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

• DOI: 10.1101/2020.06.26.173724
• Publication Date: 2020-06-29T10:45:21Z
• Authors: Alexander Kurilsh...; Carolina Medina-G...; Rodrigo Bacigalupe; Djawad Radjabzadeh; Jun Wang; Ayse Demirkan; Caroline I. Le Roy; Juan Antonio Rayg...; Casey T. Finnicum; Xingrong Liu; Daria V. Zhernakova; Marc Jan Bonder; Tue H. Hansen; Fabian Frost; Malte C. Rühlemann; Williams Turpin; Jee-Young Moon; Han-Na Kim; Kreete Lüll; Elad Barkan; Shiraz A. Shah; Myriam Fornage; Joanna Szopinska-...; 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 D...; Liesbeth Duijts; Gwen Falony; Jingyuan Fu; Adriaan van der G...; Torben Hansen; Georg Homuth; David A. Hughes; Richard G. Ijzerman; Matthew A. Jackson; Vincent W.V. Jaddoe; Marie Joossens; Torben Jørgensen; Daniel Keszthelyi; Rob Knight; Markku Laakso; Matthias Laudes; Lenore J. Launer; Wolfgang Lieb; Aldons J. Lusis; Ad A.M. Masclee; Henriette A. Moll; Zlatan Mujagic; Qi Qibin; Daphna Rothschild; Hocheol Shin; Søren J. Sørensen; Claire J. Steves; Jonathan Thorsen; Nicholas J. Timpson; Raul Y. Tito; Sara Vieira-Silva; Uwe Völker; Henry Völzke; Urmo Võsa; Kaitlin H. Wade; Susanna Walter; Kyoko Watanabe; Stefan Weiss; Frank U. Weiss; Omer Weissbrod; Harm-Jan Westra; Gonneke Willemsen; Haydeh Payami; Daisy M.A.E. Jonkers; Alejandro Arias V...; Eco J.C. de Geus; Katie A. Meyer; Jakob Stokholm; Eran Segal; Elin Org; Cisca Wijmenga; Hyung-Lae Kim; Robert C. Kaplan; Tim D. Spector; Andre G. Uitterli...; Fernando Rivadeneira; Andre Franke; Markus M. Lerch; Lude Franke; Serena Sanna; Mauro D’Amato; Oluf Pedersen; Andrew D. Paterson; Robert Kraaij; Jeroen Raes; Alexandra Zhernakova
• Keywords: EMC MM-04-54-08-A; Male; 0301 basic medicine; gut microbiome; Medical and Health Sciences; Genome-wide association studies; Oral and gastrointestinal; Linkage Disequilibrium; Cohort Studies; RNA, Ribosomal, 16S; 2.1 Biological and endogenous factors; genetics; Aetiology; Child; genotype imputation; Lactase; Genetics & Heredity; EMC OR-01-54-02; 2. Zero hunger; 0303 health sciences; Biological Sciences; Psychiatry - Radboud University Medical Center; Bioinformatics and computational biology; DISEASES; Child, Preschool; MENDELIAN RANDOMIZATION; Female; Life Sciences & Biomedicine; environment; Biotechnology; Adult; 570; 16S; GENETICS; Adolescent; Agricultural biotechnology; Quantitative Trait Loci; EMC MM-03-54-04-A; 610; GENOTYPE IMPUTATION; Microbiology; metagenome; diseases; 03 medical and health sciences; Clinical Research; framework; Genetics; Humans; GENOME-WIDE ASSOCIATION; Preschool; Nutrition; Ribosomal; 16S RNA; ecosystem; ENVIRONMENT; Science & Technology; genome-wide association study; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; IDENTIFICATION; Human Genome; Genetic Variation; Mendelian Randomization Analysis; FRAMEWORK; Gastrointestinal Microbiome; METAGENOME; Metabolism; genome-wide association; RNA; identification; mendelian randomization; ECOSYSTEM; Human Genetics - Radboud University Medical Center; Bifidobacterium; Digestive Diseases; Developmental Biology; Genome-Wide Association Study

AbstractTo 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 out of 410 genera were detected in more than 95% samples. A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 31 loci affecting microbiome at a genome-wide significant (P<5×10−8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (GWAS signal P=1.28×10−20), and it showed an age-dependent association withBifidobacteriumabundance. 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 has causal effects in ulcerative colitis and rheumatoid arthritis.