Multivariate genomic analysis of 5 million people elucidates the genetic architecture of shared components of the metabolic syndrome

Abstract

Metabolic syndrome (MetS) is a complex hereditary condition comprising various metabolic traits as risk factors. Although the genetics of individual MetS components have been investigated actively through large-scale genome-wide association studies, the conjoint genetic architecture has not been fully elucidated. Here, we performed the largest multivariate genome-wide association study of MetS in Europe (n_observed = 4,947,860) by leveraging genetic correlation between MetS components. We identified 1,307 genetic loci associated with MetS that were enriched primarily in brain tissues. Using transcriptomic data, we identified 11 genes associated strongly with MetS. Our phenome-wide association and Mendelian randomization analyses highlighted associations of MetS with diverse diseases beyond cardiometabolic diseases. Polygenic risk score analysis demonstrated better discrimination of MetS and predictive power in European and East Asian populations. Altogether, our findings will guide future studies aimed at elucidating the genetic architecture of MetS.

Fig. 1. Genetic correlations, multivariate genetic factor model and multivariate GWAS of MetS.

a, SNP-based heritability and pairwise genetic correlations for the seven MetS components were estimated using LD score regression. The off-diagonal upper, lower and diagonal triangles represent the pairwise genetic correlation, the standard error of the genetic correlation and SNP-based heritability, respectively. b, Path diagram with standardized factor loadings in the hierarchical model estimated using Genomic SEM. The U represents the residual variance that is not explained by the latent factor. The subscript g indicates that the model was built based on genetic covariances between the MetS components. c, Manhattan plot of Genomic SEM-based GWAS associations. The x axis represents the chromosomal position, and the y axis represents the uncorrected −log₁₀(P) from two-sided z tests for SNP associations with MetS. *Reverse-coded.

Fig. 2. Genetic correlation between MetS and external traits.

Among the 119 external traits, 82 Bonferroni significant r_g values are illustrated (Supplementary Tables 19 and 18 report all r_g values with 119 traits and corresponding sample size, respectively). Error bars represent 95% CIs for r_g, calculated as r_g ± 1.96 × s.e. The black dashed line indicates an r_g of 0. HOMA-IR, homeostatic model assessment of insulin resistance.

Fig. 3. Post-GWAS analyses of MetS GWAS.

a, Heritability enrichment for functional SNP categories. The x axis represents functional categories, and the y axis represents enrichment. Error bars represent the 95% CIs, calculated as enrichment ± 1.96 × s.e. Asterisks represent significant enrichment after Bonferroni correction (uncorrected P from two-sided enrichment test <9.43 × 10⁻⁴), and exact P is available in Supplementary Table 21. b, Tissue-specific enrichment analysis using LDSC-SEG. The x axis represents tissue categories, and the y axis represents the uncorrected −log₁₀(P) from one-sided z test for enrichment in specific tissues. The black dashed line represents the Bonferroni significance threshold of P = 1.02 × 10^-4. c, Circos plot for gene prioritization using SMR in four tissues. The y axis represents the uncorrected −log₁₀(P) from two-sided χ²-test with 1 degree of freedom for the gene association. Red dots with annotations show replicated genes. The dashed black line represents the Bonferroni significance threshold for the corresponding tissue. Chr, chromosome; CTCF, CCCTC-binding factor; DGF, digital genomic footprint; DHS, DNase I hypersensitivity site; TFBS, transcription factor binding site; TSS, transcription start site; UTR, untranslated region.

Fig. 4. MetS PRS analysis in European and East Asian populations.

a, Line plot representing the change in OR across deciles of the MetS PRS in 11,139 UKB individuals; error bars indicate 95% CIs, calculated as OR ± 1.96 × s.e. The red dashed line represents an OR of 1. b, Violin plot illustrating the incremental proportion of variance explained (ΔR²) by the PRS of seven MetS components and four latent factors for predicting MetS in UKB and KoGES cohorts. Each dot represents ΔR² from a single iteration of bootstrapping. Red dots represent ΔR² obtained with all individuals and error bars indicate 95% CIs estimated using the percentile bootstrapping method with 1,000 iterations.

Fig. 5. Phenome-wide association study using the MetS PRS.

Scatterplot illustrating the association between the genome-wide MetS PRS and 1,621 health outcomes in the UKB. The x axis represents uncorrected −log₁₀(P) from the two-sided z test for beta (that is, the log of the OR), and the y axis represents health outcomes. Health outcomes are color-coded by category; triangles indicate the direction of beta. Associations with high significance are labeled independently in the upper-right corner of the plot. The black dashed line represents the Bonferroni-corrected significance threshold of P < 3.08 × 10⁻⁵. NOS, nitric oxide synthase; GERD, gastroesophageal reflux disease.