A Genome-Wide Association Study of Depressive Symptoms

Abstract

Background Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. Methods In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 × 10−5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. Results The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 × 10−7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 × 10−3). This 5q21 region reached genome-wide significance (p = 4.78 × 10−8) in the overall meta-analysis combining discovery and replication studies (n = 51,258). Conclusions The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait

“…There have been numerous reports of genetic associations between polymorphisms in clock genes and psychiatric disorders (including major depressive disorder and seasonal affective disorder) (6)(7)(8)(9)(10)(11)(12)(13)(14), but neither direct causal mutations nor molecular pathways have been identified. We previously reported that in a FASP kindred with a mutation in casein kinase 1δ, four of the five affected individuals exhibited higher depression scores (17) however, the mutant mice carrying the casein kinase 1δ mutation were not phenotyped for depression-like behavior.…”

“…In addition, shift work has been suggested as a risk factor for major depressive disorder (3), and depression severity correlates with the degree of circadian misalignment (4,5). A number of genetic variants in core clock genes have been reported as statistically associated with mood disorders, including seasonal affective disorder and major depressive disorder (6)(7)(8)(9)(10)(11)(12)(13)(14), but to date none has been causally related with an understanding of specific molecular links.…”

The 52 different symptoms of major depression: lack of content overlap among seven common depression scales

“…Considering the persistent lack of progress in core research areas such as antidepressant efficacy (Khan and Brown, 2015) and biomarkers robustly associated with depression diagnosis (Hek et al, 2013;Kapur et al, 2012), this topic deserves more attention in contemporary research.…”

Role of corticosteroids in the antidepressant response

“…53 This is in addition to the finding that apparently healthy first-degree relatives of probands with major depressive episodes exhibit HPA dysregulation similar to that seen in affected relatives and different to the response seen in healthy controls. 54 The failure of genome wide association studies to identify relevant genetic polymorphisms (or for that matter any polymorphisms) associated with the HPA axis 55 is likely attributable to the complex relationship between the environmental and genetic factors that predispose to depression.…”

“…AVP1b receptor, 62 11β-HSD1 receptor, 63 amino peptidase N (which controls AVP release), 55 and P-glycoprotein genes 64 also show an association with depression and response to antidepressant treatment. 65 Epigenetic changes that include DNA methylation are responsible for a reversible functional impact 66 causing changes in the expression of genes coding for AVP, 67 and FKBP5, 22 and can arise following trauma or adversity during critical developmental periods.…”