Dataset Information

Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals.

ABSTRACT: Integrating genetic information with metabolomics has provided new insights into genes affecting human metabolism. However, gene-metabolite integration has been primarily studied in individuals of European Ancestry, limiting the opportunity to leverage genomic diversity for discovery. In addition, these analyses have principally involved known metabolites, with the majority of the profiled peaks left unannotated. Here, we perform a whole genome association study of 2,291 metabolite peaks (known and unknown features) in 2,466 Black individuals from the Jackson Heart Study. We identify 519 locus-metabolite associations for 427 metabolite peaks and validate our findings in two multi-ethnic cohorts. A significant proportion of these associations are in ancestry specific alleles including findings in APOE, TTR and CD36. We leverage tandem mass spectrometry to annotate unknown metabolites, providing new insight into hereditary diseases including transthyretin amyloidosis and sickle cell disease. Our integrative omics approach leverages genomic diversity to provide novel insights into diverse cardiometabolic diseases.

SUBMITTER: Tahir UA

PROVIDER: S-EPMC9395431 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals.

Tahir Usman A UA Katz Daniel H DH Avila-Pachecho Julian J Bick Alexander G AG Pampana Akhil A Robbins Jeremy M JM Yu Zhi Z Chen Zsu-Zsu ZZ Benson Mark D MD Cruz Daniel E DE Ngo Debby D Deng Shuliang S Shi Xu X Zheng Shuning S Eisman Aaron S AS Farrell Laurie L Hall Michael E ME Correa Adolfo A Tracy Russell P RP Durda Peter P Taylor Kent D KD Liu Yongmei Y Johnson W Craig WC Guo Xiuqing X Yao Jie J Chen Yii-Der Ida YI Manichaikul Ani W AW Ruberg Frederick L FL Blaner William S WS Jain Deepti D Bouchard Claude C Sarzynski Mark A MA Rich Stephen S SS Rotter Jerome I JI Wang Thomas J TJ Wilson James G JG Clish Clary B CB Natarajan Pradeep P Gerszten Robert E RE

Nature communications 20220822 1

Integrating genetic information with metabolomics has provided new insights into genes affecting human metabolism. However, gene-metabolite integration has been primarily studied in individuals of European Ancestry, limiting the opportunity to leverage genomic diversity for discovery. In addition, these analyses have principally involved known metabolites, with the majority of the profiled peaks left unannotated. Here, we perform a whole genome association study of 2,291 metabolite peaks (known ...[more]

PMID: 35995766

Similar Datasets

Project description:Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Warfarin is widely used in sub-Saharan Africa, but as in other populations, dosing is highly variable due to genetic and non-genetic factors. In order to identify genetic factors determining warfarin response variability, we have conducted a genome-wide association study (GWAS) of plasma concentrations of warfarin enantiomers/metabolites in sub-Saharan black-Africans. This overcomes the issue of non-adherence and may have greater sensitivity at genome-wide level, to identify pharmacokinetic gene variants than focusing on mean weekly dose, the usual end-point used in previous studies. Participants recruited at 12 outpatient sites in Uganda and South Africa on stable warfarin dose were genotyped using the Illumina Infinium H3Africa Consortium Array v2. Imputation was conducted using the 1,000 Genomes Project phase III reference panel. Warfarin/metabolite plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Multivariable linear regression was undertaken, with adjustment made for five non-genetic covariates and ten principal components of genetic ancestry. After quality control procedures, 548 participants and 17,268,054 SNPs were retained. CYP2C9*8, CYP2C9*9, CYP2C9*11, and the CYP2C cluster SNP rs12777823 passed the Bonferroni-adjusted replication significance threshold (p < 3.21E-04) for warfarin/metabolite ratios. In an exploratory GWAS analysis, 373 unique SNPs in 13 genes, including CYP2C9*8, passed the Bonferroni-adjusted genome-wide significance threshold (p < 3.846E-9), with 325 (87%, all located on chromosome 10) SNPs being associated with the S-warfarin/R-warfarin outcome (top SNP rs11188082, CYP2C19 intron variant, p = 1.55E-17). Approximately 69% of these SNPs were in linkage disequilibrium (r 2 > 0.8) with CYP2C9*8 (n = 216) and rs12777823 (n = 8). Using a pharmacokinetic approach, we have shown that variants other than CYP2C9*2 and CYP2C9*3 are more important in sub-Saharan black-Africans, mainly due to the allele frequencies. In exploratory work, we conducted the first warfarin pharmacokinetics-related GWAS in sub-Saharan Africans and identified novel SNPs that will require external replication and functional characterization before they can be considered for inclusion in warfarin dosing algorithms.

Dataset Information

Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals.

Publications

Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets