Uncovering dark mass in population proteomics: Pan-analysis of single amino acid polymorphism relevant to cognition and aging.

Human proteome data across populations have been analyzed extensively to reveal protein quantitative associations with physiological or pathological states, while the single amino acid polymorphism (SAP) has been rarely investigated. In this work, we introduce a pan-SAP workflow that relies on pan-database searching independent of individual genome sequencing. Using ten cohorts comprising 2,004 individuals related to cognition disorder and aging, we quantify the SAP sites in key proteins, such as apolipoprotein E (APOE) in plasma and cerebrospinal fluid at the proteome level. Specifically, the quantification of heterozygous APOE-C112R, including its abundance and ratio, provides insights into the dosage effect and relationship with cognition disorder, which cannot be interpreted at the genomic level. Furthermore, our approach could precisely track age-related changes in APOE-C112R levels. Taken together, this pan-SAP workflow uncovered existing but hidden SAPs in multi-populations, connecting SAP quantification to disease progression and paving the way for broader proteomic investigations in complex diseases.