A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium

Abstract

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

FIG. 1.

Genome-wide meta-analyses results. Arrow annotated loci represent genes that show significant associations with MetS and/or individual binary bivariate traits. Each subgraph exemplifies results from a binary bivariate meta-analysis results or MetS meta-analysis. A dashed line in each subgraph represents a significance threshold of negative log10 P value of 7.01 corresponding to a P value of 9.7*10⁻⁸ (see Supplementary Data). A gene name in parentheses annotates a variant close to that particular gene. (A high-quality color representation of this figure is available in the online issue.)

FIG. 2.

Top significant SNPs from meta-analyses of MetS and bivariate traits associations, tested now for their association with dichotomized risk traits (WC, HDLC, TG, GLUC, and BP) as defined in the MetS NCEP definition. The results shown in the graph are the sample weighted mean of negative log10 P values (blue bars) per trait association, for all studies combined. On the top of blue bars (mean) added are the corresponding standard errors (red bars) of these negative log10 P values. The minimal threshold of negative log10 (0.05) P value is shown with a vertical red dashed line. A gene name in parentheses means the corresponding SNP is located in a region near the gene. (A high-quality color representation of this figure is available in the online issue.)

FIG. 3.

A summary of meta-analysis on pleiotropy effects for selected SNPs on pair combinations of quantitative traits. Each study performed a pleiotropy test for selected SNPs with corresponding quantitative trait combinations. The identified meta-significant results show that variants associated more with two lipid measures and fasting glucose. (A high-quality color representation of this figure is available in the online issue.)

FIG. 4.

One of the simplified networks of the genes LPL, CETP, APOA5, GCKR, LIPC, and ABCB11 among 16 genes reported in this article with variants significantly associated to MetS and/or its bivariate traits. This network was built from curated publications based on GeneGO database. (Green arrows show activation; red arrows show suppression.) (A high-quality color representation of this figure is available in the online issue.)