Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system.
Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system.
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DOI：
10.1038/s41380-021-01412-7
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发表时间：
2022-03
影响因子：
11
通讯作者：
McIntosh, Andrew M.
中科院分区：
文献类型：
--
作者：
Barbu, Miruna C.;Huider, Floris;Campbell, Archie;Amador, Carmen;Adams, Mark J.;Lynall, Mary-Ellen;Howard, David M.;Walker, Rosie M.;Morris, Stewart W.;Van Dongen, Jenny;Porteous, David J.;Evans, Kathryn L.;Bullmore, Edward;Willemsen, Gonneke;Boomsma, Dorret I.;Whalley, Heather C.;McIntosh, Andrew M.
抗抑郁药是治疗重度抑郁症（MDD）的有效方法，尽管个体的反应是不可预测和高度可变的。虽然抗抑郁药的作用模式尚不完全清楚，但许多药物都与基因中DNA甲基化的变化有关，这似乎与它们的机制有关。因此，DNA甲基化的研究可能揭示支撑抗抑郁药疗效和副作用的生物学过程。我们对苏格兰一代（GS:SFHS, N = 6428， EPIC阵列）和荷兰双登记（NTR, N = 2449, 450 K阵列）自我报告的抗抑郁药物使用情况进行了甲基组全关联研究（MWAS），并对这两个队列的抗抑郁药物使用情况进行了meta分析。我们发现10个CpG位点与GS:SFHS患者自我报告的抗抑郁药物使用显著相关，其中顶部CpG位于先前与精神健康障碍相关的基因ATP6V1B2 （β = - 0.055, pcorrected = 0.005）。其他顶级基因座被注释为基因，包括CASP10、TMBIM1、MAPKAPK3和HEBP2，这些基因先前与先天免疫反应有关。接下来，使用惩罚回归，我们在3799名GS:SFHS个体中训练了一个基于甲基化的自我报告抗抑郁药物使用评分，该评分可以预测GS:SFHS第二子集的抗抑郁药物使用情况（N = 3360, β = 0.377, p = 3.12 × 10 - 11, R2 = 2.12%）。在处方选择性血清素再摄取抑制剂的MWAS分析中，我们显示了与基于自我报告的结果趋同的结果。在NTR中，我们没有发现任何CpGs与抗抑郁药的使用显著相关。荟萃分析发现，上述10种CpGs中有两种与抗抑郁药的使用显著相关，尽管其中一种的作用方向相反。抗抑郁药与先前与精神健康障碍和先天免疫系统相关的基因座的表观遗传改变有关。这些变化预测了GS:SFHS亚群中自我报告的抗抑郁药物使用情况，并确定了可能与我们对临床相关抗抑郁药物作用和副作用的机制理解相关的过程。
Antidepressants are an effective treatment for major depressive disorder (MDD), although individual response is unpredictable and highly variable. Whilst the mode of action of antidepressants is incompletely understood, many medications are associated with changes in DNA methylation in genes that are plausibly linked to their mechanisms. Studies of DNA methylation may therefore reveal the biological processes underpinning the efficacy and side effects of antidepressants. We performed a methylome-wide association study (MWAS) of self-reported antidepressant use accounting for lifestyle factors and MDD in Generation Scotland (GS:SFHS, N = 6428, EPIC array) and the Netherlands Twin Register (NTR, N = 2449, 450 K array) and ran a meta-analysis of antidepressant use across these two cohorts. We found ten CpG sites significantly associated with self-reported antidepressant use in GS:SFHS, with the top CpG located within a gene previously associated with mental health disorders, ATP6V1B2 (β = −0.055, pcorrected = 0.005). Other top loci were annotated to genes including CASP10, TMBIM1, MAPKAPK3, and HEBP2, which have previously been implicated in the innate immune response. Next, using penalised regression, we trained a methylation-based score of self-reported antidepressant use in a subset of 3799 GS:SFHS individuals that predicted antidepressant use in a second subset of GS:SFHS (N = 3360, β = 0.377, p = 3.12 × 10−11, R2 = 2.12%). In an MWAS analysis of prescribed selective serotonin reuptake inhibitors, we showed convergent findings with those based on self-report. In NTR, we did not find any CpGs significantly associated with antidepressant use. The meta-analysis identified the two CpGs of the ten above that were common to the two arrays used as being significantly associated with antidepressant use, although the effect was in the opposite direction for one of them. Antidepressants were associated with epigenetic alterations in loci previously associated with mental health disorders and the innate immune system. These changes predicted self-reported antidepressant use in a subset of GS:SFHS and identified processes that may be relevant to our mechanistic understanding of clinically relevant antidepressant drug actions and side effects.
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影响因子：
16.6
作者：
Gallois, Apolline;Mefford, Joel;Aschard, Hugues
通讯作者：
Aschard, Hugues
影响因子：
16.6
作者：
Chu AY;Tin A;Schlosser P;Ko YA;Qiu C;Yao C;Joehanes R;Grams ME;Liang L;Gluck CA;Liu C;Coresh J;Hwang SJ;Levy D;Boerwinkle E;Pankow JS;Yang Q;Fornage M;Fox CS;Susztak K;Köttgen A
通讯作者：
Köttgen A
影响因子：
3.7
作者：
Fernandez-Pujals, Ana Maria;Adams, Mark James;McIntosh, Andrew M.
通讯作者：
McIntosh, Andrew M.
DOI：
10.1176/appi.focus.16407
发表时间：
2018-10-01
期刊：
Focus (American Psychiatric Publishing)
影响因子：
--
作者：
Cipriani, Andrea;Furukawa, Toshi A;Geddes, John R
通讯作者：
Geddes, John R
影响因子：
64.5
作者：
Astle, William J.;Elding, Heather;Soranzo, Nicole
通讯作者：
Soranzo, Nicole