全基因组关联分析轻度认知障碍和阿尔兹海默病的遗传学差异

Analysis of genetic difference between mild cognitive impairment and Alzheimer＇s disease through genome-wide association study

目的探讨轻度认知障碍（mild cognitive impairment，MCI）与阿尔兹海默病（Alzheimer’s disease，AD）遗传因素的差异。方法收集168例阿尔兹海默病患者、380例轻度认知障碍患者和261例老年对照样本的全基因组测序检测数据。通过全基因组关联分析（genome-wide association study，GWAS）进行基因型一表型关联分析。结果共发现与AD关联的单核苷酸多态性（single nucleotide polymorphism，SNP）位点16个，绝大部分位于19号染色体上，与既往的研究结果一致。与MCI关联的SNP位点10个，绝大部分位于9号染色体上。通过PlinkSets-based检验计算SNP集合的关联生物途径，发现MCI和AD相关的SNP位点集属于不同的生物途径。结论名义显著（P〈0．01）的SNP关联位点显示MCI和AD仅共享很小一部分SNP位点（分别不到1／10和1／20），严格校正（P〈5×10^-7，FDR—BH〈0．1）的SNP关联位点显示MCI和AD关联位点并不相同，提示稳定的MCI和AD在遗传学上可能属于两种不同风险的疾病。

Objective To explore the genetic difference between mild cognitive impairment（MCI） and Alzheimer＇ s disease （AD） through association analysis of whole genome sequencing data. Methods Sequence data of 168 AD patients, 380 MCI patients and 261 elderly controls from the Alzheimer＇s Disease Neuroimaging Initiative（ADNI） project was collected. The genotype and phenotype association was analyzed through genome wide association study（GWAS）. Results Sixteen single nucleotide polymorphisms（SNPs） were found to be associated with AD, and most of them were located on chromosome 19. This was consistent with the results of previous studies. Ten SNP loci were associated with MCI, and most of them were located on chromosome 9. The biological pathways associated with the SNP sets were calculated with a Plink Sets-based algorithm, and the results showed that the SNP loci sets associated with MCI and AD belonged to different biological pathways. Conclusion The strictly adjusted result indicated that the SNP loci significantly associated with MCI and AD are different, and the nominal significant associated SNP loci showed that steady MCI and AD shared just a limited number of loci. This indicated that MCI and AD are different diseases bearing distinct genetic risks.