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阿尔茨海默病及相关痴呆症的生物样本库规模特征分析确定了不同血统中潜在的致病变异、风险因素和基因修饰因子。

Biobank-scale characterization of Alzheimer's disease and related dementias identifies potential disease-causing variants, risk factors, and genetic modifiers across diverse ancestries.

作者信息

Khani Marzieh, Akçimen Fulya, Grant Spencer M, Akerman S Can, Lee Paul Suhwan, Faghri Faraz, Leonard Hampton, Kim Jonggeol Jeffrey, Makarious Mary B, Koretsky Mathew J, Rothstein Jeffrey D, Blauwendraat Cornelis, Nalls Mike A, Singleton Andrew, Bandres-Ciga Sara

机构信息

Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

出版信息

medRxiv. 2024 Nov 17:2024.11.03.24313587. doi: 10.1101/2024.11.03.24313587.

Abstract

Alzheimer's disease and related dementias (AD/ADRDs) pose a significant global public health challenge, underscored by the intricate interplay of genetic and environmental factors that differ across ancestries. To effectively implement equitable, personalized therapeutic interventions on a global scale, it is essential to identify disease-causing mutations and genetic risk and resilience factors across diverse ancestral backgrounds. Exploring genetic-phenotypic correlations across the globe enhances the generalizability of research findings, contributing to a more inclusive and universal understanding of disease. This study leveraged biobank-scale data to conduct the largest multi-ancestry whole-genome sequencing characterization of AD/ADRDs. We aimed to build a valuable catalog of potential disease-causing, genetic risk and resilience variants impacting the etiology of these conditions. We thoroughly characterized genetic variants from key genes associated with AD/ADRDs across 11 genetic ancestries, utilizing data from All of Us, UK Biobank, 100,000 Genomes Project, Alzheimer's Disease Sequencing Project, and the Accelerating Medicines Partnership in Parkinson's Disease, including a total of 25,001 cases and 93,542 controls. We prioritized 116 variants possibly linked to disease, including 18 known pathogenic and 98 novel variants. We detected previously described disease-causing variants among controls, leading us to question their pathogenicity. Notably, we showed a higher frequency of ε4/ε4 carriers among individuals of African and African Admixed ancestry compared to other ancestries, confirming ancestry-driven modulation of -associated AD/ADRDs. A thorough assessment of revealed a disease-modifying effect conferred by the :rs11556505, :rs449647, :rs10423769, :rs13116075, :rs6024870, and :rs2732703 variants among ε4 carriers across different ancestries. In summary, we compiled the most extensive catalog of established and novel genetic variants in known genes increasing risk or conferring resistance to AD/ADRDs across diverse ancestries, providing clinical insights into their genetic-phenotypic correlations. The findings from this investigation hold significant implications for potential clinical trials and therapeutic interventions on a global scale. Finally, we present an accessible and user-friendly platform for the AD/ADRDs research community to help inform and support basic, translational, and clinical research on these debilitating conditions (https://niacard.shinyapps.io/MAMBARD_browser/).

摘要

阿尔茨海默病及相关痴呆症(AD/ADRDs)构成了重大的全球公共卫生挑战,不同种族间遗传和环境因素的复杂相互作用凸显了这一点。为了在全球范围内有效实施公平、个性化的治疗干预措施,识别不同祖先背景下的致病突变以及遗传风险和复原力因素至关重要。探索全球范围内的遗传-表型相关性可提高研究结果的普遍性,有助于更全面、普遍地理解疾病。本研究利用生物样本库规模的数据,对AD/ADRDs进行了最大规模的多祖先全基因组测序特征分析。我们旨在建立一个有价值的目录,列出影响这些疾病病因的潜在致病、遗传风险和复原力变异。我们利用来自“我们所有人”计划、英国生物样本库、“十万基因组计划”、阿尔茨海默病测序项目以及帕金森病加速药物合作伙伴计划的数据,对11个遗传祖先中与AD/ADRDs相关的关键基因的遗传变异进行了全面表征,其中包括总共25001例病例和93542例对照。我们对116个可能与疾病相关的变异进行了优先级排序,包括18个已知的致病变异和9个8新变异。我们在对照中检测到了先前描述的致病变异,这使我们对其致病性产生了质疑。值得注意的是,我们发现非洲和非裔混血个体中ε4/ε4携带者的频率高于其他种族,证实了祖先驱动的与AD/ADRDs相关的调节作用。对……的全面评估揭示了不同祖先的ε4携带者中由……的rs11556505、……的rs449647、……的rs10423769、……的rs13116075、……的rs6024870和……的rs2732703变异所赋予的疾病修饰作用。总之,我们编制了已知基因中已确定和新发现的遗传变异的最广泛目录,这些变异增加了不同祖先患AD/ADRDs的风险或赋予了对其的抵抗力,为它们的遗传-表型相关性提供了临床见解。这项调查的结果对全球范围内潜在的临床试验和治疗干预具有重要意义。最后,我们为AD/ADRDs研究界提供了一个易于访问且用户友好的平台,以帮助为这些使人衰弱的疾病的基础、转化和临床研究提供信息并提供支持(https://niacard.shinyapps.io/MAMBARD_browser/)。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/caa0/11601747/7134438760b0/nihpp-2024.11.03.24313587v4-f0001.jpg

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