Division of Neuroscience and Mental Health, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom.
PLoS One. 2023 Apr 28;18(4):e0281440. doi: 10.1371/journal.pone.0281440. eCollection 2023.
Both 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.
We 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) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set.
SNP-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 the APOE region 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.
The 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.
迟发性阿尔茨海默病（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，但仍有多少遗传缺失有待发现存在争议。基于 SNP 的遗传力估计的可变性可以解释报告的遗传力差异。
我们在五个独立的大型队列中计算遗传力（N = 7396、1566、803、12528 和 3963），以确定是否可以达成 AD 遗传力估计的共识。这些队列的样本量、病例和对照的年龄以及表型定义各不相同。我们计算了 a）所有 SNP 的遗传力，b）排除 APOE 区域，c）排除 APOE 和全基因组关联研究命中区域，以及 d）与小胶质细胞基因集重叠的 SNP 的遗传力。
在正确考虑年龄和遗传疾病结构的情况下，迟发性 AD 的基于 SNP 的遗传力在 38%至 66%之间。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%]。使用所有队列中总 SNP 的 3%，一个小胶质细胞基因集可以解释我们基于 SNP 的遗传力估计值的 69-84%。
神经退行性疾病的遗传力不能用一个单一的数字来表示，因为它取决于病例和对照的年龄。全基因组关联研究在正确考虑年龄和遗传结构时，能捕获 AD 遗传力的很大一部分。大约 13%的基于 SNP 的遗传力可以用已知的遗传位点来解释，而剩余的遗传力可能存在于与小胶质细胞相关的基因附近。
