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A comprehensive study of metabolite genetics reveals strong pleiotropy and heterogeneity across time and context.

ABSTRACT: Genetic studies of metabolites have identified thousands of variants, many of which are associated with downstream metabolic and obesogenic disorders. However, these studies have relied on univariate analyses, reducing power and limiting context-specific understanding. Here we aim to provide an integrated perspective of the genetic basis of metabolites by leveraging the Finnish Metabolic Syndrome In Men (METSIM) cohort, a unique genetic resource which contains metabolic measurements, mostly lipids, across distinct time points as well as information on statin usage. We increase effective sample size by an average of two-fold by applying the Covariates for Multi-phenotype Studies (CMS) approach, identifying 588 significant SNP-metabolite associations, including 228 new associations. Our analysis pinpoints a small number of master metabolic regulator genes, balancing the relative proportion of dozens of metabolite levels. We further identify associations to changes in metabolic levels across time as well as genetic interactions with statin at both the master metabolic regulator and genome-wide level.

SUBMITTER: Gallois A

PROVIDER: S-EPMC6803661 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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A comprehensive study of metabolite genetics reveals strong pleiotropy and heterogeneity across time and context.

Gallois Apolline A Mefford Joel J Ko Arthur A Vaysse Amaury A Julienne Hanna H Ala-Korpela Mika M Laakso Markku M Zaitlen Noah N Pajukanta Päivi P Aschard Hugues H Aschard Hugues H

Nature communications 20191021 1

Genetic studies of metabolites have identified thousands of variants, many of which are associated with downstream metabolic and obesogenic disorders. However, these studies have relied on univariate analyses, reducing power and limiting context-specific understanding. Here we aim to provide an integrated perspective of the genetic basis of metabolites by leveraging the Finnish Metabolic Syndrome In Men (METSIM) cohort, a unique genetic resource which contains metabolic measurements, mostly lipi ...[more]

PMID: 31636271

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Project description:Plant genomes are populated by different types of repetitive elements including transposable elements (TEs) and simple sequence repeats (SSRs) that can have a strong impact on genome size and dynamic as well as on the regulation of gene transcription. At least two-thirds of the tomato genome is composed of repeats. While their bulk impact on genome organization has been recently revealed by whole genome assembly, their influence on tomato biology and phenotype remains largely unaddressed. More specifically, the effects and roles of DNA repeats on the maturation of fleshy fruits, which is a complex process of key agro-economic interest, still needs to be investigated comprehensively and tomato is arguably an excellent model for such study.We have performed a comprehensive annotation of the tomato repeatome to explore its potential impact on tomato genome composition and gene transcription. Our results show that the tomato genome can be fractioned into three compartments with different gene and repeat density, each compartment presenting contrasting repeat and gene composition, repeat-gene associations and different gene transcriptional levels. In the context of fruit ripening, we found that repeats are present in the majority of differentially methylated regions (DMRs) and thousands of repeat-associated DMRs are found in gene proximity including hundreds that are differentially regulated. Furthermore, we found that repeats are also present in the proximity of binding sites of the key ripening protein RIN. We also observed that some repeat families are present at unexpected high frequency in the proximity of genes that are differentially expressed during tomato ripening.Altogether, our study emphasizes the fractionation as defined by repeat content in the tomato genome and enables to further characterize the specificities of each genomic compartment. Additionally, our results present strong associations between differentially regulated genes, differentially methylated regions and repeats, suggesting a potential adaptive function of repeats in tomato ripening. Our work therefore provides significant perspectives for the understanding of the impact of repeats on the maturation of fleshy fruits.

Dataset Information

A comprehensive study of metabolite genetics reveals strong pleiotropy and heterogeneity across time and context.

Publications

A comprehensive study of metabolite genetics reveals strong pleiotropy and heterogeneity across time and context.

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