| Title: | The influence of rare variants in circulating metabolic biomarkers |
| Journal: | PLOS Genetics |
| Published: | 9 Mar 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32150548/ |
| DOI: | https://doi.org/10.1371/journal.pgen.1008605 |
| URL: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008605&type=printable |
Publication 9106
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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.</p>
14 Authors
- Fernando Riveros-Mckay
- Clare Oliver-Williams
- Savita Karthikeyan
- Klaudia Walter
- Kousik Kundu
- Willem H. Ouwehand
- David Roberts
- Emanuele Di Angelantonio
- Nicole Soranzo
- John Danesh
- Eleanor Wheeler
- Eleftheria Zeggini
- Adam S. Butterworth
- Inês Barroso
1 Application
| Application ID | Title |
|---|---|
| 44448 | The genetic and environmental determinants of cardiometabolic and related disorders. |
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