Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort

Youwen Qin; Aki S Havulinna; Yang Liu; Pekka Jousilahti; Scott C Ritchie; Alex Tokolyi; Jon G Sanders; Liisa Valsta; Marta Brożyńska; Qiyun Zhu; Anupriya Tripathi; Yoshiki Vázquez-Baeza; Rohit Loomba; Susan Cheng; Mohit Jain; Teemu Niiranen; Leo Lahti; Rob Knight; Veikko Salomaa; Michael Inouye; Guillaume Méric

doi:10.1038/s41588-021-00991-z

Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort

Nat Genet. 2022 Feb;54(2):134-142. doi: 10.1038/s41588-021-00991-z. Epub 2022 Feb 3.

Authors

Youwen Qin^{1

2}, Aki S Havulinna^{3

4}, Yang Liu^{1

5}, Pekka Jousilahti³, Scott C Ritchie^{1

6

7}, Alex Tokolyi⁸, Jon G Sanders^{9

10}, Liisa Valsta³, Marta Brożyńska¹, Qiyun Zhu¹¹, Anupriya Tripathi^{11

12}, Yoshiki Vázquez-Baeza^{13

14}, Rohit Loomba¹⁵, Susan Cheng¹⁶, Mohit Jain^{11

13}, Teemu Niiranen^{3

17}, Leo Lahti¹⁸, Rob Knight^{11

13

14}, Veikko Salomaa³, Michael Inouye^#^{19

20

21

22

23

24

25}, Guillaume Méric^#^{26

27}

Affiliations

¹ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
² School of BioSciences, The University of Melbourne, Melbourne, Victoria, Australia.
³ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
⁴ Institute for Molecular Medicine Finland, FIMM-HiLIFE, Helsinki, Finland.
⁵ Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia.
⁶ Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁷ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
⁸ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
⁹ Department of Ecology and Evolutionary Biology, Cornell University, Ithaca, NY, USA.
¹⁰ Cornell Institute for Host-Microbe Interaction and Disease, Cornell University, Ithaca, NY, USA.
¹¹ Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA.
¹² Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
¹³ Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA.
¹⁴ Department of Computer Science & Engineering, Jacobs School of Engineering, University of California San Diego, La Jolla, CA, USA.
¹⁵ NAFLD Research Center, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
¹⁶ Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁷ Department of Medicine, Turku University Hospital and University of Turku, Turku, Finland.
¹⁸ Department of Computing, University of Turku, Turku, Finland.
¹⁹ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia. mi336@medschl.cam.ac.uk.
²⁰ School of BioSciences, The University of Melbourne, Melbourne, Victoria, Australia. mi336@medschl.cam.ac.uk.
²¹ Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. mi336@medschl.cam.ac.uk.
²² British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK. mi336@medschl.cam.ac.uk.
²³ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. mi336@medschl.cam.ac.uk.
²⁴ Health Data Research UK Cambridge, Wellcome Genome Campus & University of Cambridge, Cambridge, UK. mi336@medschl.cam.ac.uk.
²⁵ The Alan Turing Institute, London, UK. mi336@medschl.cam.ac.uk.
²⁶ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia. guillaume.meric@baker.edu.au.
²⁷ Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Victoria, Australia. guillaume.meric@baker.edu.au.

^# Contributed equally.

Abstract

Human genetic variation affects the gut microbiota through a complex combination of environmental and host factors. Here we characterize genetic variations associated with microbial abundances in a single large-scale population-based cohort of 5,959 genotyped individuals with matched gut microbial metagenomes, and dietary and health records (prevalent and follow-up). We identified 567 independent SNP-taxon associations. Variants at the LCT locus associated with Bifidobacterium and other taxa, but they differed according to dairy intake. Furthermore, levels of Faecalicatena lactaris associated with ABO, and suggested preferential utilization of secreted blood antigens as energy source in the gut. Enterococcus faecalis levels associated with variants in the MED13L locus, which has been linked to colorectal cancer. Mendelian randomization analysis indicated a potential causal effect of Morganella on major depressive disorder, consistent with observational incident disease analysis. Overall, we identify and characterize the intricate nature of host-microbiota interactions and their association with disease.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

ABO Blood-Group System / genetics
Bifidobacterium / physiology
Clostridiales / physiology
Cohort Studies
Colorectal Neoplasms / genetics
Colorectal Neoplasms / microbiology
Depressive Disorder, Major / genetics
Depressive Disorder, Major / microbiology
Diet*
Dietary Fiber
Enterococcus faecalis / physiology
Gastrointestinal Microbiome* / genetics
Gastrointestinal Tract / microbiology*
Genetic Variation*
Genome-Wide Association Study
Host Microbial Interactions*
Humans
Lactase / genetics
Mediator Complex / genetics
Mendelian Randomization Analysis
Metagenome
Morganella / physiology
Polymorphism, Single Nucleotide*

Substances

ABO Blood-Group System
Dietary Fiber
MED13L protein, human
Mediator Complex
Lactase

Abstract

Publication types

MeSH terms

Substances

Grants and funding