Whole Exome Sequencing Enhanced Imputation Identifies 85 Metabolite Associations in the Alpine CHRIS Cohort

Metabolites are intermediates or end products of biochemical processes involved in both health and disease. Here, we take advantage of the well-characterized Cooperative Health Research in South Tyrol (CHRIS) study to perform an exome-wide association study (ExWAS) on absolute concentrations of 175...

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Veröffentlicht in:Metabolites Jg. 12; H. 7; S. 604
Hauptverfasser: König, Eva, Rainer, Johannes, Hernandes, Vinicius Verri, Paglia, Giuseppe, Del Greco M., Fabiola, Bottigliengo, Daniele, Yin, Xianyong, Chan, Lap Sum, Teumer, Alexander, Pramstaller, Peter P., Locke, Adam E., Fuchsberger, Christian
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Switzerland MDPI AG 29.06.2022
MDPI
Schlagworte:
association study
Biobanks
Carnitine
Disease
Enzymes
ExWAS
Genes
Genome-wide association studies
Genomes
Genotype & phenotype
GWAS
imputation
Intermediates
Metabolic disorders
Metabolites
metabolomics
Physiology
Population
whole-exome sequencing
United Kingdom > UK
ExWAS
GWAS
imputation
metabolomics
whole-exome sequencing
association study
ISSN:2218-1989, 2218-1989
Online-Zugang:Volltext
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Zusammenfassung:Metabolites are intermediates or end products of biochemical processes involved in both health and disease. Here, we take advantage of the well-characterized Cooperative Health Research in South Tyrol (CHRIS) study to perform an exome-wide association study (ExWAS) on absolute concentrations of 175 metabolites in 3294 individuals. To increase power, we imputed the identified variants into an additional 2211 genotyped individuals of CHRIS. In the resulting dataset of 5505 individuals, we identified 85 single-variant genetic associations, of which 39 have not been reported previously. Fifteen associations emerged at ten variants with >5-fold enrichment in CHRIS compared to non-Finnish Europeans reported in the gnomAD database. For example, the CHRIS-enriched ETFDH stop gain variant p.Trp286Ter (rs1235904433-hexanoylcarnitine) and the MCCC2 stop lost variant p.Ter564GlnextTer3 (rs751970792-carnitine) have been found in patients with glutaric acidemia type II and 3-methylcrotonylglycinuria, respectively, but the loci have not been associated with the respective metabolites in a genome-wide association study (GWAS) previously. We further identified three gene-trait associations, where multiple rare variants contribute to the signal. These results not only provide further evidence for previously described associations, but also describe novel genes and mechanisms for diseases and disease-related traits.
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Current Address: Regeneron Genetics Center, Tarrytown, NY 10591, USA.
ISSN:2218-1989
2218-1989
DOI:10.3390/metabo12070604