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

MiBioGen Consortium Initiative, Alexander Kurilshikov*, Carolina Medina-Gomez, Rodrigo Bacigalupe, Djawad Radjabzadeh, Jun Wang, Ayse Demirkan, Caroline I. Le Roy, Juan Antonio Raygoza Garay, Casey T. Finnicum, Xingrong Liu, Daria V. Zhernakova, Marc Jan Bonder, Tue H. Hansen, Fabian Frost, Malte C. Ruehlemann, Williams Turpin, Jee-Young Moon, Han-Na Kim, Kreete LullElad Barkan, Shiraz A. Shah, Myriam Fornage, Joanna Szopinska-Tokov, Zachary D. Wallen, Dmitrii Borisevich, Lars Agreus, Anna Andreasson, Corinna Bang, Larbi Bedrani, Jordana T. Bell, Hans Bisgaard, Michael Boehnke, Dorret I. Boomsma, Robert D. Burk, Annique Claringbould, Kenneth Croitoru, Gareth E. Davies, Cornelia M. van Duijn, Liesbeth Duijts, Gwen Falony, Jingyuan Fu, Adriaan van der Graaf, Torben Hansen, Urmo Vosa, Harm-Jan Westra, Cisca Wijmenga, Markus M. Lerch, Lude Franke, Serena Sanna, Alexandra Zhernakova*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

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 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) <P <5 x 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.

Original languageEnglish
Pages (from-to)156-165
Number of pages19
JournalNature Genetics
Early online date18-Jan-2021
DOIs
Publication statusPublished - 18-Jan-2021

Keywords

  • GENOME-WIDE ASSOCIATION
  • MENDELIAN RANDOMIZATION
  • GENOTYPE IMPUTATION
  • GENETICS
  • IDENTIFICATION
  • ENVIRONMENT
  • METAGENOME
  • FRAMEWORK
  • ECOSYSTEM
  • DISEASES

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