Cheng Po-Liang, Wang Hui, Dombroski Beth A, Farrell John J, Horng Iris, Chung Tingting, Tosto Giuseppe, Kunkle Brian W, Bush William S, Vardarajan Badri, Schellenberg Gerard D, Lee Wan-Ping
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Biomedical Genetics, Department of Medicine, Boston University Medical School, Boston, MA, USA.
HGG Adv. 2025 Jul 31;6(4):100487. doi: 10.1016/j.xhgg.2025.100487.
We developed an imputation panel for Alzheimer disease (AD) and related dementias (ADRD) using 15,958 whole-genome sequencing (WGS) samples from the Alzheimer Disease Sequencing Project. Recognizing the importance of associations between structural variants (SVs) and AD and their underrepresentation in existing public reference panels, our panel uniquely integrates single-nucleotide variants (SNVs), short insertions or deletions (indels), and SVs. This panel enhances the imputation of rare variants underlying disease susceptibility onto genotype array data, offering a cost-effective alternative to WGS while significantly augmenting statistical power. Notably, we discovered 10 rare indels nominally significantly associated with AD that are absent in the TOPMed-r2 panel and identified one genome-wide significant (p < 5 × 10) and three suggestive significant (p < 1 × 10) AD-associated SVs. These findings provide the other insights into AD genetics and underscore the critical role of imputation panels in advancing our understanding of complex diseases like ADRD.
我们利用来自阿尔茨海默病测序项目的15958个全基因组测序(WGS)样本,开发了一个用于阿尔茨海默病(AD)及相关痴呆症(ADRD)的插补面板。认识到结构变异(SVs)与AD之间关联的重要性以及它们在现有公共参考面板中的代表性不足,我们的面板独特地整合了单核苷酸变异(SNVs)、短插入或缺失(indels)以及SVs。该面板增强了对疾病易感性潜在罕见变异到基因型阵列数据的插补能力,提供了一种经济高效的WGS替代方案,同时显著提高了统计效力。值得注意的是,我们发现了10个在TOPMed-r2面板中不存在且名义上与AD显著相关的罕见indels,并确定了1个全基因组显著(p < 5×10)和3个提示性显著(p < 1×10)的AD相关SVs。这些发现为AD遗传学提供了新的见解,并强调了插补面板在推进我们对ADRD等复杂疾病理解方面的关键作用。