Identifying Aging and Alzheimer Disease–Associated Somatic Variations in Excitatory Neurons From the Human Frontal Cortex

Abstract

Background and Objectives With age, somatic mutations accumulated in human brain cells can lead to various neurologic disorders and brain tumors. Because the incidence rate of Alzheimer disease (AD) increases exponentially with age, investigating the association between AD and the accumulation of somatic mutation can help understand the etiology of AD. Methods We designed a somatic mutation detection workflow by contrasting genotypes derived from whole-genome sequencing (WGS) data with genotypes derived from scRNA-seq data and applied this workflow to 76 participants from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP) cohort. We focused only on excitatory neurons, the dominant cell type in the scRNA-seq data. Results We identified 196 sites that harbored at least 1 individual with an excitatory neuron–specific somatic mutation (ENSM), and these 196 sites were mapped to 127 genes. The single base substitution (SBS) pattern of the putative ENSMs was best explained by signature SBS5 from the Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, a clock-like pattern correlating with the age of the individual. The count of ENSMs per individual also showed an increasing trend with age. Among the mutated sites, we found 2 sites tend to have more mutations in older individuals (16:6899517 [ RBFOX1 ], p = 0.04; 4:21788463 [ KCNIP4 ], p < 0.05). In addition, 2 sites were found to have a higher odds ratio to detect a somatic mutation in AD samples (6:73374221 [ KCNQ5 ], p = 0.01 and 13:36667102 [ DCLK1 ], p = 0.02). Thirty-two genes that harbor somatic mutations unique to AD and the KCNQ5 and DCLK1 genes were used for gene ontology (GO)–term enrichment analysis. We found the AD-specific ENSMs enriched in the GO-term “vocalization behavior” and “intraspecies interaction between organisms.” Of interest we observed both age-specific and AD-specific ENSMs enriched in the K+ channel–associated genes. Discussion Our results show that combining scRNA-seq and WGS data can successfully detect putative somatic mutations. The putative somatic mutations detected from ROSMAP data set have provided new insights into the association of AD and aging with brain somatic mutagenesis. AD= : Alzheimer disease; Aβ= : amyloid beta; COSMIC= : Catalogue of Somatic Mutations in Cancer; CSTB= : cystatin B; FDR= : false discovery rate; GO= : gene ontology; MAP= : the Rush Memory and Aging Project; ROS= : the Religious Order Study; SBS= : single base substitution; WGS= : whole-genome sequencing