Fine Mapping on Chromosome 10q22-q23 Implicates Neuregulin 3 in Schizophrenia
Fine Mapping on Chromosome 10q22-q23 Implicates Neuregulin 3 in Schizophrenia
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DOI：
10.1016/j.ajhg.2008.12.005
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发表时间：
2009-01-09
影响因子：
9.8
通讯作者：
Valle, David
中科院分区：
文献类型：
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作者：
Chen, Pei-Lung;Avramopoulos, Dimitrios;Valle, David
连锁研究表明 10q22-q23 是德系犹太人 (AJ) 和台湾汉族人群的精神分裂症 (SZ) 易感位点。为了进一步探索我们之前在 AJ 群体中的连锁信号（NPL 评分：4.27，经验 p = 2 x 10(-5)），我们使用 10q22-q23 中类似于 12.5 Mb 的 1414 个 SNP 进行了峰范围关联精细定位研究。我们对 1515 名 AJ 个体进行了基因分型，其中包括 285 名亲子三人组、173 名无关病例和 487 名无关对照。我们分析了 SZ 的二元诊断表型和 9 个可遗传的数量性状，这些性状源自我们共识诊断评级和直接评估访谈中 73 个项目的主成分因子分析。尽管没有标记能够经受住与二元 SZ 表型关联的多重检验校正，但我们通过使用“妄想”因子作为位于 Neuregulin 3 (NRG3) 内含子 I 13 kb 间隔的三个 SNP（rs10883866、rs10748842 和 rs6584400）的数量性状，发现了强有力的关联证据。基于家庭的关联分析得出的最佳 p 值为 7.26 x 10(-7)。我们在 173 个不相关的 AJ 病例集合中复制了这种关联 (p = 1.55 x 10(-2))，合并的 p 值为 2.30 x 10(-7)。对每种表型进行 10,000 次排列后，我们估计所有 9 个因素（90,000 次排列）的实证研究范围内的显着性为 p = 2.7 x 10(-3)。 NRG3 主要在中枢神经系统中表达，是 NRG1 的三个旁系同源物之一，NRG1 是与 SZ 密切相关的基因。这些生物学特性与我们的连锁和关联结果一起强烈支持 NRG3 作为参与 SZ 的基因。
Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 x 10(-5)), we performed a peakwide association fine mapping study by using 1414 SNPs across similar to 12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron I of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 x 10(-7). We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 x 10(-2)), with a combined p value of 2.30 x 10(-7). After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 x 10(-3). NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ.