Structural variants contribute to the gut microbiome, blood metabolic traits and their causal relationships

Genetic variants influencing the gut microbiome and blood metabolites have predominantly centered on the single nucleotide variants (SNPs), leaving the impact of structural variants (SVs) largely unexplored. Here, we applied an advanced structural variant calling pipeline to whole-genome sequencing data from 2,002 individuals with a mean depth of 42 folds, revealing 138,859 high-confidence SVs, of which 49.57% were not previously reported. Genome-wide association analyses were conducted for 22,519 common SVs with 616 gut microbial features and 121 blood metabolic traits, uncovering 30 significant associations between SVs and microbial taxa/pathways, as well as 48 associations between SVs and blood metabolites. Noteworthy findings include 19 associations meeting study-wide significance, such as the Asian-specific 6.5k deletion at TENT2 gene strongly linked to species Coprobacillus sp. 29_1 (β= 0.158, p =2.5 × 10 ^-9 ) and a deletion spanning HBA1/HBA2/HBM/HBQ118 associated with 9 blood metabolic traits (most significant for the mean corpuscular volume (MCV), β= −0.570, p = 1.22×10 ^-91 ). The majority of SVs demonstrated a more pronounced impact than neighboring SNPs in their associations with microbiome/metabolites. Furthermore, Mendelian randomization using SVs reveal the causal relationships between microbiome and metabolites, such as the causal effect of Clostridium ramosum on serum uric acid and MCHC on MF0064: the triacylglycerol degradation. This study presents a comprehensive SV catalog in the Chinese population and emphasizes the substantial contribution of SVs to the gut microbiome, blood metabolites and their interactions.