The study investigates the relationship between host genetics and gut microbiome composition in 18,340 individuals from 24 population-based cohorts of diverse ethnicities. The analysis includes 16S rRNA gene sequencing profiles and genotyping data, and aims to identify genetic variants affecting the gut microbiome. Key findings include: 1. **Microbial Composition Variability**: The gut microbiome showed significant variability across cohorts, with only 9 out of 410 genera detected in more than 95% of samples. The core microbiota, comprising nine genera, was less abundant in additional cohorts, suggesting that a larger sample size and higher sequencing depth are needed to capture the full diversity. 2. **Heritability of Microbial Taxa**: Heritability analysis using twin cohorts revealed that only a subset of gut bacteria is heritable, with heritable taxa showing more significant associations with genetic loci. Twin-based heritability was significantly correlated with SNP-based heritability. 3. **Genome-Wide Association Study (GWAS)**: A GWAS identified 31 loci affecting the gut microbiome at a genome-wide significant threshold (P<5×10−8). The lactase (LCT) gene locus showed the strongest association with Bifidobacterium abundance, with an age-dependent effect. Other associations were enriched for taxa with high heritability and genes expressed in the intestine and brain. 4. **Phenome-Wide Association Study (PheWAS) and Mendelian Randomization (MR)**: PheWAS identified enrichment of microbiome trait loci in metabolic, nutrition, and environmental domains. MR analysis suggested that higher abundance of Actinobacteria and Bifidobacterium may have a protective effect against ulcerative colitis, while higher abundance of Oxalobacteraceae might protect against rheumatoid arthritis. 5. **Discussion**: The study highlights the complex genetic architecture affecting the gut microbiome and its potential impact on health-related traits. The findings contribute to personalized nutrition and medication strategies based on both host genomics and microbiome data. However, the large heterogeneity in microbial composition across cohorts and methodological differences in sample processing reduced the statistical power of the analysis, limiting the number of identified loci. Future studies should aim for larger sample sizes, harmonized protocols, and advanced microbiome analysis methods.The study investigates the relationship between host genetics and gut microbiome composition in 18,340 individuals from 24 population-based cohorts of diverse ethnicities. The analysis includes 16S rRNA gene sequencing profiles and genotyping data, and aims to identify genetic variants affecting the gut microbiome. Key findings include: 1. **Microbial Composition Variability**: The gut microbiome showed significant variability across cohorts, with only 9 out of 410 genera detected in more than 95% of samples. The core microbiota, comprising nine genera, was less abundant in additional cohorts, suggesting that a larger sample size and higher sequencing depth are needed to capture the full diversity. 2. **Heritability of Microbial Taxa**: Heritability analysis using twin cohorts revealed that only a subset of gut bacteria is heritable, with heritable taxa showing more significant associations with genetic loci. Twin-based heritability was significantly correlated with SNP-based heritability. 3. **Genome-Wide Association Study (GWAS)**: A GWAS identified 31 loci affecting the gut microbiome at a genome-wide significant threshold (P<5×10−8). The lactase (LCT) gene locus showed the strongest association with Bifidobacterium abundance, with an age-dependent effect. Other associations were enriched for taxa with high heritability and genes expressed in the intestine and brain. 4. **Phenome-Wide Association Study (PheWAS) and Mendelian Randomization (MR)**: PheWAS identified enrichment of microbiome trait loci in metabolic, nutrition, and environmental domains. MR analysis suggested that higher abundance of Actinobacteria and Bifidobacterium may have a protective effect against ulcerative colitis, while higher abundance of Oxalobacteraceae might protect against rheumatoid arthritis. 5. **Discussion**: The study highlights the complex genetic architecture affecting the gut microbiome and its potential impact on health-related traits. The findings contribute to personalized nutrition and medication strategies based on both host genomics and microbiome data. However, the large heterogeneity in microbial composition across cohorts and methodological differences in sample processing reduced the statistical power of the analysis, limiting the number of identified loci. Future studies should aim for larger sample sizes, harmonized protocols, and advanced microbiome analysis methods.