1] Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York 11004, USA [2] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA [3] Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA [4] Department of Psychiatry, Hofstra University School of Medicine, Hempstead, New York 11550, USA [5] Department of Molecular Medicine, Hofstra University School of Medicine, Hempstead, New York 11550, USA [6].
Nat Commun. 2013;4:2739. doi: 10.1038/ncomms3739.
Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in Pmeta=9.49 × 10(-12) (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08-1.17) across both disorders and Pmeta=2.67 × 10(-8) (OR=1.15, 95% CI: 1.08-1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders.
精神分裂症和双相情感障碍是两种主要的精神疾病，具有较高的遗传性和重叠的遗传变异。在这里，我们对一个来自阿什肯纳兹犹太人族群的、由 904 名精神分裂症患者和 1640 名对照组成的、遗传同质性队列进行了全基因组关联研究。我们在 4q26 染色体上确定了一个新的全基因组显著风险位点，证明了这个奠基人群体在基因发现方面的潜在优势。排名最高的单核苷酸多态性 (SNP; rs11098403) 在 11 个复制和扩展队列中表现出一致的效果，在包括多种族在内的 23191 个样本中均具有显著作用，无论诊断（精神分裂症或双相情感障碍）如何，结果为 Pmeta=9.49×10(-12)（优势比（OR）=1.13，95%置信区间（CI）：1.08-1.17）在两种疾病中，而在单纯精神分裂症中 Pmeta=2.67×10(-8)（OR=1.15，95% CI：1.08-1.21）。此外，这个基因间的 SNP 显著预测了 NDST3 的死后小脑基因表达，NDST3 编码一种对肝素硫酸酯代谢至关重要的酶。肝素硫酸酯结合对于神经突生长、轴突形成和突触过程至关重要，这些过程被认为在这些疾病中是异常的。
