The influence of rare variants in circulating metabolic biomarkers.

Fernando Riveros-Mckay,Emanuele Di Angelantonio,John Danesh,Eleanor Wheeler,Clare Oliver-Williams,Kousik Kundu,David Roberts,Klaudia Walter,Willem H Ouwehand,Interval Study ,Nicole Soranzo,Adam S Butterworth,Savita Karthikeyan,Inês Barroso,Eleftheria Zeggini

doi:10.1371/journal.pgen.1008605

Abstract

Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). Here we studied, association of rare variants and 226 serum lipoproteins, lipids and amino acids in 7,142 (discovery plus follow-up) healthy participants. We leveraged the information from multiple metabolite measurements on the same participants to improve discovery in rare variant association analyses for gene-based and gene-set tests by incorporating correlated metabolites as covariates in the validation stage. Gene-based analysis corrected for the effective number of tests performed, confirmed established associations at APOB, APOC3, PAH, HAL and PCSK (p<1.32x10-7) and identified novel gene-trait associations at a lower stringency threshold with ACSL1, MYCN, FBXO36 and B4GALNT3 (p<2.5x10-6). Regulation of the pyruvate dehydrogenase (PDH) complex was associated for the first time, in gene-set analyses also corrected for effective number of tests, with IDL and LDL parameters, as well as circulating cholesterol (pMETASKAT<2.41x10-6). In conclusion, using an approach that leverages metabolite measurements obtained in the same participants, we identified novel loci and pathways involved in the regulation of these important metabolic biomarkers. As large-scale biobanks continue to amass sequencing and phenotypic information, analytical approaches such as ours will be useful to fully exploit the copious amounts of biological data generated in these efforts.

Highlights

Metabolic measurements reflect an individual’s endogenous biochemical processes and environmental exposures [1,2]
Using a novel approach leveraging the information gained from various measurements on the same participants we are able to identify a novel biological pathway involved in the regulation of intermediate-density and low-density lipoproteins as well as circulating cholesterol, confirm various established gene associations and identify potential novel gene associations that merit further replication
Genome-wide association studies (GWAS) focusing on traditionally measured lipid traits have greatly expanded our knowledge into lipid biology and to date more than 250 loci have been robustly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG) [15,16,17,18,19,20,21,22,23]

Summary

Introduction

Metabolic measurements reflect an individual’s endogenous biochemical processes and environmental exposures [1,2]. An example of this, is a novel link between the LPA locus and very-low-density lipoprotein (VLDL) metabolism (measured by high resolution NMR), with effect sizes twice as large as those found for traditionally measured lipid traits like LDL-C and TC, suggesting these measurements are better at capturing underlying biological processes in lipid metabolism than traditionally measured lipid traits [25] In this same study, by constructing a genetic risk score using variants associated with lipoprotein(a) levels and using a Mendelian randomisation approach the authors were able to determine a causal link between increased lipoprotein(a) levels on overall lipoprotein metabolism [25]

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