Genetic predisposition to advanced biological ageing increases risk for childhood-onset recurrent major depressive disorder in a large UK sample.
Genetic predisposition to advanced biological ageing increases risk for childhood-onset recurrent major depressive disorder in a large UK sample.
复制标题
DOI：
10.1016/j.jad.2017.01.017
复制
发表时间：
2017-04-15
影响因子：
6.6
通讯作者：
Powell TR
中科院分区：
文献类型：
--
作者：
Michalek JE;Kepa A;Vincent J;Frissa S;Goodwin L;Hotopf M;Hatch SL;Breen G;Powell TR
先前的研究表明，通过白细胞端粒长度（TL）的缩短，重度抑郁症（MDD）患者的生物衰老增加。应激源如童年虐待在重度抑郁症患者中更为常见，有人认为这可能导致患者的生存期较短。然而，据我们所知，目前还没有研究测试反向因果关系，即短TL的遗传倾向是否会导致重度抑郁症或早发性重度抑郁症。本研究采用孟德尔随机化设计，调查在一个相对较大的英国样本（1628例MDD病例，1140例对照）中，缩短TL是否会增加复发性MDD的风险。为了实现这一点，我们使用了样本的一个子集，其中TL数据可用，以确定合适的工具变量。我们对端粒酶RNA成分（TERC）上游的SNP rs10936599和端粒酶逆转录酶（hTERT）内的SNP rs2736100进行了单核苷酸多态性（SNP）基因分型，并试图重复将这些SNP确定为TL预测因子的发现。之后，我们进行了回归，以检验缩短TL的遗传风险是否会增加MDD、儿童期发病的MDD或儿童期/青少年发病的MDD的风险。与cc携带者相比，rs10936599的t携带者表现出更短的TL （p≤0.05；3%的方差解释），随后将其作为我们的工具变量。我们发现，与对照相比，rs10936599的t等位基因预测儿童期发病的MDD风险增加（p≤0.05），儿童期发病的MDD风险相对于成年发病的MDD病例增加（p≤0.001），但rs10936599不能预测成年发病的MDD风险。局限性包括相对较小的早发病例样本，以及发病年龄是通过回顾性回忆确定的事实。使用rs10936599检测的生物衰老的遗传易感性预测了儿童期复发性重度抑郁症的小但显著的风险增加。提前生物衰老的遗传倾向可能是驱动先前报道的较短寿命和重度抑郁症之间关联（或缺乏关联）的一个因素。我们的研究结果还表明，端粒酶可能是预防儿童期发病的重度抑郁症的潜在重要药物靶点，至少在一部分病例中是这样。未来的研究应该尝试在更大的人群中复制我们的发现。端粒酶RNA组成基因（rs10936599）内单核苷酸多态性的t载体预示着端粒长度更短，因此生物衰老更快。携带rs10936599基因的t基因携带者也更容易被诊断为儿童期复发性重度抑郁症。我们的研究表明，提前生物衰老的遗传倾向增加了早期复发性重度抑郁症的风险。
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. 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.
登录
查看更多内容
影响因子：
15.9
作者：
Eitan E;Hutchison ER;Mattson MP
通讯作者：
Mattson MP
影响因子：
15.1
作者：
Garcia-Rizo, Clemente;Fernandez-Egea, Emilio;Kirkpatrick, Brian
通讯作者：
Kirkpatrick, Brian
影响因子：
4.5
作者：
Hatch, Stephani L.;Frissa, Souci;Hotopf, Matthew
通讯作者：
Hotopf, Matthew
影响因子：
6.6
作者：
Elvsashagen, Torbjorn;Vera, Elsa;Boye, Birgitte
通讯作者：
Boye, Birgitte
影响因子：
16.6
作者：
Jurk, Diana;Wilson, Caroline;Passos, Joao F.;Oakley, Fiona;Correia-Melo, Clara;Greaves, Laura;Saretzki, Gabriele;Fox, Chris;Lawless, Conor;Anderson, Rhys;Hewitt, Graeme;Pender, Sylvia L. F.;Fullard, Nicola;Nelson, Glyn;Mann, Jelena;van de Sluis, Bart;Mann, Derek A.;von Zglinicki, Thomas
通讯作者：
von Zglinicki, Thomas