3q21 上的遗传变异和 Sp8 转录因子基因 (SP8) 作为精神障碍的易感基因座：一项遗传关联研究。
Genetic variants on 3q21 and in the Sp8 transcription factor gene (SP8) as susceptibility loci for psychotic disorders: a genetic association study.
机构信息
Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
出版信息
PLoS One. 2013 Aug 13;8(8):e70964. doi: 10.1371/journal.pone.0070964. eCollection 2013.
BACKGROUND
Recent genome-wide association studies (GWASs) investigating bipolar disorder (BD) have detected a number of susceptibility genes. These studies have also provided novel insight into shared genetic components between BD and schizophrenia (SCZ), two major psychotic disorders. To examine the replication of the risk variants for BD and the pleiotropic effect of the variants associated with BD, we conducted a genetic association study of single nucleotide polymorphisms (SNPs) that were selected based upon previous BD GWASs, which targeted psychotic disorders (BD and SCZ) in the Japanese population.
METHODS
Forty-eight SNPs were selected based upon previous GWASs. A two-stage analysis was conducted using first-set screening (for all SNPs: BD = 1,012, SCZ = 1,032 and control = 993) and second-set replication samples (for significant SNPs in the screening analysis: BD = 821, SCZ = 1,808 and control = 2,149). We assessed allelic association between BD, SCZ, psychosis (BD+SCZ) and the SNPs selected for the analysis.
RESULTS
Eight SNPs revealed nominal association signals for all comparisons (Puncorrected<0.05). Among these SNPs, the top two SNPs (associated with psychosis: Pcorrected = 0.048 and 0.037 for rs2251219 and rs2709722, respectively) were further assessed in the second-set samples, and we replicated the signals from the initial screening analysis (associated with psychosis: Pcorrected = 0.0070 and 0.033 for rs2251219 and rs2709722, respectively). The meta-analysis between the current and previous GWAS results showed that rs2251219 in Polybromo1 (PBRM1) was significant on genome-wide association level (P = 5×10(-8)) only for BD (P = 9.4×10(-9)) and psychosis (P = 2.0×10(-10)). Although the association of rs2709722 in Sp8 transcription factor (SP8) was suggestive in the Asian population (P = 2.1×10(-7) for psychosis), this signal weakened when the samples size was increased by including data from a Caucasian population (P = 4.3×10(-3)).
CONCLUSIONS
We found 3p21.1 (including PBRM1, strong linkage disequilibrium made it difficult to pinpoint the risk genes) and SP8 as risk loci for BD, SCZ and psychosis. Further replication studies will be required for conclusive results.
背景
最近的全基因组关联研究（GWASs）调查了双相情感障碍（BD），发现了许多易感基因。这些研究还为 BD 和精神分裂症（SCZ）之间的共同遗传成分提供了新的见解，这两种疾病都是主要的精神疾病。为了研究与 BD 相关的风险变异的复制和与 BD 相关的变异的多效性效应，我们对基于先前 BD GWASs 的单核苷酸多态性（SNP）进行了遗传关联研究，这些 GWASs 针对日本人群中的精神障碍（BD 和 SCZ）。
方法
基于先前的 GWASs，选择了 48 个 SNP。使用两阶段分析，第一阶段进行了全谱筛查（所有 SNP：BD=1012，SCZ=1032，对照=993），第二阶段进行了复制样本的验证（在筛查分析中发现的显著 SNP：BD=821，SCZ=1808，对照=2149）。我们评估了 BD、SCZ、精神病（BD+SCZ）和用于分析的 SNP 之间的等位基因关联。
结果
有 8 个 SNP 在所有比较中均显示出名义关联信号（未校正的 P<0.05）。在这些 SNP 中，两个最高的 SNP（与精神病相关：校正后的 P 值分别为 rs2251219 和 rs2709722 的 0.048 和 0.037）在第二阶段样本中进一步评估，我们复制了初始筛查分析的信号（与精神病相关：校正后的 P 值分别为 rs2251219 和 rs2709722 的 0.0070 和 0.033）。当前和以前 GWAS 结果的荟萃分析表明，多溴蛋白 1（PBRM1）中的 rs2251219 仅在 BD（P=9.4×10（-9））和精神病（P=2.0×10（-10））方面具有全基因组关联水平的显著意义（P=5×10（-8））。尽管 SP8 转录因子（SP8）中的 rs2709722 在亚洲人群中的关联具有提示意义（精神病的 P 值为 2.1×10（-7）），但当通过纳入白种人群的数据来增加样本量时，该信号会减弱（P=4.3×10（-3））。
结论
我们发现 3p21.1（包括 PBRM1，强连锁不平衡使得难以确定风险基因）和 SP8 是 BD、SCZ 和精神病的风险基因。需要进一步的复制研究才能得出明确的结论。
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