在一项多阶段全基因组关联研究中鉴定双相I型障碍的新基因座。
Identification of novel loci for bipolar I disorder in a multi-stage genome-wide association study.
作者信息
Kuo P H, Chuang L C, Liu J R, Liu C M, Huang M C, Lin S K, Sunny Sun H, Hsieh M H, Hung H, Lu R B
机构信息
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Research Center for Genes, Environment and Human Health, National Taiwan University, Taipei, Taiwan.
Department of Nursing, Cardinal Tien College of Healthcare & Management, I-Lan, Taiwan.
出版信息
Prog Neuropsychopharmacol Biol Psychiatry. 2014 Jun 3;51:58-64. doi: 10.1016/j.pnpbp.2014.01.003. Epub 2014 Jan 18.
OBJECTIVE
Identification of genetic variants that influence bipolar I disorder (BPD-I) through genome-wide association (GWA) studies is limited in Asian populations. The current study aimed to identify novel common variants for BPD-I in an ethnically homogeneous Taiwanese sample using a multi-stage GWA study design.
METHOD
At the discovery stage, 200 BPD-I patients and 200 controls that combined to form 16 pools were genotyped with 1 million markers. Utilizing a newly developed rank-based method, top-ranked markers were selected. After validation with individual genotyping, a fine-mapping association study was conducted to identify associated loci using 240 patients and 240 controls. At the last stage, independent samples were collected (351 cases and 341 controls) for replication.
RESULTS
Among the top-ranked markers from the discovery stage, eight genes and 15 individual SNPs were evaluated in the fine-mapping stage. At this stage, rs7619173, which is not in a gene coding region, showed the most significant association (P = 2 ∗ 10(-5)) with BPD-I. Four genes had empirical P-values<0.05, including KCNH7 (P = 0.0047), MYST4 (P = 0.0047), NRXN3 (P = 0.0095), and SEMA3D (P = 0.037). For markers genotyped in replication samples, rs7619173 exhibited a significant association (P(combined) = 2 ∗ 10(-4)) after multiple testing correction, while markers rs11001178 (MYST4) and rs2217887 (NRXN3) showed weak associations (P(combined) = 0.02) with BPD-I.
CONCLUSION
A multi-stage GWA design has the potential to uncover the underlying pathogenesis of a complex trait. Findings in the present study highlight three loci that warrant further investigation for bipolar.
目的
通过全基因组关联（GWA）研究来鉴定影响双相I型障碍（BPD-I）的基因变异，在亚洲人群中仍很有限。本研究旨在采用多阶段GWA研究设计，在一个种族同质的台湾样本中鉴定BPD-I的新型常见变异。
方法
在发现阶段，200例BPD-I患者和200例对照合并形成16个池，用100万个标记进行基因分型。利用新开发的基于秩的方法，选择排名靠前的标记。经个体基因分型验证后，进行精细定位关联研究，使用240例患者和240例对照来鉴定相关基因座。在最后阶段，收集独立样本（351例病例和341例对照）进行重复验证。
结果
在发现阶段排名靠前的标记中，在精细定位阶段评估了8个基因和15个个体单核苷酸多态性（SNP）。在此阶段，不在基因编码区的rs7619173与BPD-I显示出最显著的关联（P = 2×10⁻⁵）。四个基因的经验P值<0.05，包括KCNH7（P = 0.0047）、MYST4（P = 0.0047）、NRXN3（P = 0.0095）和SEMA3D（P = 0.037）。对于在重复样本中进行基因分型的标记，经多重检验校正后，rs7619173表现出显著关联（P（合并） = 2×10⁻⁴），而标记rs11001178（MYST4）和rs2217887（NRXN3）与BPD-I显示出弱关联（P（合并） = 0.02）。
结论
多阶段GWA设计有潜力揭示复杂性状的潜在发病机制。本研究结果突出了三个基因座，值得对双相情感障碍进行进一步研究。
Zotero 插件