Fallin M Daniele, Lasseter Virginia K, Wolyniec Paula S, McGrath John A, Nestadt Gerald, Valle David, Liang Kung-Yee, Pulver Ann E
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21231, USA.
Am J Hum Genet. 2003 Sep;73(3):601-11. doi: 10.1086/378158. Epub 2003 Aug 15.
Previous linkage studies in schizophrenia have been discouraging due to inconsistent findings and weak signals. Genetic heterogeneity has been cited as one of the primary culprits for such inconsistencies. We have performed a 10-cM autosomal genomewide linkage scan for schizophrenia susceptibility regions, using 29 multiplex families of Ashkenazi Jewish descent. Although there is no evidence that the rate of schizophrenia among the Ashkenazim differs from that in other populations, we have focused on this population in hopes of reducing genetic heterogeneity among families and increasing the detectable effects of any particular locus. We pursued both allele-sharing and parametric linkage analyses as implemented in Genehunter, version 2.0. Our strongest signal was achieved at chromosome 10q22.3 (D10S1686), with a nonparametric linkage score (NPL) of 3.35 (genomewide empirical P=.035) and a dominant heterogeneity LOD score (HLOD) of 3.14. Six other regions gave NPL scores >2.00 (on chromosomes 1p32.2, 4q34.3, 6p21.31, 7p15.2, 15q11.2, and 21q21.2). Upon follow-up with an additional 23 markers in the chromosome 10q region, our peak NPL score increased to 4.27 (D10S1774; empirical P=.00002), with a 95% confidence interval of 12.2 Mb for the location of the trait locus (D10S1677 to D10S1753). We find these results encouraging for the study of schizophrenia among Ashkenazi families and suggest further linkage and association studies in this chromosome 10q region.
先前针对精神分裂症的连锁研究结果并不理想，原因是研究结果不一致且信号微弱。遗传异质性被认为是导致这种不一致性的主要原因之一。我们利用29个阿什肯纳兹犹太裔的多重家庭，对精神分裂症易感区域进行了10厘摩的常染色体全基因组连锁扫描。尽管没有证据表明阿什肯纳兹人群中精神分裂症的发病率与其他人群不同，但我们之所以关注这个人群，是希望减少家庭间的遗传异质性，并增强任何特定基因座的可检测效应。我们采用了Genehunter 2.0版本中实现的等位基因共享和参数连锁分析。我们在10号染色体q22.3（D10S1686）处获得了最强信号，非参数连锁分数（NPL）为3.35（全基因组经验P = 0.035），显性异质性对数似然比分数（HLOD）为3.14。其他六个区域的NPL分数>2.00（位于1号染色体p32.2、4号染色体q34.3、6号染色体p21.31、7号染色体p15.2、15号染色体q11.2和21号染色体q21.2）。在对10号染色体q区域的另外23个标记进行后续分析时，我们的峰值NPL分数增加到4.27（D10S1774；经验P = 0.00002），性状基因座位置（D10S1677至D10S1753）的95%置信区间为12.2兆碱基。我们认为这些结果对于研究阿什肯纳兹家庭中的精神分裂症具有鼓舞作用，并建议在这个10号染色体q区域进一步开展连锁和关联研究。
