Melquist Stacey, Craig David W, Huentelman Matthew J, Crook Richard, Pearson John V, Baker Matt, Zismann Victoria L, Gass Jennifer, Adamson Jennifer, Szelinger Szabolcs, Corneveaux Jason, Cannon Ashley, Coon Keith D, Lincoln Sarah, Adler Charles, Tuite Paul, Calne Donald B, Bigio Eileen H, Uitti Ryan J, Wszolek Zbigniew K, Golbe Lawrence I, Caselli Richard J, Graff-Radford Neill, Litvan Irene, Farrer Matthew J, Dickson Dennis W, Hutton Mike, Stephan Dietrich A
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
Am J Hum Genet. 2007 Apr;80(4):769-78. doi: 10.1086/513320. Epub 2007 Mar 8.
To date, only the H1 MAPT haplotype has been consistently associated with risk of developing the neurodegenerative disease progressive supranuclear palsy (PSP). We hypothesized that additional genetic loci may be involved in conferring risk of PSP that could be identified through a pooling-based genomewide association study of >500,000 SNPs. Candidate SNPs with large differences in allelic frequency were identified by ranking all SNPs by their probe-intensity difference between cohorts. The MAPT H1 haplotype was strongly detected by this methodology, as was a second major locus on chromosome 11p12-p11 that showed evidence of association at allelic (P<.001), genotypic (P<.001), and haplotypic (P<.001) levels and was narrowed to a single haplotype block containing the DNA damage-binding protein 2 (DDB2) and lysosomal acid phosphatase 2 (ACP2) genes. Since DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes, both genes are viable candidates for conferring risk of disease.
迄今为止，只有H1型微管相关蛋白tau（MAPT）单倍型一直与神经退行性疾病进行性核上性麻痹（PSP）的发病风险相关。我们推测，可能存在其他基因位点参与PSP的发病风险，可通过对超过50万个单核苷酸多态性（SNP）进行基于样本池的全基因组关联研究来确定。通过根据各队列间探针强度差异对所有SNP进行排序，识别出等位基因频率差异较大的候选SNP。该方法能强烈检测到MAPT H1单倍型，同时还检测到位于11号染色体p12-p11区域的第二个主要基因位点，该位点在等位基因水平（P<0.001）、基因型水平（P<0.001）和单倍型水平（P<0.001）均显示出关联证据，并被缩小至一个单一的单倍型区域，该区域包含DNA损伤结合蛋白2（DDB₂）和溶酶体酸性磷酸酶2（ACP₂）基因。由于DNA损伤和溶酶体功能障碍与衰老及神经退行性过程有关，这两个基因均是导致疾病风险的潜在候选基因。
