Toward precision medicine: modulation of ABCA7 associated risk of Alzheimer's disease by ancestry

摘要 种族和文化多样性带来了经济和社会效益。它也给治疗带来了挑战 发展和保健提供。然而，祖先并没有被始终如一地考虑在内 直到最近，精准医学的必要性变得明显。因此，缺乏对 疾病病理学上的祖先差异，甚至是关于如何研究这种疾病的成熟方法的差异 不同之处。小鼠模型似乎不适合于祖先的病理生理学研究。目的 这项研究的目的是阐明三磷酸腺苷结合盒转运体亚家族A有多少损失 成员7(ABCA7)对欧洲、非洲和东亚人群淀粉样蛋白β(Aβ)代谢的影响 祖先使用人类诱导的多能干细胞(IPS)细胞来源的神经元。ABCA7被牵连为一名 阿尔茨海默病(AD)病理的危险因素在许多全基因组关联和基因组测序中的研究 对欧洲、非洲和东亚血统的研究。在初步数据中，我们确认 来自遗传学的观察表明，在大约145名AD和对照受试者中，大多数 在欧洲血统中，ABCA7水平非常低的个体表现出加速的AD发病。我们也 显示使用CRISPR/Cas9在欧洲人iPS细胞来源神经元中缺失ABCA7 血统导致Aβ分泌增加。最后，我们确认ABCA7功能丧失等位基因是 非洲血统中常见的(~5%的次要等位基因频率) 来自费城的一群人在生物库里。人类遗传学研究发现，功能丧失 在欧洲血统的人群中，ABCA7的等位基因会使AD的风险增加几倍，而ABCA7 非洲血统人群中的功能缺失等位基因最多会增加80%的患病风险。 在此基础上，我们提出了一个假设，即在非洲血统中丢失ABCA7的危害小于在非洲血统中丢失的ABCA7 欧洲血统。为了验证这一假设，我们建议删除iPS细胞中的ABCA7 非洲和东亚血统，并确定该基因的缺失在多大程度上影响iPS细胞的β合成- 这两个祖先来源的神经元与欧洲祖先的iPS细胞来源的神经元进行比较。 基于遗传学研究，预测在iPS细胞来源的神经元中ABCA7的丢失 非洲血统将比欧洲血统的iPS细胞来源的神经元更少地增加Aβ的产生 研究对象。这项拟议的工作将展示iPS细胞来源的神经元是否可以用于研究 根据祖先的病理生理差异，证实了从人类遗传学观察到的ABCA7在 在欧洲血统的AD发病机制中发挥更大作用，为进一步研究AD的发病机制奠定基础 ABCA7对阿尔茨海默病影响的祖先差异的机制。

Abstract Ethnic and cultural diversity offers economic and societal benefits. It also poses challenges in therapeutic development and health care provision. However, ancestry has not been taken consistently into consideration until recently, when the need for precision medicine became apparent. There is therefore lack of research into ancestral differences in disease pathology and even of well-established approaches on how to investigate such differences. Mouse models do not seem to be suitable for studies of pathophysiology by ancestry. The purpose of this study is to elucidate how much loss of adenosine triphosphate binding cassette transporter subfamily A member 7 (ABCA7) affects amyloid β (Aβ) metabolism in individuals of European, African and East Asian ancestry using human induced pluripotent stem (iPS) cell-derived neurons. ABCA7 has been implicated as a risk factor in Alzheimer's disease (AD) pathology in many genome-wide association and genome sequencing studies in European, African and, to a lesser extent, East Asian ancestry. In preliminary data, we confirm observations from genetics and show that in a cohort of approximately 145 AD and control subjects of mostly European ancestry, individuals with very low ABCA7 levels exhibited accelerated AD pathogenesis. We also show that deletion of ABCA7 using CRISPR/Cas9 in iPS cell-derived neurons from individuals of European ancestry leads to an increase in Aβ secretion. Finally, we confirm that ABCA7 loss-of-function alleles are common (~5% minor allele frequency) in African ancestry by inspecting whole-exome sequencing data from a cohort of individuals from Philadelphia in a biobank. Human genetic studies have found that loss-of-function alleles in ABCA7 in populations of European ancestry increase the risk of AD by several fold, while ABCA7 loss-of-function alleles in populations of African ancestry increase the risk of the disease by at most 80%. Based on this, we advance the hypothesis that loss of ABCA7 in African ancestry is less detrimental than in European ancestry. To test this hypothesis, we propose to delete ABCA7 in iPS cells from individuals of African and East Asian ancestry and to determine how much loss of this gene affects Aβ synthesis in iPS cell- derived neurons of these two ancestries in comparison with iPS cell-derived neurons of European ancestry. Based on the genetic studies, the prediction is that loss of ABCA7 in iPS cell-derived neurons from subjects of African ancestry will elevate Aβ production less than in iPS cell-derived neurons from European ancestry subjects. The proposed work will show whether iPS cell-derived neurons can be used to study pathophysiological differences by ancestry, conform observations from human genetics that ABCA7 plays a greater role in AD pathogenesis in European ancestry individuals and lay a foundation for further studies of the mechanisms that underlie ancestral difference in the ABCA7 effect on AD.