Michalek Julia E, Kepa Agnieszka, Vincent John, Frissa Souci, Goodwin Laura, Hotopf Matthew, Hatch Stephani L, Breen Gerome, Powell Timothy R
King's College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, London, UK.
King's College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, London, UK; National Institute for Health Research Biomedical Research Centre for Mental Health, Institute of Psychiatry, Psychology and Neuroscience at the Maudsley Hospital and King's College London, UK.
J Affect Disord. 2017 Apr 15;213:207-213. doi: 10.1016/j.jad.2017.01.017. Epub 2017 Feb 16.
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.
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.
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 include a relatively small sample of early-onset cases, and the fact that age-of-onset was ascertained by retrospective recall.
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.
既往研究显示，通过较短的白细胞端粒长度（TL）测定，重度抑郁症（MDD）患者的生物衰老有所增加。童年虐待等应激源在MDD患者中更为常见，有人认为这可能导致患者端粒长度较短。然而，据我们所知，尚无研究检验反向因果关系，即较短端粒长度的遗传易感性是否可能导致MDD或MDD更早发病。
本研究采用孟德尔随机化设计，在一个相对较大的英国样本（1628例MDD病例，1140例对照）中调查缩短的TL是否可能增加复发性MDD的风险。为实现这一目标，我们使用了样本中的一个子集（可获得TL数据）来确定一个合适的工具变量。我们对端粒酶RNA组分（TERC）上游的单核苷酸多态性（SNP）rs10936599和端粒酶逆转录酶（hTERT）内的SNP rs2736100进行了基因分型，并试图重复将这些SNP确定为TL预测因子的研究结果。之后，我们进行回归分析，以检验缩短TL的遗传风险是否会增加MDD、儿童期起病的MDD或儿童/青少年期起病的MDD的风险。
与CC携带者相比，rs10936599的T携带者端粒长度较短（p≤0.05；解释了3%的方差），随后被用作我们的工具变量。我们发现，rs10936599的T等位基因预测儿童期起病的MDD相对于对照组的风险增加（p≤0.05），以及儿童期起病的MDD相对于成人期起病的MDD病例的风险增加（p≤0.001），但rs10936599不能预测成人期起病的MDD风险。
局限性包括早发病例的样本相对较小，以及发病年龄是通过回顾性回忆确定的。
使用rs10936599测定的生物衰老提前的遗传易感性预测了儿童期起病的复发性MDD的风险虽小但显著增加。生物衰老提前的遗传易感性可能是导致先前报道的较短TL与MDD之间关联（或无关联）的一个因素。我们的结果还表明，端粒酶可能是预防儿童期起病的MDD的一个潜在重要药物靶点，至少在一部分病例中是这样。未来的研究应尝试在更大的队列中重复我们的发现。
