Petryshen T L, Middleton F A, Kirby A, Aldinger K A, Purcell S, Tahl A R, Morley C P, McGann L, Gentile K L, Rockwell G N, Medeiros H M, Carvalho C, Macedo A, Dourado A, Valente J, Ferreira C P, Patterson N J, Azevedo M H, Daly M J, Pato C N, Pato M T, Sklar P
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Mol Psychiatry. 2005 Apr;10(4):366-74, 328. doi: 10.1038/sj.mp.4001608.
Schizophrenia is a common, multigenic psychiatric disorder. Linkage studies, including a recent meta-analysis of genome scans, have repeatedly implicated chromosome 8p12-p23.1 in schizophrenia susceptibility. More recently, significant association with a candidate gene on 8p12, neuregulin 1 (NRG1), has been reported in several European and Chinese samples. We investigated NRG1 for association in schizophrenia patients of Portuguese descent to determine whether this gene is a risk factor in this population. We tested NRG1 markers and haplotypes for association in 111 parent-proband trios, 321 unrelated cases, and 242 control individuals. Associations were found with a haplotype that overlaps the risk haplotype originally reported in the Icelandic population ("Hap(ICE)"), and two haplotypes located in the 3' end of NRG1 (all P<0.05). However, association was not detected with Hap(ICE) itself. Comparison of NRG1 transcript expression in peripheral leukocytes from schizophrenia patients and unaffected siblings identified 3.8-fold higher levels of the SMDF variant in patients (P=0.039). Significant positive correlations (P<0.001) were found between SMDF and HRG-beta 2 expression and between HRG-gamma and ndf43 expression, suggesting common transcriptional regulation of NRG1 variants. In summary, our results suggest that haplotypes across NRG1 and multiple NRG1 variants are involved in schizophrenia.
精神分裂症是一种常见的多基因精神障碍。连锁研究，包括最近对基因组扫描的荟萃分析，反复表明8号染色体p12 - p23.1与精神分裂症易感性有关。最近，在几个欧洲和中国样本中报道了与8号染色体p12上的一个候选基因神经调节蛋白1（NRG1）有显著关联。我们对葡萄牙裔精神分裂症患者中的NRG1进行关联研究，以确定该基因是否是这一人群中的一个风险因素。我们在111个亲代 - 先证者三联体、321个无关病例和242个对照个体中测试了NRG1标记和单倍型的关联性。发现与一个与最初在冰岛人群中报道的风险单倍型重叠的单倍型（“Hap(ICE)”）以及位于NRG1 3'端的两个单倍型存在关联（所有P<0.05）。然而，未检测到与Hap(ICE)本身的关联。对精神分裂症患者和未受影响的同胞外周血白细胞中NRG1转录本表达的比较发现，患者中SMDF变体的水平高3.8倍（P = 0.039）。在SMDF与HRG - β2表达之间以及HRG - γ与ndf43表达之间发现了显著的正相关（P<0.001），表明NRG1变体存在共同的转录调控。总之，我们的结果表明，NRG1上的单倍型和多个NRG1变体与精神分裂症有关。
