Gauron Maria Celeste, Prokopenko Dmitry, Lee Sanghun, Wolfe Sarah A, Hecker Julian, Willett Julian, Waqas Mohammad, Lordén Gema, Yang Yimin, Mayfield Joshua E, Castanho Isabel, Mullin Kristina, Morgan Sarah, Hahn Georg, Demeo Dawn L, Hide Winston, Bertram Lars, Lange Christoph, Newton Alexandra C, Tanzi Rudolph E
Department of Pharmacology, University of California; San Diego, La Jolla, CA, USA.
Genetics and Aging Research Unit and the McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital; Charlestown, MA, USA.
medRxiv. 2025 May 14:2025.05.13.25327562. doi: 10.1101/2025.05.13.25327562.
The identification of Alzheimer's disease (AD)-associated genomic variants has provided powerful insight into disease etiology. Genome-wide association studies (GWAS) for AD have successfully identified new targets but have almost exclusively utilized additive genetic models. Here, we performed a family-based GWAS under a recessive inheritance model using whole genome sequencing from families affected by AD. We found that the variant, rs7161410, located in an intron of the gene, encoding protein kinase C eta (PKCη), was associated with AD risk (p-value=1.41 × 10-7). Further analysis revealed a rare missense mutation K65R in linkage disequilibrium with rs7161410, which was present in homozygous carriers of the rs7161410 risk allele. We show that this mutation leads to enhanced localization and signaling of PKCη at the Golgi. The novel genetically-validated association of aberrant PKCη signaling with AD opens avenues for new therapeutic targets aimed at prevention and treatment.
阿尔茨海默病（AD）相关基因组变异的鉴定为疾病病因提供了有力的见解。AD的全基因组关联研究（GWAS）已成功识别出新的靶点，但几乎完全采用了加性遗传模型。在此，我们使用来自受AD影响家庭的全基因组测序，在隐性遗传模型下进行了基于家庭的GWAS。我们发现位于编码蛋白激酶C eta（PKCη）的基因内含子中的变异rs7161410与AD风险相关（p值 = 1.41×10⁻⁷）。进一步分析揭示了一个与rs7161410处于连锁不平衡状态的罕见错义突变K65R，该突变存在于rs7161410风险等位基因的纯合携带者中。我们表明，这种突变导致PKCη在高尔基体处的定位和信号增强。异常的PKCη信号与AD新的经基因验证的关联为旨在预防和治疗的新治疗靶点开辟了道路。
