Structural variants contribute to the gut microbiome, blood metabolic traits, and their causal relationships
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Research on genetic variants affecting the gut microbiome and blood metabolites has mainly focused on single nucleotide variants (SNPs), with structural variants (SVs) remaining largely unexamined. In this study, we utilized an advanced structural variant detection pipeline on whole-genome sequencing data from 2,002 individuals with an average sequencing depth of 42 folds, identifying 138,859 high-confidence SVs, 49.57% of which were previously unreported. We performed genome-wide association studies on 22,519 common SVs with 616 gut microbial features and 121 blood metabolic traits, uncovering 30 significant links between SVs and microbial taxa/pathways and 48 connections between SVs and blood metabolites. Notable results include 19 associations reaching study-wide significance, such as an Asian-specific 6.5k deletion at the TENT2 gene, which is strongly associated with the abundance of Coprobacillus sp. 29_1 (β=0.158, p=2.5×10 −9 ), and a deletion covering HBA1/HBA2/HBM/HBQ118 linked to nine blood metabolic traits, most significantly with mean corpuscular volume (MCV; β=-0.570, p=1.22×10 −91 ). Most SVs showed a greater impact than nearby SNPs in their associations with the microbiome/metabolites. Analysis of rare SVs also identified multiple genes associated with the microbiome/metabolites. Additionally, Mendelian randomization using SVs demonstrated causal relationships, including effects from the microbiome to metabolites, such as Clostridium ramosum ’s impact on serum uric acid and hyperuricemia, and from metabolites to the microbiome, like the influence of mean corpuscular hemoglobin concentration on MF0064: triacylglycerol degradation. This study provides a detailed SV catalog for the Chinese population and highlights the significant role of SVs in the gut microbiome, blood metabolites, and their causal relationships.
Highlights
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Provides a catalog of 138,859 high-confidence SVs and 49.57% of which were novel
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Identify 30 genome-wide significant “SVs—microbial taxa/pathways” and 48 “SVs—blood metabolites” associations, respectively
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An Asian-specific 6.5k deletion at TENT2 gene associated with the species Coprobacillus sp. 29_1
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A deletion spanning HBA1/HBA2/HBM/HBQ118 associated with 9 blood metabolic traits
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The majority of SVs demonstrated a more pronounced impact than neighboring SNPs in the associations with microbiome/metabolites
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SVs help to reveal the host-microbe causal relationships such as Clostridium ramosum’ s causal effects on serum uric acid and hyperuricemia
Graphic abstract
Based on a multi-omics cohort of 2,002 individuals comprising high-depth whole genome and metagenomic sequencing data, blood metabolites, and detailed questionnaires, we identified 138,859 high-confidence SVs, uncovering 36 significant associations between SVs and microbial taxa/pathways, as well as 48 associations between SVs and blood metabolites. Mendelian randomization using SVs demonstrated causal relationships, such as Clostridium ramosum ’s causal effect on serum uric acid and hyperuricemia. This study provides a detailed SV catalog for the Chinese population and highlights the significant role of SVs in the gut microbiome, blood metabolites, and their causal relationships.
