Metabologenomic analysis identifies elevated serum sphingosine-1-phosphate as a pathogenic driver of Ménière’s disease

Our cohort comprised 28 males (45.90%) with a mean age at diagnosis of 53.5 years (range 26-76 years). To investigate the comprehensive molecular underpinnings of MD, we employed an integrative analysis framework: (1) We performed whole-exome sequencing (WES) on 49 patients and 8 controls to identify recurrently deleterious variants; (2) We conducted metabolomics profiling on 58 patients and 25 controls to uncover metabolic alterations associated with MD; (3) By integrating WES and metabolomics data, we established genotype-metabolite associations; (4) We validated our patient-derived insights using MD mouse model with transcriptome and metabolome data; (5) We further elucidated the dynamics of key metabolic pathways with three public single-cell RNA-seq datasets as well as a bulk MD patient peripheral blood mononuclear cells (PBMCs) dataset.