Large-scale searching for causal relationships of milk consumption with multi-omics and disease susceptibility: A phenome-wide Mendelian randomization study.

The causal relationship between milk consumption and a broad spectrum of health outcomes remains incompletely elucidated. This study aimed to investigate potential causal effects and explore the underlying biological pathways using an integrative multi-omics framework. We conducted a large-scale 2-sample Mendelian randomization study. Genetic predisposition for milk consumption was instrumented by the lactase persistence variant (rs4988235). We assessed causal relationships with 2459 disease phenotypes from FinnGen, and 91 inflammatory proteins, 211 gut microbial taxa, 731 immunophenotypes, and 1091 plasma metabolites. Genetically predicted higher milk consumption demonstrated robust effects on different disease outcomes. It was associated with a reduced risk of intestinal diseases, particularly colorectal cancer and its subtypes (all P <2.03 × 10-5) and a decreased risk of malnutrition (OR: 0.998, 95% confidence interval: 0.996-0.999, P = 6.02 × 10-8). Multi-omics analyses revealed nominally significant associations with specific gut microbes (e.g., Lactobacillus), inflammatory proteins (TNFSF12, CXCL5), immunophenotypes, and plasma metabolites (all P <.05). After false discovery rate correction, milk consumption significantly increased levels of N,N,N- trimethyl-5-aminovalerate (TMAVA, OR: 1.001, 95% confidence interval: 1.001-1.002, P = 5.74 × 10-5). This study provides genetic evidence supporting a potential causal relationship between milk consumption and health outcomes, exhibiting a strong protective role against intestinal diseases while also implicating potential pathways involving gut microbiota, host metabolism, and immune response.