按性别、发病年龄和载脂蛋白E基因型分层的阿尔茨海默病及相关疾病的全基因组关联研究揭示了非裔美国人中的新风险基因座。
Genome-wide association studies of Alzheimer's disease and related disorders stratified by sex, onset age, and Apolipoprotein E genotype reveal novel risk loci in African Americans.
作者信息
Sherva Richard, Zhu Congcong, Zhang Rui, Mez Jesse, Hauger Richard, Merritt Victoria C, Panizzon Matthew, Gaziano J Michael, Catanzaro Vidriana, Schellenberg Gerard D, Pericak-Vance Margaret, Haines Jonathan L, Wang Li-San, Mayeux Richard, Farrer Lindsay A, Logue Mark W
机构信息
National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.
Biomedical Genetics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
出版信息
Alzheimers Res Ther. 2025 Jul 24;17(1):171. doi: 10.1186/s13195-025-01782-y.
BACKGROUND
Alzheimer's disease (AD) risk variants have been identified in European ancestry cohorts that have stronger effects at certain ages, in individuals with a specific sex, or in those with specific isoforms of APOE, the strongest AD risk locus. However, sample sizes in African ancestry (AA) cohorts have been underpowered to perform stratified analyses.
METHODS
We generated genome-wide association study datasets stratified by sex, age at onset (< 75 vs ≥ 75), and APOE-ε4 carrier status in AA cohorts from MVP and the Alzheimer's Disease Genetics Consortium (ADGC). Outcomes in MVP were AD and related dementias (ADRD; n = 4073 cases and 19,648 controls) and proxy dementia (i.e., reported dementia in a parent, n = 6216 cases and 21,566 controls) while ADGC analyses examined AD (n = 2425 cases and 5069 controls). The proxy dementia GWASs were included in the sex-stratified meta-analysis corresponding to the sex of the affected parent. The top genes were tested for differential expression in AA brain tissue.
RESULTS
In addition to the APOE region, genome-wide significant associations were observed in an intergenic region near the EPHA5 gene (rs141838133, p = 2.19 × 10) in individuals with onset < 75 years, in GRIN3B near the known AD risk gene ABCA7 (rs115882880, p = 3.83 × 10) in females, and near TSPEAR (rs139130053, p = 4.27 × 10) in APOE-ε4 non-carriers. EPHA5 regulates glucose homeostasis, and ephrin receptors modify the strength of existing synapses in the brain and in pancreatic islets. It is unclear whether GRIN3B represents a locus distinct from ABCA7. Rs115882880 was a significant eQTL for GRIN3B but not ABCA7 in AA brain samples. TSPEAR regulates Notch signaling but has not been linked to neuronal function.
CONCLUSIONS
Age, sex, and APOE-stratified analyses of dementia in AA participants from two cohorts revealed potential new associations. Stratified analyses may yield critical information about the genetic heterogeneity underlying dementia risk and lead to advances in precision medicine.
背景
在欧洲血统队列中已鉴定出阿尔茨海默病（AD）风险变异，这些变异在特定年龄、特定性别的个体或携带载脂蛋白E（APOE，最强的AD风险基因座）特定异构体的个体中具有更强的作用。然而，非洲血统（AA）队列的样本量不足以进行分层分析。
方法
我们在来自MVP和阿尔茨海默病遗传学联盟（ADGC）的AA队列中，生成了按性别、发病年龄（<75岁与≥75岁）和APOE-ε4携带者状态分层的全基因组关联研究数据集。MVP中的结局指标是AD及相关痴呆（ADRD；4073例病例和19648例对照）和代理痴呆（即报告父母患有痴呆，6216例病例和21566例对照），而ADGC分析则研究AD（2425例病例和5069例对照）。代理痴呆全基因组关联研究纳入了与受影响父母性别对应的性别分层荟萃分析。对顶级基因在AA脑组织中的差异表达进行了检测。
结果
除APOE区域外，在发病年龄<75岁的个体中，观察到EPHA5基因附近的一个基因间区域（rs141838133，p = 2.19×10）存在全基因组显著关联；在女性中，在已知AD风险基因ABCA7附近的GRIN3B（rs115882880，p = 3.83×10）存在全基因组显著关联；在APOE-ε4非携带者中，在TSPEAR附近（rs139130053，p = 4.27×10）存在全基因组显著关联。EPHA5调节葡萄糖稳态，而 Ephrin 受体可改变大脑和胰岛中现有突触的强度。尚不清楚GRIN3B是否代表一个与ABCA7不同的基因座。在AA脑样本中，rs115882880是GRIN3B而非ABCA7的显著表达定量性状基因座。TSPEAR调节Notch信号传导，但尚未与神经元功能相关联。
结论
对来自两个队列的AA参与者的痴呆进行年龄、性别和APOE分层分析，揭示了潜在的新关联。分层分析可能会产生有关痴呆风险潜在遗传异质性的关键信息，并推动精准医学的发展。
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