Despite the meteoric rise in genome-wide association studies for metabolic diseases (MetD) over the last few years, our understanding of the pathogenesis of these diseases is still far from complete. Recent developments have established that MetD arises from complex interactions between host genetics, the gut microbiome and the environment. However, our knowledge of the genetic and microbiome components involved and the underlying molecular mechanisms remains limited. Here, we review and summarize recent studies investigating the genetic and microbiome basis of MetD. Then, given the critical importance of study-individual’s ancestry in these studies, we leverage 4932 whole-genome sequence samples from 18 worldwide ethnic groups to examine genetic diversity in currently reported variants associated with MetD. The analyses show marked differences in gene-specific proportion of pathogenic single-nucleotide polymorphisms (SNPs) and gene-specific SNPs MAFs across ethnic groups, highlighting the importance of population- and ethnic-specific investigations in pinpointing the causative factors for MetD. We conclude with a discussion of research areas where further investigation on interactions between host genetics, microbiome and the environment is needed.