UK Dementia Research Institute, School of Medicine, Cardiff University, UK; Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, UK; MRC Centre of Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, UK.
UK Dementia Research Institute, School of Medicine, Cardiff University, UK; MRC Centre of Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, UK.
Brain Behav Immun. 2019 Jul;79:267-273. doi: 10.1016/j.bbi.2019.02.011. Epub 2019 Feb 15.
Genome-wide association studies (GWAS) suggest that Alzheimer's disease (AD) is partly explained by a burden of risk alleles (single nucleotide polymorphisms; SNPs) with relatively small effects. However, the mechanisms by which these loci cumulatively confer susceptibility remain largely unknown. Accumulating evidence suggests an association between increased AD risk allele burden (measured via a polygenic risk profile score; AD-RPS) with reduced hippocampal volume (HV) across a number of independent cohorts. These lines of research suggest that the reduced HV may be a causal mechanism of risk in the development of late-onset Alzheimer's disease (AD). However, as RPS assesses broad, cumulative genetic risk, little is known about the biological processes which may explain this observation. Here, we leverage GWAS data from i) 17,008 late onset AD cases & 37,154 controls and ii) hippocampal volume (N = 12,147; N = 9707) to explore putative pathways that may explain this association. We first demonstrate an association between whole genome AD-RPS and HV (PT < 0.5, Z = -2.07, P = 0.038), confirming previous associations. Second, we restrict our analysis to SNPs within AD genes within a microglia mediated immunity network (N = 56). A microglia AD-RPS was further associated with HV (PT < 0.01; Z = -2.152, P = 0.031). Last, using a competitive, permutation based approach, we show that the common variation within this candidate gene-set is associated with HV, controlling for SNP set-size (P = 0.024). Together, the observations suggest that the relationship between AD and HV is partially explained by genes within an AD-linked microglia mediated immunity network.
全基因组关联研究（GWAS）表明，阿尔茨海默病（AD）部分是由具有相对较小效应的风险等位基因（单核苷酸多态性；SNP）负担引起的。然而，这些基因座如何累积赋予易感性的机制在很大程度上仍然未知。越来越多的证据表明，在多个独立队列中，AD 风险等位基因负担（通过多基因风险评分[AD-RPS]衡量）增加与海马体积（HV）减少之间存在关联。这些研究表明，HV 减少可能是晚发性阿尔茨海默病（AD）发展过程中风险的因果机制。然而，由于 RPS 评估广泛的、累积的遗传风险，对于可能解释这一观察结果的生物学过程知之甚少。在这里，我们利用来自 i）17008 例迟发性 AD 病例和 37154 例对照和 ii）海马体积（N=12147；N=9707）的 GWAS 数据来探索可能解释这种关联的潜在途径。我们首先证明了全基因组 AD-RPS 与 HV 之间存在关联（PT<0.5，Z=-2.07，P=0.038），证实了之前的关联。其次，我们将分析仅限于 AD 基因内的微胶质细胞介导免疫网络内的 SNP（N=56）。微胶质细胞 AD-RPS 与 HV 进一步相关（PT<0.01；Z=-2.152，P=0.031）。最后，使用竞争性、基于置换的方法，我们表明，在候选基因集中，常见变异与 HV 相关，控制 SNP 集大小（P=0.024）。总之，这些观察结果表明，AD 与 HV 之间的关系部分是由 AD 相关的微胶质细胞介导免疫网络内的基因解释的。
