Bacteria are recognized to play important roles in health and disease, including obesity, diabetes, cardiovascular diseases, mental diseases, and autoimmune diseases. However, owing to modulation by diet and drugs, the gut microbiota is commonly viewed as highly dynamic, whereas disease markers are considered to be stable. Several genome-wide association studies mostly using 16S rRNA sequencing have reported associations between the host genetics and individual bacterial taxa, beta-diversity, or pathways. Yet, doubts remain as to the significance of genetic associations. Here, we conducted large-scale metagenome-genome wide association study (MGWAS) to illustrate the impact of the host genetics on the microbiome including gut microbiome and oral microbiome. Then based on the associations, we carried out Mendelian randomization to infer the causal relationship between the microbiome and the metabolites and diseases and we found abundantcausalities between the oral microbiome and serum metabolites which will lay the foundation for future analysis of the microbiome and other phenotypes.