Large-scale association analyses identify host factors influencing human gut microbiome composition.
Kurilshikov A., Medina-Gomez C., Bacigalupe R., Radjabzadeh D., Wang J., Demirkan A., Le Roy CI., Raygoza Garay JA., Finnicum CT., Liu X., Zhernakova DV., Bonder MJ., Hansen TH., Frost F., Rühlemann MC., Turpin W., Moon J-Y., Kim H-N., Lüll K., Barkan E., Shah SA., Fornage M., Szopinska-Tokov J., Wallen ZD., Borisevich D., Agreus L., Andreasson A., Bang C., Bedrani L., Bell JT., Bisgaard H., Boehnke M., Boomsma DI., Burk RD., Claringbould A., Croitoru K., Davies GE., van Duijn CM., Duijts L., Falony G., Fu J., van der Graaf A., Hansen T., Homuth G., Hughes DA., Ijzerman RG., Jackson MA., Jaddoe VWV., Joossens M., Jørgensen T., Keszthelyi D., Knight R., Laakso M., Laudes M., Launer LJ., Lieb W., Lusis AJ., Masclee AAM., Moll HA., Mujagic Z., Qibin Q., Rothschild D., Shin H., Sørensen SJ., Steves CJ., Thorsen J., Timpson NJ., Tito RY., Vieira-Silva S., Völker U., Völzke H., Võsa U., Wade KH., Walter S., Watanabe K., Weiss S., Weiss FU., Weissbrod O., Westra H-J., Willemsen G., Payami H., Jonkers DMAE., Arias Vasquez A., de Geus EJC., Meyer KA., Stokholm J., Segal E., Org E., Wijmenga C., Kim H-L., Kaplan RC., Spector TD., Uitterlinden AG., Rivadeneira F., Franke A., Lerch MM., Franke L., Sanna S., D'Amato M., Pedersen O., Paterson AD., Kraaij R., Raes J., Zhernakova A.
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.