Kozlova Alena, Zhang Siwei, Sudwarts Ari, Zhang Hanwen, Smirnou Stanislau, Sun Xiaotong, Stephenson Kimberly, Zhao Xiaojie, Jamison Brendan, Ponnusamy Moorthi, He Xin, Pang Zhiping P, Sanders Alan R, Bellen Hugo J, Thinakaran Gopal, Duan Jubao
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.
Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA.
Res Sq. 2024 May 24:rs.3.rs-4407146. doi: 10.21203/rs.3.rs-4407146/v1.
Despite genome-wide association studies of late-onset Alzheimer's disease (LOAD) having identified many genetic risk loci, the underlying disease mechanisms remain largely unknown. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Leveraging our approach for identifying functional GWAS risk variants showing allele-specific open chromatin (ASoC), we systematically identified putative causal LOAD risk variants in human induced pluripotent stem cells (iPSC)-derived neurons, astrocytes, and microglia (MG) and linked risk allele to a previously unappreciated MG-specific role of in lipid droplet (LD) accumulation. ASoC mapping uncovered functional risk variants for 26 LOAD risk loci, mostly MG-specific. At the MG-specific locus, the LOAD risk allele of rs10792832 reduced transcription factor (PU.1) binding and expression, impairing the uptake of amyloid beta (Aβ) and myelin debris. Interestingly, MG with risk allele showed transcriptional enrichment of pathways for cholesterol synthesis and LD formation. Genetic and pharmacological perturbations of MG further established a causal link between the reduced expression, LD accumulation, and phagocytosis deficits. Our work elucidates the selective LOAD vulnerability in microglia for the locus through detrimental LD accumulation, providing a neurobiological basis that can be exploited for developing novel clinical interventions.
尽管全基因组关联研究已确定了许多晚发性阿尔茨海默病（LOAD）的遗传风险位点，但其潜在的疾病机制仍大多未知。确定因果疾病变异及其与LOAD相关的细胞表型一直是一项挑战。利用我们识别显示等位基因特异性开放染色质（ASoC）的功能性全基因组关联研究风险变异的方法，我们在人诱导多能干细胞（iPSC）衍生的神经元、星形胶质细胞和小胶质细胞（MG）中系统地鉴定了推定的因果LOAD风险变异，并将风险等位基因与脂质滴（LD）积累中以前未被认识到的MG特异性作用联系起来。ASoC图谱揭示了26个LOAD风险位点的功能性风险变异，其中大部分是MG特异性的。在MG特异性位点，rs10792832的LOAD风险等位基因减少了转录因子（PU.1）的结合和表达，损害了淀粉样β蛋白（Aβ）和髓鞘碎片的摄取。有趣的是，具有风险等位基因的MG显示出胆固醇合成和LD形成途径的转录富集。MG的遗传和药理学扰动进一步建立了表达降低、LD积累和吞噬功能缺陷之间的因果联系。我们的工作通过有害的LD积累阐明了小胶质细胞中该位点的选择性LOAD易感性，为开发新的临床干预措施提供了神经生物学基础。
