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Age at onset, episodicity, familiality, GCTA, heritability, major depression
Abstract:
Background. Strategies to dissect phenotypic and genetic heterogeneity
of major depressive disorder (MDD) have mainly relied on subphenotypes,
such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on
whether these subphenotypes are familial or heritable is scarce. The
aims of this study are to investigate the familiality of AAO and episode
frequency in MDD and to assess the proportion of their variance
explained by common single nucleotide polymorphisms (SNP heritability).
Method. For investigating familiality, we used 691 families with 2-5
full siblings with recurrent MDD from the DeNt study. We fitted (square
root) AAO and episode count in a linear and a negative binomial mixed
model, respectively, with family as random effect and adjusting for sex,
age and center. The strength of familiality was assessed with intraclass
correlation coefficients (ICC). For estimating SNP heritabilities, we
used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies.
After similarly adjusting for covariates, derived residuals were used
with the GREML method in GCTA (genome-wide complex trait analysis)
software.
Results. Significant familial clustering was found for both AAO (ICC =
0.28) and episodicity (ICC = 0.07). We calculated from respective ICC
estimates the maximal additive heritability of AAO (0.56) and
episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04);
analysis was underpowered for calculating SNP heritability of
episodicity.
Conclusions. AAO and episodicity aggregate in families to a moderate and
small degree, respectively. AAO is under stronger additive genetic
control than episodicity. Larger samples are needed to calculate the SNP
heritability of episodicity. The described statistical framework could
be useful in future analyses.
