Dissecting the Genetic Heterogeneity of Depression Through Age at Onset

Abstract

Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder.

Serum Cytokine Levels in Major Depressive Disorder and Its Role in Antidepressant Response

“…Our patients were mostly elderly (age >60 years, 74.2%), and a large portion of them had late-onset illness (age of first onset >60 years, 45.5%). Several studies have suggested that the age at onset can vary in different subtypes of depression, especially in terms of heritability 3738. In addition, previous studies reported that proinflammatory cytokines increase in healthy elderly people,394041 although, we could not find a significant relationship between age, age on onset and sCD40L in our study subjects.…”

Age of onset and family history as indicators of polygenic risk for major depression

“…A genome-wide association study has examined AO of MD as a quantitative trait (in European samples with mean AO of ∼20 years of age, N < 2,000 cases and controls). 28 While specific genome-wide hits did not replicate, results did suggest that common genetic variants may explain a large portion of the variance in AO in European samples (55%, p =.02). Finally, in a report by the Psychiatric Genomics Consortium working group, polygenic score analyses across mixed-ancestry samples suggested that earlier-onset MD is genetically more similar to major psychiatric disorders like schizophrenia and bipolar disorder than is adult-onset MDD.…”

“…Using molecular data on common variants, preliminary research thus far has found a marginally significant single nucleotide polymorphism (SNP)-based heritability estimate of .17 (P = .04 ;Ferentinos et al, 2015) for presence/absence of early AO. A genome-wide association study has examined AO of MD as a quantitative trait (in European samples with mean AO of ∼20 years of age, N < 2,000 cases and controls; Power et al, 2012). Although specific genome-wide hits did not replicate, results did suggest that common genetic variants may explain a large portion of the variance in AO in European samples (55%, P = .02).…”

Additive genetic contribution to symptom dimensions in major depressive disorder.

“…Of interest for this study, GREML demonstrated that common SNPs explained 32% of the variance in depression severity (Lubke et al, 2012) and 51% of the variance in age at onset of MDD (Power et al, 2012). Furthermore, common SNPs accounted for 42% of the variance in pharmacological treatment response of patients with MDD (Tansey et al, 2013).…”