Department of Psychiatry and Psychology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Departments of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.
J Clin Psychiatry. 2017 Nov-Dec;78(9):1337-1343. doi: 10.4088/JCP.15m10314.
In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD).
Treatment of Early Age Mania (TEAM) study enrollment and sample collection took place from 2003 to 2008. Mayo Clinic Bipolar Biobank samples were collected from 2009 to 2013. Genotyping and analyses for the present study took place from 2013 to 2014. The diagnosis of BD was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Eight single-nucleotide polymorphisms (SNPs), previously reported in genome-wide association studies to be associated with BD, were chosen for GRS analysis in early-onset bipolar disease. These SNPs map to 3 genes: CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit), ANK3 (ankyrin-3, node of Ranvier [ankyrin G]), and ODZ4 (teneurin transmembrane protein 4 [formerly "odz, odd Oz/10-m homolog 4 {Drosophila}, ODZ4"]). The 8 candidate SNPs were genotyped in patients from the TEAM study (n = 69); adult patients with BD (n = 732), including a subset with early-onset illness (n = 192); and healthy controls (n = 776). GRS analyses were performed to compare early-onset cases with controls. In addition, associations of early-onset BD with individual SNPs and haplotypes were explored.
GRS analysis revealed associations of the risk score with early-onset BD (P = .01). Gene-level haplotype analysis comparing TEAM patients with controls suggested association of early-onset BD with a CACNA1C haplotype (global test, P = .01). At the level of individual SNPs, comparison of TEAM cases with healthy controls provided nominally significant evidence for association of SNP rs10848632 in CACNA1C with early-onset BD (P = .017), which did not remain significant after correction for multiple comparisons.
These preliminary analyses suggest that previously identified BD risk loci, especially CACNA1C, have a role in early-onset BD, possibly with stronger effects than for late-onset BD.
本研究对早发性双相障碍（BD）进行候选遗传风险评分（GRS）分析。
TEAM 研究于 2003 年至 2008 年进行患者入组和样本采集。梅奥诊所双相情感障碍生物样本库于 2009 年至 2013 年采集样本。本研究的基因分型和分析于 2013 年至 2014 年进行。BD 的诊断基于《精神障碍诊断与统计手册》第四版修订本（DSM-IV-TR）标准。先前全基因组关联研究报道与 BD 相关的 8 个单核苷酸多态性（SNP）被选择用于早发性双相疾病的 GRS 分析。这些 SNP 映射到 3 个基因：CACNA1C（钙通道，电压依赖性，L 型，α 1C 亚基）、ANK3（锚蛋白 3，Ranvier 结[锚蛋白 G]）和 ODZ4（teneurin 跨膜蛋白 4 [以前称为“odz，奇数 Oz/10-m 同源物 4 [果蝇]，ODZ4”]）。TEAM 研究中的患者（n=69）、成人 BD 患者（n=732），包括亚组早发性疾病患者（n=192）和健康对照者（n=776）进行了 8 个候选 SNP 的基因分型。进行 GRS 分析以比较早发性病例与对照者。此外，还探索了早发性 BD 与个体 SNP 和单体型的关联。
GRS 分析显示风险评分与早发性 BD 相关（P=0.01）。与对照组相比，TEAM 患者的基因水平单体型分析提示早发性 BD 与 CACNA1C 单体型相关（全局检验，P=0.01）。在单个 SNP 水平上，与健康对照组相比，TEAM 病例提供了 CACNA1C 中 SNP rs10848632 与早发性 BD 相关的名义显著证据（P=0.017），但在进行多次比较校正后并不显著。
这些初步分析表明，先前确定的 BD 风险位点，尤其是 CACNA1C，在早发性 BD 中起作用，与晚发性 BD 相比，其作用可能更强。
