Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses

Als, Thomas Damm; Kurki, Mitja; Grove, Jakob; Voloudakis, Georgios; Therrien, Karen; Tasanko, Elisa; Nielsen, Trine Tollerup; Naamanka, Joonas; Veerapen, Kumar; Levey, Daniel F.; Bendl, Jaroslav; Bybjerg‐Grauholm, Jonas; Zeng, Biao; Demontis, Ditte; Rosengren, Anders; Athanasiadis, Georgios; Bækvad-Hansen, Marie; Qvist, Per; Walters, G. Bragi; Thorgeirsson, Thorgeir E.; Stefánsson, Kári; Musliner, Katherine L.; Rajagopal, Veera M.; Farajzadeh, Leila; Thirstrup, Janne Pia; Vilhjálmsson, Bjarni J.; McGrath, John; Mattheisen, Manuel; Meier, Sandra; Agerbo, Esben; Stefánsson, Kāri; Nordentoft, Merete; Werge, Thomas; Hougaard, David M.; Mortensen, Preben Bo; Stein, Murray B.; Hovatta, Iiris; Roussos, Panos; Daly, Mark J.; Mors, Ole; Palotie, Aarno; Børglum, Anders D.

doi:10.1038/s41591-023-02352-1

Cited by 77 publications

(39 citation statements)

References 133 publications

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“…Tentative evidence further suggests that individuals with comorbid anxiety have higher PGSs for a broad depression phenotype (odds ratio per SD PGS = 1.17) compared to participants meeting only MDD criteria (20). These results have been corroborated by recent findings, indicating that depression with comorbid anxiety, as defined by ICD codes, is associated with higher polygenic load for several psychopathological traits in comparison with depression without anxiety (21). Although these reports suggest increased genetic liability for combined anxiety and depression compared to when anxiety or depression occur alone, the limited number of studies and the differences in how cases have been ascertained, make generalizable conclusions premature.…”

supporting

confidence: 80%

Heritability and polygenic load for combined anxiety and depression

Tabrizi,

Rosén,

Grönvall

et al. 2024

Preprint

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Anxiety and depression commonly occur together resulting in worse health outcomes than when they occur in isolation. We aimed to determine whether the genetic liability for combined anxiety and depression was greater than when anxiety or depression occurred alone. Data from 12,558 genotyped twins (ages 38-85) were analysed, including 1,986 complete monozygotic and 1,809 complete dizygotic pairs. Outcomes were prescription of antidepressant and anxiolytic drugs, as demined by the World Health Organization Anatomical Therapeutic Chemical Classimication System (ATC) convention, for combined anxiety and depression (n= 1054), anxiety only (n= 744), and depression only (n= 511). Heritability of each outcome was estimated using twin modelling, and the inmluence of common genetic variation was assessed from polygenic scores (PGS) for depressive symptoms, anxiety, and 40 other traits. Heritability of combined anxiety and depression was 79% compared with 41% for anxiety and 50% for depression alone. The PGS for depressive symptoms likewise predicted more variation in combined anxiety and depression (adjusted odds ratio perSDPGS = 1.53, 95% CI = 1.43-1.63; ΔR2= .031, ΔAUC = .044) than the other outcomes, with nearly identical results when combined anxiety and depression was demined by International Classimication of Diseases (ICD) diagnoses (adjusted odds ratio perSDPGS = 1.70, 95% CI = 1.53-1.90; ΔR2= .036, ΔAUC = .051). Individuals in the highest decile of PGS for depressive symptoms had over 5 times higher odds of being prescribed medication for combined anxiety and depression compared to those in the lowest decile. We conclude that genetic factors explain substantially more variation in combined anxiety and depression than anxiety or depression alone.

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supporting

confidence: 80%

Heritability and polygenic load for combined anxiety and depression

Tabrizi,

Rosén,

Grönvall

et al. 2024

Preprint

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“…64,65 These pathways included MATN2 and/or ZEB2, genes linked to CpG sites with suggestive levels of differential methylation in MDD groups (see: Supplementary Note -MATN2 & ZEB2), and were enriched for common variants associated with MDD and adult trauma. GABA-ergic signalling has previously been associated with depression 66 and trauma, particularly involving the limbic system. [67][68][69][70] and may be important in the response to cognitive therapy targeting the suppression of traumatic memories.…”

Section: Discussionmentioning

confidence: 99%

Methylome-wide association studies of traumatic injury identifies differential DNA methylation of synaptic plasticity and GABAergic-signalling

Brown,

Marshall,

Walker

et al. 2023

Preprint

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Physical trauma is often associated with psychological trauma and is a risk factor for the development of major depressive disorder (MDD). We derived a traumatic physical injury phenotype in the Generation Scotland cohort and showed that it was significantly associated with a diagnosis of recurrent major depression and measures of related symptoms, particularly disorganised thought. Blood-based methylome-wide analyses of traumatic injury were performed in groups of individuals with or without diagnoses of MDD. Nominally significant differences in DNA methylation were identified at 40,003 CpG sites in the effect size of the association of DNA methylation in individuals with and without MDD. Individuals with recurrent MDD showed a significant higher levels of DNA methylation at CpG sites associated with the first exon and lower levels associated with exon boundaries. This may suggest alterations in gene expression and splicing in individuals with recurrent MDD compared to controls. Analyses at the level of CpG site, genes and gene ontologies implicated dysregulation in neuronal development, e.g.MATN2andZEB2, and processes related to synaptic plasticity, including dendrite development, excitatory synapse and GABAergic signalling. Analyses of brain-expression patterns highlight the limbic lobe and supraoptic nuclei, brain regions associated with fear memory encoding. The results suggest that traumatic injury is associated with patterns of DNA methylation but that the direction of these associations differ in individuals with MDD compared to controls, highlighting the need for novel analysis approaches.

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“…Summary statistics from eight GWAS in EUR individuals were selected to capture the internalizing spectrum (Supplementary Table 1). Three were the largest available GWAS of internalizing disorders: (1) anorexia nervosa (AN; n = 72,517), 33 (2) major depressive disorder (MDD; n = 1,074,629), 34 and (3) posttraumatic stress disorder (PTSD; n = 214,408). 35 To reflect a broad liability to internalizing, we included irritability (http://www.nealelab.is/ukbiobank/; n = 345,231), loneliness (n = 490,689), 36 subjective wellbeing (SWB; reverse-coded; n = 298,420), 37 miserableness (http://www.nealelab.is/uk-biobank/; n = 355,182), and anxiety (ANX; n = 280,490).…”

Section: Summary Statisticsmentioning

confidence: 99%

Genetic Insights into Externalizing and Internalizing Traits through Integration of the Research Domain Criteria and Hierarchical Taxonomy of Psychopathology

Davis,

Khan,

Toikumo

et al. 2024

Preprint

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There is considerable comorbidity across externalizing and internalizing behavior dimensions of psychopathology. We applied genomic structural equation modeling (gSEM) to genome-wide association study (GWAS) summary statistics to evaluate the factor structure of externalizing and internalizing psychopathology across 16 traits and disorders among European-ancestry individuals (ns = 16,400 to 1,074,629). We conducted GWAS on factors derived from well-fitting models. Downstream analyses served to identify biological mechanisms, explore drug repurposing targets, estimate genetic overlap between the externalizing and internalizing spectra, and evaluate causal effects of psychopathology liability on physical health. Both a correlated factors model, comprising two factors of externalizing and internalizing risk, and a higher-order single-factor model of genetic effects contributing to both spectra demonstrated acceptable fit. GWAS identified 409 lead single nucleotide polymorphisms (SNPs) associated with externalizing and 85 lead SNPs associated with internalizing, while the second-order GWAS identified 256 lead SNPs contributing to broad psychopathology risk. In bivariate causal mixture models, nearly all externalizing and internalizing causal variants overlapped, despite a genetic correlation of only 0.37 (SE = 0.02) between them. Externalizing genes showed cell-type specific expression in GABAergic, cortical, and hippocampal neurons, and internalizing genes were associated with reduced subcallosal cortical volume, providing insight into the neurobiological underpinnings of psychopathology. Genetic liability for externalizing, internalizing, and broad psychopathology exerted causal effects on pain, general health, cardiovascular diseases, and chronic illnesses. These findings underscore the complex genetic architecture of psychopathology, identify potential biological pathways for the externalizing and internalizing spectra, and highlight the physical health burden of psychiatric comorbidity.

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Depression pathophysiology, risk prediction of recurrence and comorbid psychiatric disorders using genome-wide analyses

Cited by 77 publications

References 133 publications

Heritability and polygenic load for combined anxiety and depression

Heritability and polygenic load for combined anxiety and depression

Methylome-wide association studies of traumatic injury identifies differential DNA methylation of synaptic plasticity and GABAergic-signalling

Genetic Insights into Externalizing and Internalizing Traits through Integration of the Research Domain Criteria and Hierarchical Taxonomy of Psychopathology

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