Roche S, Cassidy F, Zhao C, Badger J, Claffey E, Mooney L, Delaney C, Dobrin S, McKeon P
Smurfit Institute of Genetics, Trinity College, Dublin, Ireland.
Am J Med Genet B Neuropsychiatr Genet. 2007 Dec 5;144B(8):1094-6. doi: 10.1002/ajmg.b.30556.
A genome-wide scan in 60 bipolar affective disorder (BPAD) affected sib-pairs (ASPs) identified linkage on chromosome 21 at 21q22 (D21S1446, NPL = 1.42, P = 0.08), a BPAD susceptibility locus supported by multiple studies. Although this linkage only approaches significance, the peak marker is located 12 Kb upstream of S100B, a neurotrophic factor implicated in the pathology of psychiatric disorders, including BPAD and schizophrenia. We hypothesized that the linkage signal at 21q22 may result from pathogenic disease variants within S100B and performed an association analysis of this gene in a collection of 125 BPAD type I trios. S100B single nucleotide polymorphisms (SNPs) rs2839350 (P = 0.022) and rs3788266 (P = 0.031) were significantly associated with BPAD. Since variants within S100B have also been associated with schizophrenia susceptibility, we reanalyzed the data in trios with a history of psychosis, a phenotype in common between the two disorders. SNPs rs2339350 (P = 0.016) and rs3788266 (P = 0.009) were more significantly associated in the psychotic subset. Increased significance was also obtained at the haplotype level. Interestingly, SNP rs3788266 is located within a consensus-binding site for Six-family transcription factors suggesting that this variant may directly affect S100B gene expression. Fine-mapping analyses of 21q22 have previously identified transient receptor potential gene melastatin 2 (TRPM2), which is 2 Mb upstream of S100B, as a possible BPAD susceptibility gene at 21q22. We also performed a family-based association analysis of TRPM2 which did not reveal any evidence for association of this gene with BPAD. Overall, our findings suggest that variants within the S100B gene predispose to a psychotic subtype of BPAD, possibly via alteration of gene expression.
在60对双相情感障碍（BPAD）受累同胞对（ASP）中进行的全基因组扫描，在21号染色体21q22区域（D21S1446，NPL = 1.42，P = 0.08）发现了连锁关系，这是一个得到多项研究支持的BPAD易感基因座。尽管这种连锁关系仅接近显著性水平，但峰值标记位于S100B基因上游12千碱基处，S100B是一种神经营养因子，与包括BPAD和精神分裂症在内的精神疾病病理学有关。我们推测21q22处的连锁信号可能是由S100B基因内的致病疾病变异导致的，并在125个I型BPAD三联体样本中对该基因进行了关联分析。S100B单核苷酸多态性（SNP）rs2839350（P = 0.022）和rs3788266（P = 0.031）与BPAD显著相关。由于S100B基因内的变异也与精神分裂症易感性有关，我们对有精神病病史的三联体数据进行了重新分析，精神病是这两种疾病共有的一种表型。SNP rs2339350（P = 0.016）和rs3788266（P = 0.009）在精神病亚组中关联更为显著。在单倍型水平上也获得了更高的显著性。有趣的是，SNP rs3788266位于Six家族转录因子的一个共有结合位点内，这表明该变异可能直接影响S100B基因的表达。先前对21q22的精细定位分析已确定瞬时受体电位基因褪黑素2（TRPM2），它位于S100B上游2兆碱基处，是21q22处一个可能的BPAD易感基因。我们还对TRPM2进行了基于家系的关联分析，未发现该基因与BPAD有关联的任何证据。总体而言，我们的研究结果表明，S100B基因内的变异可能通过改变基因表达，使人易患BPAD的一种精神病亚型。
