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Metabolome Genome-Wide Association Study Identifies 74 Novel Genomic Regions Influencing Plasma Metabolites Levels.

ABSTRACT: Metabolites are small products of metabolism that provide a snapshot of the wellbeing of an organism and the mechanisms that control key physiological processes involved in health and disease. Here we report the results of a genome-wide association study of 722 circulating metabolite levels in 8809 subjects of European origin, providing both breadth and depth. These analyses identified 202 unique genomic regions whose variations are associated with the circulating levels of 478 different metabolites. Replication with a subset of 208 metabolites that were available in an independent dataset for a cohort of 1768 European subjects confirmed the robust associations, including 74 novel genomic regions not associated with any metabolites in previous works. This study enhances our knowledge of genetic mechanisms controlling human metabolism. Our findings have major potential for identifying novel targets and developing new therapeutic strategies.

SUBMITTER: Hysi PG

PROVIDER: S-EPMC8777659 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Metabolome Genome-Wide Association Study Identifies 74 Novel Genomic Regions Influencing Plasma Metabolites Levels.

Hysi Pirro G PG Mangino Massimo M Christofidou Paraskevi P Falchi Mario M Karoly Edward D ED Nihr Bioresource Investigators Mohney Robert P RP Valdes Ana M AM Spector Tim D TD Menni Cristina C

Metabolites 20220111 1

Metabolites are small products of metabolism that provide a snapshot of the wellbeing of an organism and the mechanisms that control key physiological processes involved in health and disease. Here we report the results of a genome-wide association study of 722 circulating metabolite levels in 8809 subjects of European origin, providing both breadth and depth. These analyses identified 202 unique genomic regions whose variations are associated with the circulating levels of 478 different metabol ...[more]

PMID: 35050183

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Project description:BACKGROUND:Plasma neurofilament light (NFL) is a promising biomarker for Alzheimer disease (AD), which increases in the early stage of AD and is associated with the progression of AD. We performed a genome-wide association study (GWAS) of plasma NFL in Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) cohort to identify novel variants associated with AD. METHODS:This study included 179 cognitively healthy controls (HC), 176 patients with mild cognitive impairment (MCI), and 172 patients with AD. All subjects were restricted to non-Hispanic Caucasian derived from the ADNI cohort and met all quality control (QC) criteria. Association of plasma NFL with the genetic variants was assessed using PLINK with an additive genetic model, i.e.dose-dependent effect of the minor alleles. The influence of a genetic variant associated with plasma NFL (rs7943454) on brain structure was further assessed using PLINK with a linear regression model. RESULTS:The minor allele (T) of rs7943454 in leucine zipper protein 2 gene (LUZP2) was associated with higher plasma NFL at suggestive levels (P = 1.39 × 10- 6) in a dose-dependent fashion. In contrast, the minor allele (G) of rs640476 near GABRB2 was associated with lower plasma NFL at suggestive levels (P = 6.71 × 10- 6) in a dose-dependent effect in all diagnostic groups except the MCI group. Furthermore, the minor allele (T) of rs7943454 within LUZP2 increased the onset risk of AD (odds ratio = 1.547, confidence interval 95% = 1.018-2.351) and was associated with atrophy of right middle temporal gyrus in the whole cohort in the longitudinal study (P = 0.0234). CONCLUSION:GWAS found the associations of two single nucleotide polymorphisms (rs7943454 and rs640476) with plasma NFL at suggestive levels. Rs7943454 in LUZP2 was associated with the onset risk of AD and atrophy of right middle temporal gyrusin the whole cohort. Using an endophenotype-based approach, we identified rs7943454 as a new AD risk locus.

Dataset Information

Metabolome Genome-Wide Association Study Identifies 74 Novel Genomic Regions Influencing Plasma Metabolites Levels.

Publications

Metabolome Genome-Wide Association Study Identifies 74 Novel Genomic Regions Influencing Plasma Metabolites Levels.

Similar Datasets

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