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

By 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. Rühlemann, Williams Turpin, Jee-Young Moon, Han-Na Kim, Kreete Lüll, Elad 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, 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 Vasquez, 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 Uitterlinden, 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

Posted 28 Jun 2020
bioRxiv DOI: 10.1101/2020.06.26.173724

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 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<5x10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (GWAS signal P=1.28x10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95x10-10<P<5x10-8) 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.

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