Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder.
Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder.
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DOI：
10.1371/journal.pone.0169158
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Willour VL
中科院分区：
文献类型：
--
作者：
Breen ME;Gaynor SC;Monson ET;de Klerk K;Parsons MG;Braun TA;DeLuca AP;Zandi PP;Potash JB;Willour VL
FKBP 5是下丘脑-垂体-肾上腺（HPA）轴的重要组成部分，该轴调节我们对压力的反应。它是分子伴侣复合物的一部分，可抑制皮质醇和糖皮质激素受体转运到细胞核的结合。HPA轴和FKBP 5的变异与自杀行为相关。我们开发了一种系统的，有针对性的测序方法，以调查476双相情感障碍自杀未遂者和473双相情感障碍非自杀者的FKBP 5或附近的编码和调控区域。在严格的质量控制检查后，我们对产生的481个变体进行了单变体，基因水平和单倍型测试。次要分析调查了FKBP 5的性别特异性变异是否会增加自杀未遂的风险。其中一个变体rs 141713011在自杀未遂者中显示出了过量的次要等位基因，在多重检验校正后具有统计学显著性（比值比= 6.65，P值= 7.5 x 10−4，置换P值= 0.038）。然而，这一结果无法在独立队列中重复（比值比= 0.90，P值= 0.78）。还鉴定了具有名义显著性的三种雌性特异性变体和四种雄性特异性变体（P值< 0.05）。基因水平和单倍型关联检验没有产生任何显著结果。这项对FKBP 5常见和罕见变异的综合研究集中在与自杀未遂相关的调控和编码区域。一种罕见的变异在多次检验校正后仍显着，但无法重复。需要在更大的样本集中进行进一步的研究，以充分阐明这种变异与自杀行为的关联。
FKBP5 is a critical component of the Hypothalamic-Pituitary-Adrenal (HPA) axis, a system which regulates our response to stress. It forms part of a complex of chaperones, which inhibits binding of cortisol and glucocorticoid receptor translocation to the nucleus. Variations in both the HPA axis and FKBP5 have been associated with suicidal behavior. We developed a systematic, targeted sequencing approach to investigate coding and regulatory regions in or near FKBP5 in 476 bipolar disorder suicide attempters and 473 bipolar disorder non-attempters. Following stringent quality control checks, we performed single-variant, gene-level and haplotype tests on the resulting 481 variants. Secondary analyses investigated whether sex-specific variations in FKBP5 increased the risk of attempted suicide. One variant, rs141713011, showed an excess of minor alleles in suicide attempters that was statistically significant following correction for multiple testing (Odds Ratio = 6.65, P-value = 7.5 x 10−4, Permuted P-value = 0.038). However, this result could not be replicated in an independent cohort (Odds Ratio = 0.90, P-value = 0.78). Three female-specific and four male-specific variants of nominal significance were also identified (P-value < 0.05). The gene-level and haplotype association tests did not produce any significant results. This comprehensive study of common and rare variants in FKBP5 focused on both regulatory and coding regions in relation to attempted suicide. One rare variant remained significant following correction for multiple testing but could not be replicated. Further investigation is required in larger sample sets to fully elucidate the association of this variant with suicidal behavior.
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影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
2.6
作者：
Laje G;Allen AS;Akula N;Manji H;John Rush A;McMahon FJ
通讯作者：
McMahon FJ
影响因子：
5.8
作者：
Barnett, Derek W.;Garrison, Erik K.;Marth, Gabor T.
通讯作者：
Marth, Gabor T.
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
3.7
作者：
Binder, E. B.;Kuenzel, H. E.;Holsboer, F.
通讯作者：
Holsboer, F.