Chen Xiangning, Wang Xu, Hossain Shaon, O'Neill F Anthony, Walsh Dermot, Pless Lora, Chowdari Kodavali V, Nimgaonkar Vishwajit L, Schwab Sibylle G, Wildenauer Dieter B, Sullivan Patrick F, van den Oord Edwin, Kendler Kenneth S
Department of Psychiatry and Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richimond, VA 23298, USA.
Hum Mol Genet. 2006 Nov 15;15(22):3329-42. doi: 10.1093/hmg/ddl409. Epub 2006 Oct 9.
Chromosome 5q22-33 is a region where studies have repeatedly found evidence for linkage to schizophrenia. In this report, we took a stepwise approach to systematically map this region in the Irish Study of High Density Schizophrenia Families (ISHDSF, 267 families, 1337 subjects) sample. We typed 289 SNPs in the critical interval of 8 million basepairs and found a 758 kb interval coding for the SPEC2/PDZ-GEF2/ACSL6 genes to be associated with the disease. Using sex and genotype-conditioned transmission disequilibrium test analyses, we found that 19 of the 24 typed markers were associated with the disease and the associations were sex-specific. We replicated these findings with an Irish case-control sample (657 cases and 414 controls), an Irish parent-proband trio sample (187 families, 564 subjects), a German nuclear family sample (211 families, 751 subjects) and a Pittsburgh nuclear family sample (247 families, 729 subjects). In all four samples, we replicated the sex-specific associations at the levels of both individual markers and haplotypes using sex- and genotype-conditioned analyses. Three risk haplotypes were identified in the five samples, and each haplotype was found in at least two samples. Consistent with the discovery of multiple estrogen-response elements in this region, our data showed that the impact of these haplotypes on risk for schizophrenia differed in males and females. From these data, we concluded that haplotypes underlying the SPEC2/PDZ-GEF2/ACSL6 region are associated with schizophrenia. However, due to the extended high LD in this region, we were unable to distinguish whether the association signals came from one or more of these genes.
5号染色体的q22 - 33区域是一个研究反复发现与精神分裂症存在连锁证据的区域。在本报告中，我们采用逐步推进的方法，在爱尔兰高密度精神分裂症家族研究（ISHDSF，267个家族，1337名受试者）样本中对该区域进行系统定位。我们在800万个碱基对的关键区间内对289个单核苷酸多态性（SNP）进行分型，发现一个编码SPEC2 / PDZ - GEF2 / ACSL6基因的758 kb区间与该疾病相关。通过性别和基因型条件下的传递不平衡检验分析，我们发现24个分型标记中的19个与该疾病相关，且这些关联具有性别特异性。我们在一个爱尔兰病例对照样本（657例病例和414名对照）、一个爱尔兰亲子三联体样本（187个家族，564名受试者）、一个德国家庭核心样本（211个家族，751名受试者）和一个匹兹堡家庭核心样本（247个家族，729名受试者）中重复了这些发现。在所有这四个样本中，我们使用性别和基因型条件分析在单个标记和单倍型水平上重复了性别特异性关联。在这五个样本中鉴定出了三种风险单倍型，并且每种单倍型至少在两个样本中被发现。与在该区域发现多个雌激素反应元件一致，我们的数据表明这些单倍型对精神分裂症风险的影响在男性和女性中有所不同。基于这些数据，我们得出结论，SPEC2 / PDZ - GEF2 / ACSL6区域的单倍型与精神分裂症相关。然而，由于该区域存在广泛的高连锁不平衡，我们无法区分这些关联信号是来自这些基因中的一个还是多个。
