考虑到健康与退休研究中阿尔茨海默病多基因评分的 APOE 基因座：一项纵向面板研究。
Considering the APOE locus in Alzheimer's disease polygenic scores in the Health and Retirement Study: a longitudinal panel study.
机构信息
Survey Research Center, Institute for Social Research, University of Michigan, 426 Thompson St., Rm. 3320 ISR-Thompson, Ann Arbor, MI, 48104, USA.
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
出版信息
BMC Med Genomics. 2020 Nov 3;13(1):164. doi: 10.1186/s12920-020-00815-9.
BACKGROUND
Polygenic scores are a strategy to aggregate the small, additive effects of single nucleotide polymorphisms across the genome. With phenotypes like Alzheimer's disease, which have a strong and well-established genomic locus (APOE), the cumulative effect of genetic variants outside of this area has not been well established in a population-representative sample.
METHODS
Here we examine the association between polygenic scores for Alzheimer's disease both with and without the APOE region (chr19: 45,384,477 to 45,432,606, build 37/hg 19) at different P value thresholds and dementia. We also investigate the addition of APOE-ε4 carrier status and its effect on the polygenic score-dementia association in the Health and Retirement Study using generalized linear models accounting for repeated measures by individual and use a binomial distribution, logit link, and unstructured correlation structure.
RESULTS
In a large sample of European ancestry participants of the Health and Retirement Study (n = 9872) with an average of 5.2 (standard deviation 1.8) visit spaced two years apart, we found that including the APOE region through weighted variants in a polygenic score was insufficient to capture the large amount of risk attributed to this region. We also found that a polygenic score with a P value threshold of 0.01 had the strongest association with the odds of dementia in this sample (odds ratio = 1.10 95%CI 1.0 to 1.2).
CONCLUSION
We recommend removing the APOE region from polygenic score calculation and treating the APOE locus as an independent covariate when modeling dementia. We also recommend using a moderately conservative P value threshold (e.g. 0.01) when creating polygenic scores for Alzheimer's disease on dementia. These recommendations may help elucidate relationships between polygenic scores and regions of strong significance for phenotypes similar to Alzheimer's disease.
背景
多基因评分是一种策略，可以整合基因组中单核苷酸多态性的微小、累加效应。对于像阿尔茨海默病这样具有强大且明确的基因组位置（APOE）的表型，在具有代表性的人群样本中，该区域以外的遗传变异的累积效应尚未得到很好的确定。
方法
在这里，我们研究了在不同 P 值阈值下，包含或不包含 APOE 区域（chr19: 45,384,477 至 45,432,606，构建 37/hg 19）的阿尔茨海默病多基因评分与痴呆症之间的关联。我们还使用广义线性模型，通过个体的重复测量进行了分析，并使用二项分布、对数链接和非结构相关结构，调查了在健康与退休研究中加入 APOE-ε4 携带者状态及其对多基因评分-痴呆症关联的影响。
结果
在健康与退休研究中具有代表性的欧洲血统参与者的大样本（n=9872）中，平均随访时间为 5.2 年（标准差为 1.8 年），两次随访间隔两年，我们发现，在多基因评分中包含 APOE 区域的加权变体不足以捕获归因于该区域的大量风险。我们还发现，在该样本中，具有 0.01 P 值阈值的多基因评分与痴呆症的发病几率具有最强的关联（优势比=1.10，95%置信区间为 1.0 至 1.2）。
结论
我们建议在计算多基因评分时去除 APOE 区域，并在建模痴呆症时将 APOE 基因座视为独立的协变量。我们还建议在为阿尔茨海默病创建多基因评分时使用适度保守的 P 值阈值（例如 0.01）。这些建议可能有助于阐明多基因评分与类似阿尔茨海默病的表型的强显著性区域之间的关系。
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