Interplay between host genetics and gut microbiome composition in the Japanese population

David Ortega-Reyes^1,2,3,4Tadashi Takeuchi⁵Yusuke Ogata⁶Takuro Iwami^1,7Wataru Suda^8,9Tetsuya Kubota^10,11,12,13Naoto Kubota¹⁴Takashi Kadowaki¹²Kohei Tomizuka¹Hiroshi Ohno^10,15,16Momoko Horikoshi^2*Chikashi Terao^1,17,18*

• ¹Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
• ²Laboratory for Genomics of Diabetes and Metabolism, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
• ³Laboratory for DNA Data Analysis, National Institute of Genetics, Shizuoka, Japan
• ⁴Department of Genetics, School of Life Science, The Graduate University for Advanced Studies, SOKENDAI, Kanagawa, Japan
• ⁵Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohma, Japan
• ⁶Laboratory for Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
• ⁷Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
• ⁸Laboratory for Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yohohama, Japan
• ⁹Laboratory for Symbiotic Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
• ¹⁰Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
• ¹¹Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
• ¹²Division of Diabetes and Metabolism, The Institute for Medical Science Asahi Life Foundation, Tokyo, Japan
• ¹³Department of Clinical Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Tokyo, Japan
• ¹⁴Department of Metabolic Medicine, Faculty of Life Sciences Kumamoto, Kumamoto, Japan
• ¹⁵Laboratory for Immune Regulation, Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chiba, Japan
• ¹⁶Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan
• ¹⁷Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
• ¹⁸Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

Background: Host genetics significantly influence the composition of the gut microbiota, but this relationship remains poorly understood, especially in non-European populations. This study aims to investigate the associations between host genetic variation and gut microbiome composition in the Japanese population and to assess methodological factors affecting reproducibility in microbiome research.We performed whole-genome sequencing on 306 Japanese individuals and obtained their gut microbiome profiles using shotgun metagenomic sequencing. Genome-wide association studies (GWAS) were conducted to identify associations between host genetic variants and the relative abundance of microbial taxa and bacterial pathways. Phenome-wide association studies (PheWAS) were performed on predicted high-impact variants. Additionally, we compared methodological approaches to assess their impact on microbiome composition and reproducibility.We identified significant associations between host genetic variants and the relative abundance of one bacterial family, one genus, one species and eight bacterial pathways (p ≤ 5×10 -8 ). However, none of these associations surpassed the stringent significance threshold of p ≤ 2.75×10 -11 . Notably, we were unable to replicate associations reported in prior studies, including those conducted in Japanese populations, even regarding the direction of effects. Our PheWAS analysis uncovered a frameshift variant in the OR6C1 gene (rs5798345-CA) that was significantly associated with an increased abundance of Bacteroides uniformis. Furthermore, comparative analyses highlighted that methodological differences, particularly in sample processing and DNA extraction protocols, substantially influence the observed gut microbiome composition. This variability may be a key factor contributing to the lack of reproducibility across studies.Our findings enhance the understanding of how host genetics shape the gut microbiota in the Japanese population and underscore the importance of methodological standardization in microbiome research. The identified associations between host genetic variants and specific microbial taxa provide insights into the complex interplay between genetics and the gut microbiome. Addressing methodological discrepancies is crucial for improving reproducibility and advancing knowledge of host-microbiome interactions.