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Heritable components of the human fecal microbiome are associated with visceral fat

View Article: PubMed Central - PubMed

ABSTRACT

Background: Variation in the human fecal microbiota has previously been associated with body mass index (BMI). Although obesity is a global health burden, the accumulation of abdominal visceral fat is the specific cardio-metabolic disease risk factor. Here, we explore links between the fecal microbiota and abdominal adiposity using body composition as measured by dual-energy X-ray absorptiometry in a large sample of twins from the TwinsUK cohort, comparing fecal 16S rRNA diversity profiles with six adiposity measures.

Results: We profile six adiposity measures in 3666 twins and estimate their heritability, finding novel evidence for strong genetic effects underlying visceral fat and android/gynoid ratio. We confirm the association of lower diversity of the fecal microbiome with obesity and adiposity measures, and then compare the association between fecal microbial composition and the adiposity phenotypes in a discovery subsample of twins. We identify associations between the relative abundances of fecal microbial operational taxonomic units (OTUs) and abdominal adiposity measures. Most of these results involve visceral fat associations, with the strongest associations between visceral fat and Oscillospira members. Using BMI as a surrogate phenotype, we pursue replication in independent samples from three population-based cohorts including American Gut, Flemish Gut Flora Project and the extended TwinsUK cohort. Meta-analyses across the replication samples indicate that 8 OTUs replicate at a stringent threshold across all cohorts, while 49 OTUs achieve nominal significance in at least one replication sample. Heritability analysis of the adiposity-associated microbial OTUs prompted us to assess host genetic-microbe interactions at obesity-associated human candidate loci. We observe significant associations of adiposity-OTU abundances with host genetic variants in the FHIT, TDRG1 and ELAVL4 genes, suggesting a potential role for host genes to mediate the link between the fecal microbiome and obesity.

Conclusions: Our results provide novel insights into the role of the fecal microbiota in cardio-metabolic disease with clear potential for prevention and novel therapies.

Electronic supplementary material: The online version of this article (doi:10.1186/s13059-016-1052-7) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus

Peak genetic associations between obesity human genetic variants and adiposity-associated OTUs in the twin fecal microbiome. a Association between OTU 181702 and FHIT SNP rs74331972. The boxplot indicates change in OTU 181702 abundance with genotype at SNP rs74331972. The LocusZoom plot denotes the strength of association of OTU 181702 with SNP rs74331972, as well as the SNPs in the surrounding region. b Association between open reference OTU 25576 and TDRG1 SNP rs1433723. The boxplot indicates change in open reference OTU 25576 abundance with genotype at SNP rs1433723. The LocusZoom plot denotes the strength of association of open reference OTU 25576 with SNP rs1433723, as well as the SNPs in the surrounding region. c Association between OTU 194733 and ELAVL4 SNP rs2480677. The boxplot indicates change in OTU 194733 abundance with genotype at SNP rs2480677. The LocusZoom plot denotes the strength of association of OTU 194733 with SNP rs2480677, as well as the SNPs in the surrounding region. SNPs in all LocusZoom plots are coloured according to their strength of linkage disequilibrium with the peak SNP plotted
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Fig5: Peak genetic associations between obesity human genetic variants and adiposity-associated OTUs in the twin fecal microbiome. a Association between OTU 181702 and FHIT SNP rs74331972. The boxplot indicates change in OTU 181702 abundance with genotype at SNP rs74331972. The LocusZoom plot denotes the strength of association of OTU 181702 with SNP rs74331972, as well as the SNPs in the surrounding region. b Association between open reference OTU 25576 and TDRG1 SNP rs1433723. The boxplot indicates change in open reference OTU 25576 abundance with genotype at SNP rs1433723. The LocusZoom plot denotes the strength of association of open reference OTU 25576 with SNP rs1433723, as well as the SNPs in the surrounding region. c Association between OTU 194733 and ELAVL4 SNP rs2480677. The boxplot indicates change in OTU 194733 abundance with genotype at SNP rs2480677. The LocusZoom plot denotes the strength of association of OTU 194733 with SNP rs2480677, as well as the SNPs in the surrounding region. SNPs in all LocusZoom plots are coloured according to their strength of linkage disequilibrium with the peak SNP plotted

Mentions: To explore the hypothesis that host genetics may influence the observed microbial-adiposity associations, we performed candidate gene analysis comparing host genetic variants at human obesity candidate loci with the adiposity-associated fecal microbiome profiles. We selected single nucleotide polymorphisms (SNPs) within human loci previously associated with obesity as reported by Locke et al. [8], using common genetic variants within 97 50-kb regions, centred around the peak BMI-associated GWAS SNP in each region. At a Bonferroni-corrected P-value threshold (P = 5.31 × 10−06) taking into account the total number of genomic regions and adiposity OTUs considered, OTU associations with genetic variants in three genomic regions surpassed multiple testing. The strongest association between host genotype and adiposity-associated OTUs was observed between an OTU within the Clostridiales order (Greengenes OTU 181702) and a host genetic variant within an intron of the FHIT gene (rs74331972 with OTU 181702, P = 2.49 × 10−06, Fig. 5a). FHIT encodes the fragile histidine triad protein and is a tumour suppressor gene that has been linked to cancers of the digestive tract. Although the most significant FHIT association was obtained with OTU 181702 (h2 = 0.13), which we identified as significantly associated with SFM and VFM (P = 1.18 × 10−06 and 1.27 × 10−06 respectively), the same genetic variant was also associated with another VFM- and SFM-associated OTU (rs74331972 with OTU 287790, P = 5.38 × 10−05). The second ranked significant genetic association was obtained between variants near gene TDRG1 (peak SNP rs1433723, P = 4.32 × 10−06) with an open reference unknown Clostridiales OTU (h2 = 0.14), which we had identified as significantly associated with VFM (P = 4.97 × 10−07, Fig. 5b). The final significant genetic association was observed at a variant in an intron of the gene ELAVL4 (rs2480677, P = 4.95 × 10−06, Fig. 5c) with an unknown Blautia OTU, 194733 (h2 = 0.02), which we had identified as significantly associated with VFM (P = 1.27 × 10−07), SFM (P = 2.26 × 10−06) and AGR (P = 3.11 × 10−07) in the peak 149 adiposity-OTU results. When we considered the genetic-OTU association results at a less conservative significance threshold (P = 5 × 10−4), there were in total 412 suggestive OTU-genetic associations located within or near 48 unique genes, including obesity genes such as FTO, RPTOR and TMEM18.Fig. 5


Heritable components of the human fecal microbiome are associated with visceral fat
Peak genetic associations between obesity human genetic variants and adiposity-associated OTUs in the twin fecal microbiome. a Association between OTU 181702 and FHIT SNP rs74331972. The boxplot indicates change in OTU 181702 abundance with genotype at SNP rs74331972. The LocusZoom plot denotes the strength of association of OTU 181702 with SNP rs74331972, as well as the SNPs in the surrounding region. b Association between open reference OTU 25576 and TDRG1 SNP rs1433723. The boxplot indicates change in open reference OTU 25576 abundance with genotype at SNP rs1433723. The LocusZoom plot denotes the strength of association of open reference OTU 25576 with SNP rs1433723, as well as the SNPs in the surrounding region. c Association between OTU 194733 and ELAVL4 SNP rs2480677. The boxplot indicates change in OTU 194733 abundance with genotype at SNP rs2480677. The LocusZoom plot denotes the strength of association of OTU 194733 with SNP rs2480677, as well as the SNPs in the surrounding region. SNPs in all LocusZoom plots are coloured according to their strength of linkage disequilibrium with the peak SNP plotted
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Related In: Results  -  Collection

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Fig5: Peak genetic associations between obesity human genetic variants and adiposity-associated OTUs in the twin fecal microbiome. a Association between OTU 181702 and FHIT SNP rs74331972. The boxplot indicates change in OTU 181702 abundance with genotype at SNP rs74331972. The LocusZoom plot denotes the strength of association of OTU 181702 with SNP rs74331972, as well as the SNPs in the surrounding region. b Association between open reference OTU 25576 and TDRG1 SNP rs1433723. The boxplot indicates change in open reference OTU 25576 abundance with genotype at SNP rs1433723. The LocusZoom plot denotes the strength of association of open reference OTU 25576 with SNP rs1433723, as well as the SNPs in the surrounding region. c Association between OTU 194733 and ELAVL4 SNP rs2480677. The boxplot indicates change in OTU 194733 abundance with genotype at SNP rs2480677. The LocusZoom plot denotes the strength of association of OTU 194733 with SNP rs2480677, as well as the SNPs in the surrounding region. SNPs in all LocusZoom plots are coloured according to their strength of linkage disequilibrium with the peak SNP plotted
Mentions: To explore the hypothesis that host genetics may influence the observed microbial-adiposity associations, we performed candidate gene analysis comparing host genetic variants at human obesity candidate loci with the adiposity-associated fecal microbiome profiles. We selected single nucleotide polymorphisms (SNPs) within human loci previously associated with obesity as reported by Locke et al. [8], using common genetic variants within 97 50-kb regions, centred around the peak BMI-associated GWAS SNP in each region. At a Bonferroni-corrected P-value threshold (P = 5.31 × 10−06) taking into account the total number of genomic regions and adiposity OTUs considered, OTU associations with genetic variants in three genomic regions surpassed multiple testing. The strongest association between host genotype and adiposity-associated OTUs was observed between an OTU within the Clostridiales order (Greengenes OTU 181702) and a host genetic variant within an intron of the FHIT gene (rs74331972 with OTU 181702, P = 2.49 × 10−06, Fig. 5a). FHIT encodes the fragile histidine triad protein and is a tumour suppressor gene that has been linked to cancers of the digestive tract. Although the most significant FHIT association was obtained with OTU 181702 (h2 = 0.13), which we identified as significantly associated with SFM and VFM (P = 1.18 × 10−06 and 1.27 × 10−06 respectively), the same genetic variant was also associated with another VFM- and SFM-associated OTU (rs74331972 with OTU 287790, P = 5.38 × 10−05). The second ranked significant genetic association was obtained between variants near gene TDRG1 (peak SNP rs1433723, P = 4.32 × 10−06) with an open reference unknown Clostridiales OTU (h2 = 0.14), which we had identified as significantly associated with VFM (P = 4.97 × 10−07, Fig. 5b). The final significant genetic association was observed at a variant in an intron of the gene ELAVL4 (rs2480677, P = 4.95 × 10−06, Fig. 5c) with an unknown Blautia OTU, 194733 (h2 = 0.02), which we had identified as significantly associated with VFM (P = 1.27 × 10−07), SFM (P = 2.26 × 10−06) and AGR (P = 3.11 × 10−07) in the peak 149 adiposity-OTU results. When we considered the genetic-OTU association results at a less conservative significance threshold (P = 5 × 10−4), there were in total 412 suggestive OTU-genetic associations located within or near 48 unique genes, including obesity genes such as FTO, RPTOR and TMEM18.Fig. 5

View Article: PubMed Central - PubMed

ABSTRACT

Background: Variation in the human fecal microbiota has previously been associated with body mass index (BMI). Although obesity is a global health burden, the accumulation of abdominal visceral fat is the specific cardio-metabolic disease risk factor. Here, we explore links between the fecal microbiota and abdominal adiposity using body composition as measured by dual-energy X-ray absorptiometry in a large sample of twins from the TwinsUK cohort, comparing fecal 16S rRNA diversity profiles with six adiposity measures.

Results: We profile six adiposity measures in 3666 twins and estimate their heritability, finding novel evidence for strong genetic effects underlying visceral fat and android/gynoid ratio. We confirm the association of lower diversity of the fecal microbiome with obesity and adiposity measures, and then compare the association between fecal microbial composition and the adiposity phenotypes in a discovery subsample of twins. We identify associations between the relative abundances of fecal microbial operational taxonomic units (OTUs) and abdominal adiposity measures. Most of these results involve visceral fat associations, with the strongest associations between visceral fat and Oscillospira members. Using BMI as a surrogate phenotype, we pursue replication in independent samples from three population-based cohorts including American Gut, Flemish Gut Flora Project and the extended TwinsUK cohort. Meta-analyses across the replication samples indicate that 8 OTUs replicate at a stringent threshold across all cohorts, while 49 OTUs achieve nominal significance in at least one replication sample. Heritability analysis of the adiposity-associated microbial OTUs prompted us to assess host genetic-microbe interactions at obesity-associated human candidate loci. We observe significant associations of adiposity-OTU abundances with host genetic variants in the FHIT, TDRG1 and ELAVL4 genes, suggesting a potential role for host genes to mediate the link between the fecal microbiome and obesity.

Conclusions: Our results provide novel insights into the role of the fecal microbiota in cardio-metabolic disease with clear potential for prevention and novel therapies.

Electronic supplementary material: The online version of this article (doi:10.1186/s13059-016-1052-7) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus