Horowitz Anat, Shifman Sagiv, Rivlin Nehama, Pisanté Anne, Darvasi Ariel
The Life Science Institute, The Hebrew University of Jerusalem, Israel.
Psychiatr Genet. 2005 Sep;15(3):163-9. doi: 10.1097/00041444-200509000-00005.
Association studies are now primarily being conducted with single nucleotide polymorphisms because they are present everywhere in the genome and can be genotyped in "high throughput" formats. Microsatellite markers have a higher degree of polymorphism than single nucleotide polymorphisms and have been widely used in both linkage and association studies of disease. Polymorphic microsatellite markers with several alleles can readily detect linkage disequilibrium but at any given locus there may be differences between single nucleotide polymorphisms and microsatellites in their power to detect linkage disequilibrium because of the evolutionary history of the locus, especially the rate at which both the single nucleotide polymorphisms and microsatellite polymorphisms have mutated and the number of disease mutations and their history. In the current study, we examined the efficiency of microsatellite markers in association analysis by looking at all existent microsatellite markers in the catechol-O-methyltransferase gene region and by genotyping these microsatellites in a large cohort of schizophrenia patients and healthy controls, a subset of a sample where catechol-O-methyltransferase and schizophrenia were found to be associated. We also estimated the levels of linkage disequilibrium between these microsatellites and the previously reported single nucleotide polymorphisms (within the catechol-O-methyltransferase gene) found to be associated with schizophrenia. A modest allelic association of P=0.041 was found between schizophrenia and the microsatellite marker D22S944, which was not significant, however, when corrected for all microsatellites tested. Nevertheless, significant linkage disequilibrium was found between this marker and the three single nucleotide polymorphisms within the catechol-O-methyltransferase gene that displayed association with the disease in the previously published research on this sample. Significant linkage disequilibrium was also observed between microsatellites up to approximately 300 kb distant from those single nucleotide polymorphisms. Although significant, the extent of linkage disequilibrium in terms of r2 was small (in the order of 0.01).
关联研究目前主要针对单核苷酸多态性进行，因为它们存在于基因组的各个位置，并且可以采用“高通量”方式进行基因分型。微卫星标记比单核苷酸多态性具有更高程度的多态性，并且已广泛应用于疾病的连锁和关联研究。具有多个等位基因的多态性微卫星标记能够很容易地检测连锁不平衡，但在任何给定基因座上，由于该基因座的进化历史，特别是单核苷酸多态性和微卫星多态性的突变率以及疾病突变的数量及其历史，单核苷酸多态性和微卫星在检测连锁不平衡的能力上可能存在差异。在本研究中，我们通过查看儿茶酚-O-甲基转移酶基因区域内所有现有的微卫星标记，并在一大群精神分裂症患者和健康对照中对这些微卫星进行基因分型，来检验微卫星标记在关联分析中的效率，该样本子集是儿茶酚-O-甲基转移酶与精神分裂症被发现存在关联的样本。我们还估计了这些微卫星与先前报道的（儿茶酚-O-甲基转移酶基因内）与精神分裂症相关的单核苷酸多态性之间的连锁不平衡水平。在精神分裂症与微卫星标记D22S944之间发现了适度的等位基因关联，P = 0.041，但在对所有测试的微卫星进行校正后，该关联并不显著。然而，在该标记与儿茶酚-O-甲基转移酶基因内先前在该样本的已发表研究中显示与疾病相关的三个单核苷酸多态性之间发现了显著的连锁不平衡。在距离那些单核苷酸多态性约300 kb远的微卫星之间也观察到了显著的连锁不平衡。尽管显著，但就r2而言，连锁不平衡的程度较小（约为0.01）。
