Large-scale association analyses identify host factors influencing human gut microbiome composition

  • Nat Genet. 2021 Feb;53(2):156-165. doi: 10.1038/s41588-020-00763-1.
Alexander Kurilshikov  #  1 ,  Carolina Medina-Gomez  #  2  3 ,  Rodrigo Bacigalupe  #  4  5 ,  Djawad Radjabzadeh  #  2 ,  Jun Wang  #  4  5  6 ,  Ayse Demirkan  7  8 ,  Caroline I Le Roy  9 ,  Juan Antonio Raygoza Garay  10  11 ,  Casey T Finnicum  12 ,  Xingrong Liu  13 ,  Daria V Zhernakova  7  14 ,  Marc Jan Bonder  7 ,  Tue H Hansen  15 ,  Fabian Frost  16 ,  Malte C Rühlemann  17 ,  Williams Turpin  10  11 ,  Jee-Young Moon  18 ,  Han-Na Kim  19  20 ,  Kreete Lüll  21 ,  Elad Barkan  22 ,  Shiraz A Shah  23 ,  Myriam Fornage  24  25 ,  Joanna Szopinska-Tokov  26 ,  Zachary D Wallen  27 ,  Dmitrii Borisevich  15 ,  Lars Agreus  28 ,  Anna Andreasson  29 ,  Corinna Bang  17 ,  Larbi Bedrani  10 ,  Jordana T Bell  9 ,  Hans Bisgaard  23 ,  Michael Boehnke  30 ,  Dorret I Boomsma  31 ,  Robert D Burk  32  33 ,  Annique Claringbould  7 ,  Kenneth Croitoru  10  11 ,  Gareth E Davies  12  31 ,  Cornelia M van Duijn  34  35 ,  Liesbeth Duijts  3  36 ,  Gwen Falony  4  5 ,  Jingyuan Fu  7  37 ,  Adriaan van der Graaf  7 ,  Torben Hansen  15 ,  Georg Homuth  38 ,  David A Hughes  39  40 ,  Richard G Ijzerman  41 ,  Matthew A Jackson  9  42 ,  Vincent W V Jaddoe  3  34 ,  Marie Joossens  4  5 ,  Torben Jørgensen  43 ,  Daniel Keszthelyi  44  45 ,  Rob Knight  46  47  48 ,  Markku Laakso  49 ,  Matthias Laudes  50 ,  Lenore J Launer  51 ,  Wolfgang Lieb  52 ,  Aldons J Lusis  53  54 ,  Ad A M Masclee  44  45 ,  Henriette A Moll  36 ,  Zlatan Mujagic  44  45 ,  Qi Qibin  18 ,  Daphna Rothschild  22 ,  Hocheol Shin  55  56 ,  Søren J Sørensen  57 ,  Claire J Steves  9 ,  Jonathan Thorsen  23 ,  Nicholas J Timpson  39  40 ,  Raul Y Tito  4  5 ,  Sara Vieira-Silva  4  5 ,  Uwe Völker  38 ,  Henry Völzke  58 ,  Urmo Võsa  7 ,  Kaitlin H Wade  39  40 ,  Susanna Walter  59  60 ,  Kyoko Watanabe  61 ,  Stefan Weiss  16  38 ,  Frank U Weiss  16 ,  Omer Weissbrod  62 ,  Harm-Jan Westra  7 ,  Gonneke Willemsen  31 ,  Haydeh Payami  27 ,  Daisy M A E Jonkers  44  45 ,  Alejandro Arias Vasquez  26  63 ,  Eco J C de Geus  31  64 ,  Katie A Meyer  65  66 ,  Jakob Stokholm  23 ,  Eran Segal  22 ,  Elin Org  21 ,  Cisca Wijmenga  7 ,  Hyung-Lae Kim  67 ,  Robert C Kaplan  68 ,  Tim D Spector  9 ,  Andre G Uitterlinden  2  3  34 ,  Fernando Rivadeneira  2  3 ,  Andre Franke  17 ,  Markus M Lerch  16 ,  Lude Franke  7 ,  Serena Sanna  7  69 ,  Mauro D'Amato  13  70  71  72 ,  Oluf Pedersen  15 ,  Andrew D Paterson  73 ,  Robert Kraaij  2 ,  Jeroen Raes  4  5 ,  Alexandra Zhernakova  74
Affiliations
  • 1. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. [email protected].
  • 2. Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
  • 3. The Generation R Study, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
  • 4. Department of Microbiology and Immunology, Rega Institute, KU Leuven, Leuven, Belgium.
  • 5. Center for Microbiology, VIB, Leuven, Belgium.
  • 6. Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • 7. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • 8. Section of Statistical Multi-Omics, Department of Clinical & Experimental Medicine, School of Biosciences & Medicine, University of Surrey, Guildford, UK.
  • 9. Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.
  • 10. Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
  • 11. Division of Gastroenterology, Mount Sinai Hospital, Toronto, Ontario, Canada.
  • 12. Avera Institute of Human Genetics, Avera McKennan Hospital & University Health Center, Sioux Falls, SD, USA.
  • 13. Center for Molecular Medicine and Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
  • 14. Laboratory of Genomic Diversity, Center for Computer Technologies, ITMO University, St. Petersburg, Russia.
  • 15. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 16. Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.
  • 17. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
  • 18. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 19. Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
  • 20. Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
  • 21. Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
  • 22. Department of Computer Science and Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
  • 23. COPSAC, Copenhagen University Hospital, Copenhagen, Denmark.
  • 24. Institute of Molecular Medicine McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 25. Human Genetics Center School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 26. Department of Psychiatry, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
  • 27. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 28. Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
  • 29. Stress Research Institute, Stockholm University, Stockholm, Sweden.
  • 30. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
  • 31. Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.
  • 32. Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 33. Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 34. Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
  • 35. Nuffield Department of Population Health, University of Oxford, Oxford, UK.
  • 36. Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
  • 37. Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • 38. Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
  • 39. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
  • 40. Population Health Sciences, Bristol Medical School, Bristol, UK.
  • 41. Department of Endocrinology, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands.
  • 42. Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
  • 43. Centre for Clinical Research and Prevention, Bispebjerg/Frederiksberg Hospital, Capital Region of Copenhagen and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 44. Division of Gastroenterology-Hepatology, Maastricht University Medical Center+, Maastricht, the Netherlands.
  • 45. NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
  • 46. Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
  • 47. Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA.
  • 48. Center for Microbiome Innovation and Department of Bioengeering, University of California, San Diego, La Jolla, CA, USA.
  • 49. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
  • 50. Department of Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • 51. Laboratory of Epidemiology and Population Science, National Institute on Aging, Bethesda, MD, USA.
  • 52. Institute of Epidemiology, Kiel University, Kiel, Germany.
  • 53. Departments of Microbiology, Immunology and Molecular Genetics, and Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • 54. Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • 55. Department of Family Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
  • 56. Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
  • 57. Department of Biology, University of Copenhagen, Copenhagen, Denmark.
  • 58. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
  • 59. Department of Biomedical and Clinical Sciences, University of Linköping, Linköping, Sweden.
  • 60. Department of Gastroenterology, County Council of Östergötland, Linköping, Sweden.
  • 61. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, the Netherlands.
  • 62. School of Public Health, Harvard University, Boston, MA, USA.
  • 63. Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.
  • 64. Amsterdam Public Health, Amsterdam UMC, Amsterdam, the Netherlands.
  • 65. Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 66. Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA.
  • 67. Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, Republic of Korea.
  • 68. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 69. Istituto di Ricerca Genetica e Biomedica, National Research Council, Monserrato, Italy.
  • 70. School of Biological Sciences, Monash University, Clayton, Victoria, Australia.
  • 71. Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, San Sebastián, Spain.
  • 72. Ikerbasque, Basque Science Foundation, Bilbao, Spain.
  • 73. Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
  • 74. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. [email protected].
  • # Contributed equally.
PMID: 33462485 DOI: 10.1038/s41588-020-00763-1
Abstract

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10-10 < P < 5 × 10-8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in Ulcerative Colitis and Rheumatoid Arthritis.