What does heritability of Alzheimer's disease represent?

What does heritability of Alzheimer's disease represent?
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阿尔茨海默病的遗传性代表什么？

DOI：
10.1101/2022.09.07.506912
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发表时间：
2022
期刊：
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通讯作者：
Baker E
Baker E
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作者：
Baker E

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晚发性阿尔茨海默病（AD）和衰老都有很强的遗传成分。在每种情况下，都发现了许多相关的变异，但仍有多少缺失的遗传性有待发现。在基于SNP的遗传力估计的变异可以解释的差异，在报告heritability.MethodsWe计算遗传力在五个大的独立coholts（N = 7,396，1,566，803，12,528和3,963），以确定是否可以达成共识的AD遗传力估计。这些队列因样本量、病例和对照的年龄以及表型定义而异。我们计算遗传性a）为所有的SNP，B）excludingAPOE区域，c）排除两个APOE和全基因组关联研究命中区域，和d）SNP重叠的小胶质细胞gene-set. Results-based遗传性晚发性阿尔茨海默病是38和66%之间的年龄和遗传疾病的架构是正确的占。当排除APOE区域时，遗传力估计值平均降低12% [SD = 8%]，当去除全基因组显著区域时，遗传力估计值额外降低1% [SD = 3%]。一个小胶质细胞基因组解释了69-84%，我们的估计SNP为基础的遗传性仅使用3%的总SNPs在所有cohols.ConclusionThe遗传性神经退行性疾病不能表示为一个单一的数字，因为它是依赖于病例和对照组的年龄。当年龄和遗传结构被正确考虑时，全基因组关联研究获得了总AD遗传率的很大一部分。大约13%的基于SNP的遗传力可以通过已知的遗传基因座来解释，其余的遗传力可能存在于小胶质细胞相关基因周围。
IntroductionBoth late-onset Alzheimer’s disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability.MethodsWe compute heritability in five large independent cohorts (N = 7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excludingAPOEregion, c) excluding bothAPOEand genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set.ResultsSNP-based heritability of late onset Alzheimer’s disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% [SD = 8%] on average when theAPOEregion is excluded and an additional 1% [SD = 3%] when genome-wide significant regions were removed. A microglia gene-set explains 69–84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts.ConclusionThe heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes.