A large-scale genome-wide association study (GWAS) identified 31 loci influencing human gut microbiome composition, with the lactase (LCT) gene locus showing the strongest association with Bifidobacterium abundance. The study analyzed 18,340 individuals from 24 cohorts, revealing high variability in microbial composition across populations. Only 9 out of 410 genera were detected in over 95% of samples. The study found that microbial taxa with high heritability and genes expressed in the intestine and brain were enriched in association signals. Phenome-wide association studies and Mendelian randomization suggested that the microbiome has causal effects in ulcerative colitis and rheumatoid arthritis. The study also identified that the LCT locus showed age-dependent and ethnic heterogeneity in its association with Bifidobacterium abundance. The mbTLs (microbiome trait loci) were enriched for genes related to metabolism, with the FUT2 gene showing a significant association with Ruminococcus torques abundance. The study also found that the LCT locus was associated with multiple dietary and metabolic traits, including Type 2 diabetes and obesity. The results suggest that a subset of gut bacteria is heritable, and the genetic architecture affecting their abundance is complex and polygenic. The study highlights the importance of the gut microbiome in health-related traits and suggests that future research should focus on larger sample sizes, harmonized protocols, and advanced microbiome analysis methods. The study provides insights into the genetic factors influencing the gut microbiome and their potential impact on health.A large-scale genome-wide association study (GWAS) identified 31 loci influencing human gut microbiome composition, with the lactase (LCT) gene locus showing the strongest association with Bifidobacterium abundance. The study analyzed 18,340 individuals from 24 cohorts, revealing high variability in microbial composition across populations. Only 9 out of 410 genera were detected in over 95% of samples. The study found that microbial taxa with high heritability and genes expressed in the intestine and brain were enriched in association signals. Phenome-wide association studies and Mendelian randomization suggested that the microbiome has causal effects in ulcerative colitis and rheumatoid arthritis. The study also identified that the LCT locus showed age-dependent and ethnic heterogeneity in its association with Bifidobacterium abundance. The mbTLs (microbiome trait loci) were enriched for genes related to metabolism, with the FUT2 gene showing a significant association with Ruminococcus torques abundance. The study also found that the LCT locus was associated with multiple dietary and metabolic traits, including Type 2 diabetes and obesity. The results suggest that a subset of gut bacteria is heritable, and the genetic architecture affecting their abundance is complex and polygenic. The study highlights the importance of the gut microbiome in health-related traits and suggests that future research should focus on larger sample sizes, harmonized protocols, and advanced microbiome analysis methods. The study provides insights into the genetic factors influencing the gut microbiome and their potential impact on health.