Large-scale association analyses identify host factors influencing human gut microbiome composition
Autoren
Alexander Kurilshikov, Carolina Medina-Gomez, Rodrigo Bacigalupe, Djawad Radjabzadeh, Jun Wang, Ayse Demirkan, Caroline Le Roy, Juan Raygoza Garay, Casey Finnicum, Xingrong Liu, Daria Zhernakova, Marc Bonder, Tue Hansen, Fabian Frost, Malte Rühlemann, Williams Turpin, Jee-Young Moon, Han-Na Kim, Kreete Lüll, Elad Barkan, Shiraz Shah, Myriam Fornage, Joanna Szopinska-Tokov, Zachary Wallen, Dmitrii Borisevich, Lars Agreus, Anna Andreasson, Corinna Bang, Larbi Bedrani, Jordana Bell, Hans Bisgaard, Michael Boehnke, Dorret Boomsma, Robert Burk, Annique Claringbould, Kenneth Croitoru, Gareth Davies, Cornelia van Duijn, Liesbeth Duijts, Gwen Falony, Jingyuan Fu, Adriaan van der Graaf, Torben Hansen, Georg Homuth, David Hughes, Richard Ijzerman, Matthew Jackson, Vincent Jaddoe, Marie Joossens, Torben Jørgensen, Daniel Keszthelyi, Rob Knight, Markku Laakso, Matthias Laudes, Lenore Launer, Wolfgang Lieb, Aldons Lusis, Ad Masclee, Henriette Moll, Zlatan Mujagic, Qi Qibin, Daphna Rothschild, Hocheol Shin, Søren Sørensen, Claire Steves, Jonathan Thorsen, Nicholas Timpson, Raul Tito, Sara Vieira-Silva, Uwe Völker, Henry Völzke, Urmo Võsa, Kaitlin Wade, Susanna Walter, Kyoko Watanabe, Stefan Weiss, Frank Weiss, Omer Weissbrod, Harm-Jan Westra, Gonneke Willemsen, Haydeh Payami, Daisy Jonkers, Alejandro Arias Vasquez, Eco Geus, Katie Meyer, Jakob Stokholm, Eran Segal, Elin Org, Cisca Wijmenga, Hyung-Lae Kim, Robert Kaplan, Tim Spector, Andre Uitterlinden, Fernando Rivadeneira, Andre Franke, Markus Lerch, Lude Franke, Serena Sanna, Mauro D'Amato, Oluf Pedersen, Andrew Paterson, Robert Kraaij, Jeroen Raes, Alexandra Zhernakova
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.