Yin Honglei, Galfalvy Hanga, Pantazatos Spiro P, Huang Yung-Yu, Rosoklija Gorazd B, Dwork Andrew J, Burke Ainsley, Arango Victoria, Oquendo Maria A, Mann J John
now at Department of Psychiatry, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, Columbia University, New York.
Depress Anxiety. 2016 Jun;33(6):531-540. doi: 10.1002/da.22499. Epub 2016 Mar 31.
We tested the relationship between genotype, gene expression and suicidal behavior and major depressive disorder (MDD) in live subjects and postmortem samples for three genes, associated with the hypothalamic-pituitary-adrenal axis, suicidal behavior, and MDD; FK506-binding protein 5 (FKBP5), Spindle and kinetochore-associated protein 2 (SKA2), and Glucocorticoid Receptor (NR3C1).
Single-nucleotide polymorphisms (SNPs) and haplotypes were tested for association with suicidal behavior and MDD in a live (N = 277) and a postmortem sample (N = 209). RNA-seq was used to examine gene and isoform-level brain expression postmortem (Brodmann Area 9; N = 59). Expression quantitative trait loci (eQTL) relationships were examined using a public database (UK Brain Expression Consortium).
We identified a haplotype within the FKBP5 gene, present in 47% of the live subjects, which was associated with increased risk of suicide attempt (OR = 1.58, t = 6.03, P = .014). Six SNPs on this gene, three SNPs on SKA2, and one near NR3C1 showed before-adjustment association with attempted suicide, and two SNPs of SKA2 with suicide death, but none stayed significant after adjustment for multiple testing. Only the SKA2 SNPs were related to expression in the prefrontal cortex (pFCTX). One NR3C1 transcript had lower expression in suicide relative to nonsuicide sudden death cases (b = -0.48, SE = 0.12, t = -4.02, adjusted P = .004).
We have identified an association of FKBP5 haplotype with risk of suicide attempt and found an association between suicide and altered NR3C1 gene expression in the pFCTX. Our findings further implicate hypothalamic pituitary axis dysfunction in suicidal behavior.
我们在活体受试者和尸检样本中检测了与下丘脑 - 垂体 - 肾上腺轴、自杀行为和重度抑郁症（MDD）相关的三个基因（FK506结合蛋白5（FKBP5）、纺锤体和动粒相关蛋白2（SKA2）以及糖皮质激素受体（NR3C1））的基因型、基因表达与自杀行为及MDD之间的关系。
在一个活体样本（N = 277）和一个尸检样本（N = 209）中检测单核苷酸多态性（SNP）和单倍型与自杀行为及MDD的关联。RNA测序用于检测尸检后的基因和异构体水平的脑表达（布罗德曼区9；N = 59）。使用公共数据库（英国脑表达联盟）检查表达数量性状位点（eQTL）关系。
我们在FKBP5基因中鉴定出一种单倍型，存在于47%的活体受试者中，它与自杀未遂风险增加相关（比值比 = 1.58，t = 6.03，P = 0.014）。该基因上的六个SNP、SKA2上的三个SNP以及NR3C1附近的一个SNP在调整前与自杀未遂相关，SKA2的两个SNP与自杀死亡相关，但在多重检验调整后均无显著意义。只有SKA2的SNP与前额叶皮质（pFCTX）的表达相关。相对于非自杀性猝死病例，一种NR3C1转录本在自杀者中的表达较低（b = -0.48，标准误 = 0.12，t = -4.02，调整后P = 0.004）。
我们已鉴定出FKBP5单倍型与自杀未遂风险的关联，并发现自杀与pFCTX中NR3C1基因表达改变之间存在关联。我们的研究结果进一步表明下丘脑 - 垂体轴功能障碍与自杀行为有关。
