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. 2017 May;34(5):446-452.
doi: 10.1002/da.22607. Epub 2017 Feb 2.

Age of Onset and Family History as Indicators of Polygenic Risk for Major Depression

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Age of Onset and Family History as Indicators of Polygenic Risk for Major Depression

Anna R Docherty et al. Depress Anxiety. .
Free PMC article


Background: The extent to which earlier age of onset (AO) is a reflection of increased genetic risk for major depression (MD) is still unknown. Previous biometrical research has provided mixed empirical evidence for the genetic overlap of AO with MD. If AO is demonstrated to be relevant to molecular polygenic risk for MD, incorporation of AO as a phenotype could enhance future genetic studies.

Methods: This research estimated the SNP-based heritability of AO in the China, Oxford and VCU Experimental Research on Genetic Epidemiology (CONVERGE) case-control sample (N = 9,854; MD case, n = 4,927). Common single nucleotide polymorphism heritability of MD was also examined across both high and low median-split AO groups, and best linear unbiased predictor (BLUP) scores of polygenic risk, in split-halves, were used to predict AO. Distributions of genetic risk across early and late AO were compared, and presence of self-reported family history (FH) of MD was also examined as a predictor of AO.

Results: AO was not significantly heritable and polygenic risk derived from the aggregated effects of common genetic variants did not significantly predict AO in any analysis. AO was modestly but significantly lower in cases with a first-degree genetic FH of MD.

Conclusions: Findings indicate that AO is associated with greater self-reported genetic risk for MD in cases, yet not associated with common variant polygenic risk for MD. Future studies of early MD may benefit more from the examination of important moderating variables such as early life events.

Keywords: CONVERGE; GCTA; age of onset; depression; family history; genome; genome-wide complex trait analysis.


Figure 1
Figure 1. Kernel density plot of age at onset in CONVERGE major depression cases
Figure 2
Figure 2. Major depression best linear unbiased predictor score densities across <16 and ≥ 34 AO groups
The solid line reflects cases with age at onset <16, the dotted line reflects age at onset of the median (34) and above. The band reflects upper and lower end-points of the reference band for equality. This test of equal densities is a permutation test, where the standard error of the sum of the squared differences of the density distributions is used to paint the band shown here. This plot conveys that the distributions of polygenic scores across groups of early and high AO groups are roughly equivalent.

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