Novel Insights Into the Genetic Basis Between Cholelithiasis and Four Dietary Patterns

Previous epidemiological evidence has demonstrated that cheese, dried fruit, oily fish, and raw vegetables intake is inversely associated with the risk of cholelithiasis. Nevertheless, the underlying genetic mechanisms responsible for this relationship remain elusive, warranting a genomic-level investigation into the molecular pathways mediating these associations. To investigate potential genetic linkages, genome-wide association study (GWAS) datasets pertaining to cholelithiasis and four specific dietary patterns (cheese, dried fruit intake, oily fish, and raw vegetables) were employed within a multi-stage analytical framework. Initially, genome-wide genetic correlations were assessed through a combination of linkage disequilibrium score regression, genetic covariance analysis, and high-definition likelihood methodologies. Concurrently, local genetic variation analyses were conducted to pinpoint relevant genomic loci. Mendelian randomization (MR) was employed to assess causal effects. Subsequently, conditional/conjunctional false discovery rate (cond/conjFDR) approaches were utilized to evaluate the genetic overlap between cholelithiasis and dietary traits. Integration of conjFDR with multi-trait analysis of GWAS (MTAG) facilitated the identification of shared genetic loci. Significant inverse genome-wide genetic correlations were identified between cholelithiasis and all four dietary patterns. Analyses of local genetic variation revealed overlapping genetic signals across several chromosomal regions. The application of cond/conjFDR approaches provided further validation of genetic commonality between the traits. Integration of conjFDR with MTAG led to the successful identification and validation of several key shared genetic loci. This investigation represents the first genomic-level analysis establishing genetic associations between cholelithiasis and cheese, dried fruit intake, oily fish, and raw vegetable intake. The elucidated shared genetic loci offer novel molecular insights supporting dietary strategies for cholelithiasis prevention.