Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
Mol Psychiatry. 2012 Apr;17(4):433-44. doi: 10.1038/mp.2011.4. Epub 2011 Mar 22.
The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. Although attempted suicide linkage regions have been identified on 2p11-12 and 6q25-26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single-nucleotide polymorphism (SNP) genotypes of 1201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1497 BP subjects without a history of suicide attempts. In all, 2507 SNPs with evidence for association at P<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (P=5.07 × 10(-8)). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 (acid phosphatase 1) gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide.
自杀未遂和自杀完成的遗传成分部分与精神障碍有关，部分与精神障碍无关。虽然已经确定了与自杀未遂相关的区域位于 2p11-12 和 6q25-26，但可能还有更多这样的区域，发现这些区域需要更高分辨率的方法，如全基因组关联研究（GWAS）。考虑到这一点，我们进行了一项自杀未遂 GWAS 研究，将 1201 名有自杀未遂史的双相情感障碍（BP）患者的单核苷酸多态性（SNP）基因型与 1497 名无自杀未遂史的 BP 患者的基因型进行了比较。总共鉴定出 2507 个具有 P<0.001 关联证据的 SNP。随后，在一个大型且独立的 BP 样本集中测试了这些关联 SNP。在复制样本中，经过多重检验校正后，没有一个 SNP 具有显著相关性，但两个样本集的综合分析在全基因组显著水平（P=5.07×10(-8)）上产生了与 2p25（rs300774）相关的信号。2p25 上的关联 SNP 位于一个包含 ACP1（酸性磷酸酶 1）基因的大连锁不平衡块中，该基因在有自杀完成史的 BP 患者中的表达显著升高。此外，ACP1 蛋白是一种酪氨酸磷酸酶，它影响 Wnt 信号通路，该通路受锂调节，这使得 ACP1 成为参与表型的功能候选基因。需要更大的 GWAS 样本集来确认 2p25 上的信号，并确定增加自杀未遂易感性的其他遗传风险因素。
