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

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 childhood maltreatment are more common amongst MDD patients, and it has been suggested that this might contribute to shorter TL present amongst patients. However, to our knowledge, no study has yet tested for reverse causality, i.e. whether a genetic predisposition to shorter TL might predispose to MDD or an earlier onset of MDD.

Methods: This study used a Mendelian randomisation design to investigate if shortened TL might increase risk for recurrent MDD in a relatively large UK sample (1628 MDD cases, 1140 controls). To achieve this, we used a subset of our sample, for which TL data was available, to identify a suitable instrumental variable. We performed single nucleotide polymorphism (SNP) genotyping on rs10936599, a SNP upstream of telomerase RNA component (TERC), and rs2736100, a SNP within telomerase reverse transcriptase (hTERT), and attempted to replicate findings which identified these SNPs as predictors of TL. After which, we performed regressions 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 variance explained) and was subsequently used as our instrumental variable. We found that the T-allele of rs10936599 predicted increased risk for childhood-onset MDD relative to controls (p≤0.05), and increased risk for childhood-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-onset was ascertained by retrospective recall.

Conclusion: Genetic predisposition to advanced biological ageing, as assayed using rs10936599, predicted a small, but significant, increased risk for childhood-onset recurrent MDD. Genetic predisposition to advanced biological ageing may be one factor driving previously reported associations (or lack of associations) between shorter TL and MDD. Our results also suggest that the telomerase enzyme may act as a potentially important drug target for the prevention of childhood-onset MDD, at least in a subset of cases. Future studies should attempt to replicate our findings in a larger cohort.