combined effects of host genetics and diet on human gut microbiota and incident disease CORD-Papers-2021-10-25 (Version 1)

Title: Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort
Abstract: Co-evolution between humans and the microbial communities colonizing them has resulted in an intimate assembly of thousands of microbial species mutualistically living on and in their body and impacting multiple aspects of host physiology and health. Several studies examining whether human genetic variation can affect gut microbiota suggest a complex combination of environmental and host factors. Here, we leverage a single large-scale population-based cohort of 5,959 genotyped individuals with matched gut microbial shotgun metagenomes, dietary information and health records up to 16 years post-sampling, to characterize human genetic variations associated with microbial abundances, and predict possible causal links with various diseases using Mendelian randomization (MR). Genome-wide association study (GWAS) identified 583 independent SNP-taxon associations at genome-wide significance (p<5.0x10-8), which included notable strong associations with LCT (p=5.02x10-35), ABO (p=1.1x10-12), and MED13L (p=1.84x10-12). A combination of genetics and dietary habits was shown to strongly shape the abundances of certain key bacterial members of the gut microbiota, and explain their genetic association. Genetic effects from the LCT locus on Bifidobacterium and three other associated taxa significantly differed according to dairy intake. Variation in mucin-degrading Faecalicatena lactaris abundances were associated with ABO, highlighting a preferential utilization of secreted A/B/AB-antigens as energy source in the gut, irrespectively of fibre intake. Enterococcus faecalis levels showed a robust association with a variant in MED13L, with putative links to colorectal cancer. Finally, we identified putative causal relationships between gut microbes and complex diseases using MR, with a predicted effect of Morganella on major depressive disorder that was consistent with observational incident disease analysis. Overall, we present striking examples of the intricate relationship between humans and their gut microbial communities, and highlight important health implications.
Published: 9/13/2020
DOI: 10.1101/2020.09.12.20193045
DOI_URL: http://doi.org/10.1101/2020.09.12.20193045
Author Name: Qin, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/qin_y
Author Name: Havulinna, A S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/havulinna_a_s
Author Name: Liu, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_y
Author Name: Jousilahti, P
Author link: https://covid19-data.nist.gov/pid/rest/local/author/jousilahti_p
Author Name: Ritchie, S C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ritchie_s_c
Author Name: Tokolyi, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tokolyi_a
Author Name: Sanders, J G
Author link: https://covid19-data.nist.gov/pid/rest/local/author/sanders_j_g
Author Name: Valsta, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/valsta_l
Author Name: Brozynska, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/brozynska_m
Author Name: Zhu, Q
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhu_q
Author Name: Tripathi, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tripathi_a
Author Name: Vazquez Baeza, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/vazquez_baeza_y
Author Name: Loomba, R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/loomba_r
Author Name: Cheng, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/cheng_s
Author Name: Jain, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/jain_m
Author Name: Niiranen, T
Author link: https://covid19-data.nist.gov/pid/rest/local/author/niiranen_t
Author Name: Lahti, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lahti_l
Author Name: Knight, R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/knight_r
Author Name: Salomaa, V
Author link: https://covid19-data.nist.gov/pid/rest/local/author/salomaa_v
Author Name: Inouye, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/inouye_m
Author Name: Meric, G
Author link: https://covid19-data.nist.gov/pid/rest/local/author/meric_g
sha: 11b61b83916b5f6976ff0df167fce3094b16c44b
license: medrxiv
source_x: MedRxiv
url: http://medrxiv.org/cgi/content/short/2020.09.12.20193045v1?rss=1
has_full_text: TRUE
Keywords Extracted from Text Content: SNP-taxon 5,959 gut Morganella 56 colorectal cancer ABO A/B/AB-antigens p<5.0×10 p=1.1×10 × humans medRxiv Bifidobacterium p=1.84×10 human LCT body dentium vascular berries rs545971:TT gastric 361 cancers CBM32 colorectal cells medRxiv Figure 1 pre-521 blood antigens LCT-M 1039 MED13L loci beta carbon IgM B-and 229 AB-antigens MR-PRESSO 126 ABO blood beta coefficient k-mer-based CDK8 cell 96,97 NCBI nomenclature 553 p=7.26× fiber-227 SARS-CoV-2 77,78 rs4988235:TT Figure 3A stem Bifidobacterium B-204 antigens central root E. faecalis chromosomes LCT-Bifidobacterium rs4988235 p=1.70×10 GH53 F. 238 lactaris genome-w 1040 × Blood Bifidobacterium species 191 GA p=1.15×10 Faecalicatena lactaris 205 RNA polymerase II 57 individuals cardiovascular alpha 213 p<0.05 lactose carbohydrates cell surface glycoproteins humans cancers LCT-MCM6-ZRANB3 Human610-Quad SNP-taxon bone blue edges gut blood zeros SNPs 117 611 GH112 colon p<2.2× CO 2 e 696 PDE1A LCT-330 p=1.10×10 human-microbe GreenAlgorithms German low-vs Bifidobacterium 168 67,68 p=9×10 F. lactaris CAG-81 164 sp000435795 p=1.3× Firmicutes_A GH26 Enterococcus faecalis ABO histo-blood nodes B-antigens CAZymes p=6.16×10 -8 colorectal tumours GCTA-COJO 114 secretor individuals rs4988235:CT Morganella AG AB blood type groups human gut 49 GH136 46 LCT locus 163 S8B Bifidobacterium species 185 186 ~6,000 heart LD (r 2 fruits Collinsella were 223 human gut cholera ×10 -6 B-and AB-antigens O blood Rs187309577 139 node B. dentium CAG-81 sp000435795 Collinsella ( Figure 3D bovine milk oligosaccharides lactase CRC Firmicutes_A GTDB 118 phyla non-human primates CO 2 e gut mucosa colorectal cancer joint p=1.24×10 -5 ) MED13 Mediator transcriptional 250 coactivator colonic bacteria ×10 -8 12,71,72 unit-669 human populations 65 human LCT Human gut MAGs Eagle2 GG GCTA-COJO secretor chr9:133271182 time-on-study B 614 high-fiber bread people 922 genera LCT-MCM6 host-427 Hardy-520 Weinberg Equilibrium p=4.4×10 gut-brain Mediator complex subunit 13L p<5.0×10 purple edges TwoSampleMR GH94 cyclin-dependent kinase 8 milk p=1.75×10 λ GC =1.0051 https://gtdb.ecogenomic.org/taxon_history/. 554 FUT2 lipopolysaccharide ABO FR02 metagenome-assembled lactose-179 A/B/AB-secretors cancer MR-Egger 531.94 non-secretors fiber-209 CAG-81 180 Lactase HumanOmniExpress Alpha F. 214 lactaris Figure 1C line n=1,132 GH129 GTDB histo-blood 136 Bifidobacterium dentium gut barrier alpha-or intestines CAG-81 p=5.0×10 A/B/AB-antigens 100,106 zero-mean vegetables 508 GTDB 551 UBA3855 sp900316885 176 B
Extracted Text Content in Record: First 5000 Characters:Co-evolution between humans and the microbial communities colonizing them has resulted in 37 an intimate assembly of thousands of microbial species mutualistically living on and in their 38 body and impacting multiple aspects of host physiology and health. Several studies examining 39 whether human genetic variation can affect gut microbiota suggest a complex combination of 40 environmental and host factors. Here, we leverage a single large-scale population-based cohort 41 of 5,959 genotyped individuals with matched gut microbial shotgun metagenomes, dietary 42 information and health records up to 16 years post-sampling, to characterize human genetic 43 variations associated with microbial abundances, and predict possible causal links with various 44 diseases using Mendelian randomization (MR). Genome-wide association study (GWAS) 45 identified 583 independent SNP-taxon associations at genome-wide significance (p<5.0×10 -8 ), 46 which included notable strong associations with LCT (p=5.02×10 -35 ), ABO (p=1.1×10 -12 ), and 47 MED13L (p=1.84×10 -12 ). A combination of genetics and dietary habits was shown to strongly 48 shape the abundances of certain key bacterial members of the gut microbiota, and explain their 49 genetic association. Genetic effects from the LCT locus on Bifidobacterium and three other 50 associated taxa significantly differed according to dairy intake. Variation in mucin-degrading 51 Faecalicatena lactaris abundances were associated with ABO, highlighting a preferential 52 utilization of secreted A/B/AB-antigens as energy source in the gut, irrespectively of fibre 53 intake. Enterococcus faecalis levels showed a robust association with a variant in MED13L, 54 with putative links to colorectal cancer. Finally, we identified putative causal relationships 55 between gut microbes and complex diseases using MR, with a predicted effect of Morganella 56 on major depressive disorder that was consistent with observational incident disease analysis. 57 Overall, we present striking examples of the intricate relationship between humans and their 58 gut microbial communities, and highlight important health implications. 59 60 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Introduction discovered to be prevalent in >25% of the cohort (Methods). Using a genome-wide 112 significance threshold (p<5.0×10 -8 ), a total of 478 distinct GTDB taxa, which represented 17% 113 of all tested taxa and included 11 phyla, 19 classes, 24 orders, 63 families, 148 genera and 213 114 species, were found to be associated with at least one genetic variant (Figure 1, Table S1 ). 115 Conditional analysis found 583 independent SNP-taxon associations at genome-wide 116 significance (Table S1) . Heritability across the 2,801 taxa ranged between h 2 =0.001 to 0.214, 117 with the highest values observed for taxa belonging to the Firmicutes and Firmicutes_A GTDB 118 phyla, both of which encompassed half (241/476, 50.4%) of all associated taxa with genetic 119 variation ( Figure S2 ). There were no differences in SNP heritability between groups of 120 associated or non-associated taxa at genome-wide significance (p=0.23). 121 122 Three loci were strongly associated with microbial variation at study-wide significance, as 123 shown on a Manhattan plot showing the lowest resulting p-value for each SNP tested against 124 each of the 2,801 taxa (Figure 1, Table 1 ). There was no evidence of excess false positive rate 125 in the GWAS (median λ GC =1.0051) ( Figure 1B) . After conditional analysis, the strongest 126 association by far (p=5.0×10 -35 ) involved members of class Actinobacteria and rs3940549, a 127 variant in the LCT-MCM6-ZRANB3 locus region which is in high LD (r 2 =0.87) with the well-128 described LCT variant rs4988235 causing lactase persistence in adults of European ancestry 129 ( Figure S3 ). In total, 29 taxa were associated with the LCT-MCM6 region, including 18 below 130 study-wide significance (Figure 1 , Table S1 ). These involved Bifidobacterium-related 131 Actinobacteriota and three taxa from the GTDB Firmicutes_A phylum which included 2 132 uncultured species defined from metagenome-assembled reference genomes (UBA3855 133 sp900316885 and CAG-81 sp000435795) ( Table 1) . The association of these three 134 Firmicutes_A with LCT was still genome-wide significant after adjusting for Bifidobacterium 135 abundances (Table S2) . A variant in ABO (rs545971), expressing the histo-blood 136 group ABO system transferase, was strongly associated (p=1.1×10 -12 ) with levels of 137 Faecalicatena lactaris. There was evidence for a second independent signal at ABO associated 138 with the Collinsella genus (chr9:133271182; p=2.5×10 -8 ) (Table S1, Figure 1 ). Rs187309577 139 and rs143507801 in MED13L, expressing the Mediator complex subunit 13L, were found to be 140 associated with genus Enterococcus (p=1.8×10 -12 ) an
PDF JSON Files: document_parses/pdf_json/11b61b83916b5f6976ff0df167fce3094b16c44b.json
G_ID: combined_effects_of_host_genetics_and_diet_on_human_gut_microbiota_and_incident_disease
S2 ID: 221634972