Genetic predisposition to advanced biological ageing increases risk for childhood-onset recurrent major depressive disorder in a large UK sample
| العنوان: | Genetic predisposition to advanced biological ageing increases risk for childhood-onset recurrent major depressive disorder in a large UK sample |
|---|---|
| المؤلفون: | Michalek, Julia E., Kepa, Agnieszka, Vincent, John, Frissa, Souci, Goodwin, Laura, Hotopf, Matthew, Hatch, Stephani L., Breen, Gerome, Powell, Timothy R. |
| المصدر: | Journal of Affective Disorders Michalek, J E, Kepa, A, Vincent, J, Frissa, S, Goodwin, L, Hotopf, M, Hatch, S L, Breen, G & Powell, T 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, vol. 213, pp. 207-213 . https://doi.org/10.1016/j.jad.2017.01.017Test JOURNAL OF AFFECTIVE DISORDERS |
| بيانات النشر: | Elsevier/North-Holland Biomedical Press, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Adult, Male, Aging, Genotype, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Article, Recurrence, Risk Factors, mental disorders, Leukocytes, Humans, Genetic Predisposition to Disease, Age of Onset, Telomerase, Alleles, Telomere Shortening, Retrospective Studies, Depressive Disorder, Major, Middle Aged, United Kingdom, Clinical Psychology, Psychiatry and Mental health, Case-Control Studies, RNA, Female |
| الوصف: | 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. Highlights • T-carriers of a single nucleotide polymorphism within the telomerase RNA component gene (rs10936599) predicts shorter telomere lengths, and therefore advanced biological ageing. • T-carriers of rs10936599 are also significantly more likely to be diagnosed with childhood-onset recurrent major depression. • Our study suggests that a genetic predisposition to advanced biological ageing increases risk for early onset recurrent major depression. |
| وصف الملف: | application/pdf; application/vnd.openxmlformats-officedocument.wordprocessingml.document |
| اللغة: | English |
| تدمد: | 1573-2517 0165-0327 1093-6599 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::61dcbd85e69c06b109bc22bc529e6af0Test http://europepmc.org/articles/PMC6191533Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.pmid.dedup....61dcbd85e69c06b109bc22bc529e6af0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15732517 01650327 10936599 |
|---|