John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; Dr. John T. MacDonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.
John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA.
Neurobiol Aging. 2024 Jan;133:125-133. doi: 10.1016/j.neurobiolaging.2023.10.010. Epub 2023 Oct 31.
There is a paucity of genetic studies of Alzheimer Disease (AD) in individuals of African Ancestry, despite evidence suggesting increased risk of AD in the African American (AA) population. We performed whole-genome sequencing (WGS) and multipoint linkage analyses in 51 multi-generational AA AD families ascertained through the Research in African American Alzheimer Disease Initiative (REAAADI) and the National Institute on Aging Late Onset Alzheimer's disease (NIA-LOAD) Family Based Study. Variants were prioritized on minor allele frequency (<0.01), functional potential of coding and noncoding variants, co-segregation with AD and presence in multi-ancestry ADSP release 3 WGS data. We identified a significant linkage signal on chromosome 5q35 (HLOD=3.3) driven by nine families. Haplotype segregation analysis in the family with highest LOD score identified a 3'UTR variant in INSYN2B with the most functional evidence. Four other linked AA families harbor within-family shared variants located in INSYN2B's promoter or enhancer regions. This AA family-based finding shows the importance of diversifying population-level genetic data to better understand the genetic determinants of AD on a global scale.
针对非裔美国人（African American，AA）群体阿尔茨海默病（Alzheimer Disease，AD）风险增加的证据，我们对通过“非洲裔美国人 AD 研究（Research in African American Alzheimer Disease Initiative，REAAADI）”和美国国家老龄化研究所（National Institute on Aging）迟发性 AD 家族性研究（National Institute on Aging Late Onset Alzheimer's disease，NIA-LOAD）确定的 51 个多代 AA AD 家族进行了全基因组测序（Whole-Genome Sequencing，WGS）和多点连锁分析。根据次要等位基因频率（<0.01）、编码和非编码变异的功能潜力、与 AD 的共分离以及在多血统 ADSP 释放 3 WGS 数据中的存在情况，对变异进行了优先级排序。由九个家族驱动，在 5q35 染色体上发现了一个显著的连锁信号（HLOD=3.3）。在具有最高 LOD 评分的家族中进行的单体型分离分析，确定了 INSYN2B 中具有最多功能证据的 3'UTR 变异。其他四个连锁的 AA 家族在 INSYN2B 的启动子或增强子区域内存在家族内共享变异。这项基于 AA 家族的发现表明，为了更好地在全球范围内了解 AD 的遗传决定因素，必须使人群水平的遗传数据多样化。
