The influence of rare variants in circulating metabolic biomarkers

Abstract

Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). We tested association between rare sequence variants and 226 serum lipoproteins, lipids and amino acids in 7,142 healthy participants. Gene-based association analyses identified novel gene-trait associations with ACSL1, MYCN, FBXO36 and B4GALNT3 (p<2.5 × 10−6), and confirmed established associations. Regulation of the pyruvate dehydrogenase (PDH) complex was associated for the first time, in gene set analyses, with IDL and LDL parameters, as well as circulating cholesterol (pMETASKAT <2.41 × 10−6). Individuals at the lower tails of the distributions of four out of 49 lipoproteins and lipids had an excess of predicted deleterious variants in lipoprotein disorder and metabolism gene sets (ppermutation<0.00037). These four traits were CVD risk factors (e.g. S-VLDL-C), demonstrating that rare “protective” variation is a significant contributor to lipoprotein levels in a healthy population. In conclusion, rare variant analysis of these important metabolic biomarkers reveals novel loci and pathways involved in their regulation.

An atlas of genetic scores to predict multi-omic traits

“…The residuals were then inverse normal rank transformed, which were finally used to perform GWAS of these traits and their genetic score development. Details of quality control and GWAS for these traits can be found in the previous study 48 .…”

“…The residuals were then inverse normal rank transformed, which were finally used to perform GWAS of these traits and their genetic score development. Details of quality control and GWAS for these traits can be found in the previous study 48 . RNA sequencing was performed on the NovaSeq 6000 system (S4 flow cell, Xp workflow; Illumina) with 75 bp paired-end sequencing reads (reverse stranded) in INTERVAL, which were aligned to the GRCh38 human reference genome (Ensembl GTF annotation v99) using STAR (v2.7.3.a) 49 and obtained the gene count matrix using featureCounts (v2.0.0) 50 .…”

Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites

“…A total of 230 metabolic biomarkers were produced by the serum nuclear magnetic resonance (NMR) metabolomics platform (Nightingale Health) 9 on 46,097 samples in the INTERVAL cohort. Glucose, lactose, pyruvate, and acetate were excluded initially because of unreliable measurements.…”

“…We also attempted to replicate associations by using an independent metabolomic platform (Nightingale Health) based on NMR, 9 which includes 226 metabolites of different classes (ketone bodies, glycolysis related metabolites, amino acids, fluid balance, inflammation, fatty acids and saturation, cholesterol, glycerides and phospholipids, apolipoproteins, lipoprotein subclasses, and lipoprotein particle sizes). We tested the 27 genes by using models identical to the Metabolon-based discovery.…”

Molecular Quantitative Trait Locus Mapping in Human Complex Diseases

“…More recently, Riveros‐Mckay et al. showed an effect of rare metaQTL on serum metabolite concentrations (Riveros‐Mckay et al., 2020).…”