Identification of susceptibility genes for functional psychoses by whole genome scan

基于家系的连锁不平衡(LD)作图已被认为是一种强大而实用的连锁分析替代方法。我们对日本人群中精神分裂症的易感基因进行了全基因组LD调查。我们首先用444个微卫星标记对119个精神分裂症家系(357个个体)进行分型，并用家系不平衡检验对数据进行分析。这项分析揭示了14个标记，它们显示出显著的传递失真。为了证实这些发现，我们将我们的统计方法改为扩展传递不平衡检验(ETDT)，使用了80个独立的完整三联体(一个精神分裂症患者的后代及其父母)，其中68个来自最初的家系，12个新招募的三联体。Etdt支持两个标记继续关联，D11S987位于11q13.3(P=0.00009)，D16S423位于16p13.3(P=0.002)。通过添加26个新的标记进行分析，我们仔细研究了11q11-13上最重要的基因组座位。该地区的三标记单倍型分析结果显示与精神分裂症有关(最显著的单倍型P=0.0005，全球P=0.022)。尽管由于图谱密度的稀疏，本研究可能遗漏了其他潜在的基因组区间，但我们希望它已经为进一步研究确定日本精神分裂症的风险相关基因找到了有希望的锚点。

Family-based linkage disequilibrium (LD) mapping has been suggested as a powerful and practical alternative to linkage analysis. We have performed a genome-wide LD survey of susceptibility loci for schizophrenia in a Japanese population. We first typed 119 schizophrenic pedigrees (357 individuals) with 444 microsatellite markers, and analyzed the data using the pedigree disequilibrium test. This analysis revealed 14 markers that showed significant transmission distortion. To corroborate these findings, we changed our statistical methods to the extended transmission disequilibrium test (ETDT) , using 80 independent complete trios (a schizophrenic offspring and their parents), 68 of which were derived from the initial pedigrees and 12 newly recruited trios. ETDT supported two markers for continued association, D11S987 on 11q13.3 (P=0.00009) and D16S423 on 16p13.3 (P=0.002). We scrutinized the most significant genomic locus on 11q11-13 by adding 26 new markers for analysis. Results of three-marker haplotype analysis in the region showed evidence of association with schizophrenia (most significant haplotype P=0.0005, global P=0.022). Although the present study may have missed other potential genomic intervals because of the sparse mapping density, we hope that it has identified promising anchor points for further studies to identify risk-conferring genes in Japanese schizophrenia.