Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

/pdf/major-depressive-disorder-4dnf4f9a0d.pdf

Major depressive disorder

https://spiral.imperial.ac.uk/bitstream/10044/1/61989/2/JPSYCHIATRRES_2017_941_Original_V0%20%282%29.pdf

Mapping risk factors for depression across the lifespan: An umbrella review of evidence from meta-analyses and Mendelian randomization studies.

https://research.vu.nl/ws/files/121324265/The_Genetics_of_the_Mood_Disorder_Spectrum_Genomewide_Association_Analyses_of_More_Than_185000_Cases_and_439000_Controls.pdf

The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls

https://espace.library.uq.edu.au/view/UQ:688922/UQ688922_OA.pdf

Does Childhood Trauma Moderate Polygenic Risk for Depression? A Meta-analysis of 5765 Subjects From the Psychiatric Genomics Consortium

An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14 949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15 138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884 105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on ∼120 000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status.

The association between lower educational attainment and depression owing to shared genetic effects? Results in ∼25 000 subjects

Objective: Parkinson s disease (PD) is a neurodegenerative disorder with complex aetiology. Multiple genetic and environmental factors have been associated with PD, but most PD risk remains unexplained. The aim of this study was to test for statistical interactions between PD-related genetic and environmental exposures/phenotypic traits in the 23andMe, Inc. research dataset. Methods: Using a validated PD polygenic risk score (PRS) and common PD-associated variants in the GBA gene, we explored interactions between genetic susceptibility factors and phenotypic traits: body mass index (BMI), type 2 diabetes (T2D), tobacco use, caffeine consumption, pesticide exposure, head injury, and physical activity (PA). Results: In models without gene-by-environment interactions, we observed that higher BMI, T2D, caffeine consumption, and tobacco use were associated with lower odds of PD, while head injury, pesticide exposure, and GBA carrier status were associated with increased odds. We observed no significant association between PA and PD. PRS was associated with increased odds of PD and there was statistical evidence for an interaction between PRS and BMI, PRS and T2D, PRS and PA, and PRS and tobacco use (p=4.314E-4; p=6.502E-8; p=8.745E-5, p=2.236E-3, respectively). Whilst BMI and tobacco use were associated with lower odds of PD regardless of the extent of individual genetic liability, the direction of the relationship between odds of PD and T2D as well as PA, varied depending on PRS. Interpretation: We provide preliminary evidence that associations between phenotypic traits and PD may be modified by genotype.

/pdf/gene-environment-interactions-for-parkinson-disease-17mb5y2f.pdf

Gene-environment interactions for Parkinson disease

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The association between lower educational attainment and depression owing to shared genetic effects? Results in ∼25 000 subjects

Gene-environment interactions for Parkinson disease