. E. Astn2, a novel member of the astrotactin gene family, regulates the trafficking of ASTN1 during glial-guided neuronal migration. J. Neurosci. 30, 8529–8540 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Variant-based heritability enrichment across brain regions and a complementary gene-set analysis both pointed to the importance of prefrontal brain regions.

    “We have used variant-based analyses to calculate heritability enrichment across different brain regions and then also applied a complimentary approach using the genes assigned to functional gene-sets, with both methods highlighting the importance of the prefrontal brain regions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The analysis could not test smoking's effect on depression due to too few instruments, but found a genetic correlation and a causal effect of depression on smoking.

    “In the current analysis there was an insufficient number of instrumental variants to test the effect of smoking on depression, but there was evidence of a genetic correlation between depression and cigarette smoking as well as a causal effect of depression on smoking.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    No analyses were dropped because of directional horizontal pleiotropy.

    “However, no tests were excluded due to directional horizontal pleiotropy.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Twin studies estimate that depression is about 30-40% heritable.

    “Twin studies have provided heritability estimates of the disease of approximately 30-40% 3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Sullivan, P. F., Neale, M. C. & Kendler, K. S. Genetic epidemiology of major depression: review and meta-analysis. Am. J. Psychiatry 157, 1552–1562 (2000). source

      Not checked in the free run.

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

    Premisecitation

    Howard and colleagues' UK Biobank GWAS found 17 variants associated across three depression phenotypes (maximum n = 322,580).

    “More recently, a genome-wide association analysis of UK Biobank by Howard, et al. 5 identified 17 variants associated across three depression phenotypes (maximum total n = 322,580; 113,769 cases and 208,811 controls).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Howard, D. M. et al. Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways. Nat. Commun. 9, 1470 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Overlap among the gene-sets suggests two clusters: one related to synaptic structure and activity, the other to response or behaviour to stimuli.

    “The gene overlap between these gene-sets (Supplementary Table 10) suggests that the gene-sets generally fall within two clusters. One gene-set cluster typically relates to synaptic structure and activity while the other gene-set cluster relates to the response or behaviour to stimuli.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Depression is a polygenic condition shaped by numerous genetic variants, each with a small effect.

    “however depression is a polygenic trait influenced by many genetic variants each of small effect 4”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Ripke, S. et al. Major depressive disorder working group of the psychiatric GWAS Consortium. A mega-analysis of genome-wide association studies for major depressive disorder. Mol. Psychiatry 18, 497–511 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two earlier efforts, a mega-analysis of 9 cohorts and a meta-analysis of 17 cohorts, did not find replicated depression-associated variants.

    “However, both of these studies failed to find any replicated variants associated with depression.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Ripke, S. et al. Major depressive disorder working group of the psychiatric GWAS Consortium. A mega-analysis of genome-wide association studies for major depressive disorder. Mol. Psychiatry 18, 497–511 (2013). source

      Not checked in the free run.

    • cites [6] Hek, K. et al. A genome-wide association study of depressive symptoms. Biol. Psychiatry 73, 667–678 (2013). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Using larger samples with varied diagnostic methods may improve knowledge of depression genetics.

    “Therefore, analysing larger samples, which have used different approaches to diagnosis, may provide advances in our understanding of the genetics of depression.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Prior work links ESR2 to antidepressant effects via up-regulation by 3β-hydroxysteroid dehydrogenase.

    “Estrogen Receptor 2 (ESR2) has previously been implicated in antidepressant action through up-regulation by 3β-hydroxysteroid dehydrogenase 47.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Espallergues, J., Temsamani, J., Laruelle, C. & Urani, A. & Maurice, T. The antidepressant-like effect of the 3β-hydroxysteroid dehydrogenase inhibitor trilostane involves a regulation of β-type estrogen receptors. Psychopharmacology (Berl.) 214, 455–463 (2011). source

      Not checked in the free run.

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

    Premisecitation

    A recent review noted that serotonergic and other frequently studied candidate genes have not shown association with depression.

    “Indeed, a recent review of the genetics studies of depression has remarked upon the failure to demonstrate association with depression for serotonergic and other popular candidate genes 49.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Dunn, E. C. et al. Genetic determinants of depression: recent findings and future directions. Harv. Rev. Psychiatry 23, 1–18 (2015). source

      Not checked in the free run.

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

    Study design and conductown data

    Sample sizes were not pre-determined statistically, though they resemble those in earlier reports.

    “No statistical methods were used to pre-determine sample sizes but our sample sizes are similar to those reported in previous publications 5, 8, 9.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5] Howard, D. M. et al. Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways. Nat. Commun. 9, 1470 (2018). source

      Not checked in the free run.

    • cites [8] Hyde, C. L. et al. Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nat. Genet. 48, 1031–1036 (2016). source

      Not checked in the free run.

    • cites [9] Wray, N. R. et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat. Genet. 50, 668–681 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Dopamine transmission may contribute to both ADHD and depression, with DRD2 and ANKK1 implicated.

    “Dopamine transmission may also underlie ADHD and depression with both the DRD2 and ankyrin repeat and kinase domain containing 1 (ANKK1) genes implicated in our analysis of depression and in ADHD 34.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Mota, N. R. et al. NCAM1-TTC12-ANKK1-DRD2 gene cluster and the clinical and genetic heterogeneity of adults with ADHD.Am. J. Med. Genet. B Neuropsychiatr. Genet. 168, 433–444 (2015). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Genomic inflation was controlled using LDSC regression intercepts for each contributing cohort and the final meta-analysis.

    “Linkage disequilibrium score (LDSC) regression intercepts 10 were used for genomic inflation control of the three contributing cohorts and the final meta-analysis results.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Bulik-Sullivan, B. K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015). source

      Not checked in the free run.

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

    Interpretationreasoning

    Alternatively, the pathways for depression and for serotonergic antidepressant effects could be distinct yet connected via shared intermediary genes.

    “It may also be that the pathways of depression and serotonergic antidepressant effect are separate but entwine through common intermediary genes.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    ErbB4, the receptor for NRG1 on GABAergic neurons, has been proposed as a possible drug target for depression, anxiety, and schizophrenia.

    “The Neuregulin 1 (NRG1) receptor ErbB4, found on GABAergic neurones, has been identified as a potentially druggable target for depression, anxiety and schizophrenia 45.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Bi, L.-L. et al. Amygdala NRG1-ErbB4 is critical for the modulation of anxiety-like behaviors. Neuropsychopharmacology 40, 974–986 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Basimglurant and fenobam are being explored as antidepressants and anxiolytics acting on glutamatergic receptors.

    “There is interest in developing agents, such as basimglurant and fenobam, as antidepressants and anxiolytics that target glutamatergic receptors 46.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Fuxe, K. & Borroto-Escuela, D. O. Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5. Expert. Opin. Investig. Drugs. 24, 1247–1260 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    RSRC1 and MEF2C have been linked to schizophrenia and were both putatively associated with depression here.

    “Additionally, associations have been found between schizophrenia and the arginine and serine rich coiled-coil 1 (RSRC1) 28 and myocyte enhancer factor 2C (MEF2C) 21 genes, both of which we found to be putatively associated with depression.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Potkin, S. G. et al. Gene discovery through imaging genetics: identification of two novel genes associated with schizophrenia. Mol. Psychiatry 14, 416–428 (2009). source

      Not checked in the free run.

    • cites [21] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014). source

      Not checked in the free run.

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

    Premisecitation

    Prior work links the dopaminergic system to depression, especially anhedonia and reduced motivation.

    “The dopaminergic system has been previously implicated in depression, particularly the symptoms of anhedonia and decreased motivation”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Bonci, A. & Hopf, F. W. The dopamine D2 receptor: new surprises from an old friend. Neuron 47, 335–338 (2005). source

      Not checked in the free run.

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

    Interpretationreasoning

    Because depression is causally heterogeneous, dividing it into subtypes will probably clarify distinctions among subtypes and treatments.

    “however, due to the causal heterogeneity of depression, it is likely that stratifying depression will lead to clearer distinction between depression subtypes and potential treatments.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Data collection was not randomized, and experimental conditions and stimulus presentations were not randomized.

    “Data collection was not randomized and there was no randomization in the organization of the experimental conditions or stimulus presentations.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Neither data collection nor analysis was blinded to experimental conditions.

    “Data collection and analysis were not performed blind to the conditions of the experiments.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In rodent models of depression, estrogenic compounds show antidepressant effects.

    “Estrogenic compounds have also been found to have antidepressant effects in rodent models of depression 48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Estrada-Camarena, E., Fernández-Guasti, A. & López-Rubalcava, C. Antidepressant-like effect of different estrogenic compounds in the forced swimming test. Neuropsychopharmacology 28, 830–838 (2003). source

      Not checked in the free run.

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

    Premisecitation

    In animal models of depression, dopamine reuptake inhibitors and D2-receptor agonists have shown antidepressant effects.

    “antidepressant action has been reported for dopamine reuptake inhibitors and D2-receptor agonists in animal models of depression 44.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Bonci, A. & Hopf, F. W. The dopamine D2 receptor: new surprises from an old friend. Neuron 47, 335–338 (2005). source

      Not checked in the free run.

50 of 50

  • The authors state this as an assumption.

    The analysis assumed normal distributions for all data without formally testing this.

    “All data distributions were assumed to be normal but this was not formally tested.”

  • The authors state this as an assumption.

    For Mendelian randomization, the instruments must be associated with the exposure.

    “the genetic variants are associated with the exposure”

  • The authors state this as an assumption.

    For Mendelian randomization, the instruments must not be associated with confounders of the exposure-outcome relationship.

    “the genetic variants are independent of confounders in the exposure-outcome association”

  • The authors state this as an assumption.

    For Mendelian randomization, the instruments must affect the outcome only through the exposure, without horizontal pleiotropy.

    “the genetic variants are associated with the outcome only via their effect on the exposure, i.e. there is no horizontal pleiotropy whereby the variants affect both exposure and outcome independently.”

  • The paper relies on this without support.

    Most antidepressant treatments work by interacting with the serotonergic system.

    “This is surprising, as interaction with the serotonergic system forms the basis of most antidepressant treatments.”

  • The authors state this as an assumption.

    The principal Mendelian randomization test (inverse-variance weighted regression) assumes a zero intercept.

    “This method is based on a regression of the exposure and the outcome which assumes the intercept is constrained to zero”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The latest GWAS of MDD meta-analyzed data from 807,553 individuals and identified 102 loci associated with MDD at genome-wide significance.

    “The latest GWAS of MDD meta-analyzed data from 807 553 individuals and identified 102 loci that were associated with the disorder at genome-wide significance.”

    From Epigenetics and depression (2019) · cites this paper as [5]

    The Results section, “102 independent genetic variants associated with depression,” confirms a meta-analysis of 807,553 individuals and genome-wide significant associations. It reports 102 independently segregating variants in 101 loci, not 102 loci. The study also combined several definitions of depression rather than exclusively clinically diagnosed MDD. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • MDD is a polygenic disorder with multiple loci identified, each with a small effect.

    “What has become clear from these studies is that MDD is a polygenic disorder, with multiple loci being identified, but each with a small effect.”

    From Epigenetics and depression (2019) · cites this paper as [5]

  • GWAS have discovered and successfully replicated genome-wide associations of common gene variants for schizophrenia and major depression.

    “large consortia that have discovered and successfully replicated genome-wide associations of common gene variants (single nucleotide polymorphisms, SNPs) for several disorders including schizophrenia [2] and major depression [3–6].”

    From Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes (2022) · cites this paper as [6]

  • Meta-analysis of GWAS studies identified 102 genetic risk variants in MDD patients, many of which display high expression in frontal cortex and are enriched in biological pathways related to synaptic transmission.

    “A meta-analysis of GWAS studies identified 102 genetic risk variants in MDD patients, many of which display high expression in frontal cortex and are enriched in biological pathways related to synaptic transmission 208.”

    From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [208]

  • Several prospective studies suggest that depression prior to completing education predicts substantially reduced income-earnings in adulthood after adjusting for level of educational attainment.

    “Several prospective studies suggest that depression prior to completing education predicts substantially reduced income-earnings in adulthood after adjusting for level of educational attainment. 230,231”

    From Time for united action on depression: a Lancet–World Psychiatric Association Commission (2022) · cites this paper as [231]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. First, M. B., Spitzer, R. L., Gibbon, M. & Williams, J. B. W. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P). (BiometricsResearch, New York State Psychiatric Institute, New York, NY, USA, 2002).

Cited by

Sorted by citations

Related

Authors
Howard, D. M., Adams, M. J., Clarke, T.-K., Hafferty, J. D., Gibson, J., Shirali, M., Coleman, J. R. I., Hagenaars, S. P., Ward, J., Wigmore, E. M., Alloza, C., Shen, X., Barbu, M. C., Xu, E. Y., Whalley, H. C., Marioni, R. E., Porteous, D. J., Davies, G., Deary, I. J., Hemani, G., Berger, K., Teismann, H., Rawal, R., Arolt, V., Baune, B. T., Dannlowski, U., Domschke, K., Tian, C., Hinds, D. A., 23andMe Research Team, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Trzaskowski, M., Byrne, E. M., Ripke, S., Smith, D. J., Sullivan, P. F., Wray, N. R., Breen, G., Lewis, C. M., & McIntosh, A. M.
Affiliations
  • Royal Edinburgh Hospital (GB)
  • King's College London (GB)
  • University of Glasgow (GB)
  • University of Edinburgh (GB)
  • University of Bristol (GB)
  • University of Münster (DE)
  • The University of Melbourne (AU)
  • University of Freiburg (DE)
  • 23andMe (United States) (US)
  • The University of Queensland (AU)
  • Broad Institute (US)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
Howard, David M.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2019-02-04
Volume
22
Issue
3
Pages
343-352
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-018-0326-7
PMC
PMC6522363
OpenAlex
W2911487850
Semantic Scholar
4577583573d02a179e1e2779ffe112fe516f64f5
Cited by
2,565
References
114
Citations by year
2026: 235 · 2025: 386 · 2024: 512 · 2023: 452 · 2022: 383 · 2021: 304 · 2020: 206 · 2019: 80 · 2018: 1 · 2017: 1 · 2014: 2 · 2012: 1
FWCI
32.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Bristol Research (University of Bristol) (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
  • Research Portal (Queen's University Belfast) (submittedVersion)
Funders
  • South London and Maudsley NHS Foundation Trust
  • Wellcome Trust (208806, Z/17/Z, 104036/Z/14/Z, 208806/Z/17/Z, 104036, 2016-2021)
  • National Institute for Health and Care Research
  • King's College London
  • Lister Institute of Preventive Medicine
  • Deutsche Forschungsgemeinschaft (Dan3/012/17, grant FOR2107, FOR 2107/ DA1151/5-1, DA 1151/5-2 to UD), DA1151/5-2, TRR‐58, DA1151/5-1, FOR 2107, DA1151, SFB TRR 58)
  • Bundesministerium für Bildung und Forschung (DA1151/5-2, FOR2107 DA1151/5-1, 01ER0816, 01ER1506, 01ER0816 and 01ER1506)
  • Dr Mortimer and Theresa Sackler Foundation
  • Westfälische Wilhelms-Universität Münster (DA1151/5-2, FOR2107 DA1151/5-1)
  • Centre for Cognitive Ageing and Cognitive Epidemiology (MR/K026992/1)
  • Directorate for Biological Sciences
  • Medical Research Council (MC_PC_17209, MR/K026992/1, 104036/Z/14/Z, 11/NW/0382, MR/S015132/1, MR/J000914/1, 1078901, MC_PC_17228)
  • Biotechnology and Biological Sciences Research Council (MR/K026992/1)
  • National Institute of Mental Health (U01MH109528, SFB-TRR58, U01MH109536, DA 1151/5-1, U01 MH1095320, MH109528, MH1095320, FOR2107, DA 1151/5-2, U01MH109532)
  • National Institute of Environmental Health Sciences (P01ES000040)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
major depressive disorder, genetic architecture, genome-wide association study, prefrontal cortex, synaptic structure, neurotransmission, gene pathways, neuroticism, smoking, drug repurposing, heritability
MeSH terms
Depression, Major Depressive Disorder, Female, Humans, Male, Genetic Variation, Cohort Studies, Prefrontal Cortex, Genetic Predisposition to Disease, Multifactorial Inheritance, Polymorphism, Single Nucleotide, 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 under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

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 ›

Are you an author, or do you see a problem with this page? Request a review