Genetic predisposition to advanced biological ageing increases risk for childhood-onset recurrent major depressive disorder in a large UK sample

Michalek, JE, Kepa, A, Vincent, J, Frissa, S, Goodwin, L, Hotopf, M, Hatch, SL, Breen, G and Powell, TR (2017) Genetic predisposition to advanced biological ageing increases risk for childhood-onset recurrent major depressive disorder in a large UK sample. JOURNAL OF AFFECTIVE DISORDERS, 213. pp. 207-213.

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Abstract

Background:Previous studies have revealed increased biological ageing amongst major depressive disorder(MDD) patients, as assayed by shorter leukocyte telomere lengths (TL). Stressors such as childhoodmaltreatment are more common amongst MDD patients, and it has been suggested that this might contributeto shorter TL present amongst patients. However, to our knowledge, no study has yet tested for reversecausality, i.e. whether a genetic predisposition to shorter TL might predispose to MDD or an earlier onset ofMDD.Methods:This study used a Mendelian randomisation design to investigate if shortened TL might increase riskfor recurrent MDD in a relatively large UK sample (1628 MDD cases, 1140 controls). To achieve this, we used asubset of our sample, for which TL data was available, to identify a suitable instrumental variable. Weperformed single nucleotide polymorphism (SNP) genotyping on rs10936599, a SNP upstream of telomeraseRNA component (TERC), and rs2736100, a SNP within telomerase reverse transcriptase (hTERT), andattempted to replicatefindings which identified these SNPs as predictors of TL. After which, we performedregressions to test if genetic risk for shortened TL increased risk for MDD, childhood-onset MDD or childhood/adolescent-onset MDD.Results:T-carriers of rs10936599 demonstrated shorter TL compared to CC-carriers (p≤0.05; 3% of varianceexplained) and was subsequently used as our instrumental variable. We found that the T-allele of rs10936599predicted increased risk for childhood-onset MDD relative to controls (p≤0.05), and increased risk forchildhood-onset MDD relative to adult-onset MDD cases (p≤0.001), but rs10936599 did not predict adult-onset MDD risk.Limitations:Limitations include a relatively small sample of early-onset cases, and the fact that age-of-onsetwas ascertained by retrospective recall.Conclusion:Genetic predisposition to advanced biological ageing, as assayed using rs10936599, predicted asmall, but significant, increased risk for childhood-onset recurrent MDD. Genetic predisposition to advancedbiological ageing may be one factor driving previously reported associations (or lack of associations) betweenshorter TL and MDD. Our results also suggest that the telomerase enzyme may act as a potentially importantdrug target for the prevention of childhood-onset MDD, at least in a subset of cases. Future studies shouldattempt to replicate ourfindings in a larger cohort.

Item Type:	Article
Uncontrolled Keywords:	Leukocytes, Humans, Genetic Predisposition to Disease, Recurrence, Telomerase, RNA, Risk Factors, Case-Control Studies, Retrospective Studies, Depressive Disorder, Major, Age of Onset, Aging, Genotype, Polymorphism, Single Nucleotide, Alleles, Adult, Middle Aged, Female, Male, Telomere Shortening, United Kingdom
Depositing User:	Symplectic Admin
Date Deposited:	07 Apr 2017 14:53
Last Modified:	19 Jan 2023 07:06
DOI:	10.1016/j.jad.2017.01.017
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3006891