CRP-albumin-lymphocyte index and multisystem diseases: a phenome-wide Mendelian randomization study

The C-reactive protein-albumin-lymphocyte (CALLY) index is a composite biomarker integrating inflammation, nutrition, and immune function, but its causal relationships with a broad spectrum of human diseases and potential utility for public health risk prediction remain unclear. We conducted a population-based genetic epidemiological study combining genome-wide association study (GWAS), phenome-wide association study (PheWAS), and two-sample Mendelian randomization (MR), using data from the UK Biobank (265,409 participants for GWAS; 113,747 participants for PheWAS) and FinnGen to construct genetic instruments for the CALLY index, perform PheWAS across 713 phenotypes, evaluate causal associations via two-sample MR, and conduct sensitivity analyses including linkage disequilibrium score regression and pleiotropy testing. GWAS identified 154 genomic loci significantly associated with the CALLY index; PheWAS detected 24 significant phenotype associations, with higher genetically predicted CALLY index linked to lower risks of Alzheimer's disease, Alzheimer's dementia, unspecified dementia, and lipid metabolism disorders. MR confirmed causal protective effects for these neurodegenerative outcomes while indicating a causal association with increased sleep disorder risk, and pleiotropic analyses highlighted shared biological pathways in lipid metabolism and inflammation. These findings demonstrate that the CALLY index is causally associated with neurodegenerative, metabolic, and sleep disorders, supporting its role as a promising integrated biomarker for disease risk stratification and public health applications.