Dataset Information

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci.

ABSTRACT: Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.

SUBMITTER: Yin X

PROVIDER: S-EPMC8960770 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci.

Yin Xianyong X Chan Lap Sum LS Bose Debraj D Jackson Anne U AU VandeHaar Peter P Locke Adam E AE Fuchsberger Christian C Stringham Heather M HM Welch Ryan R Yu Ketian K Fernandes Silva Lilian L Service Susan K SK Zhang Daiwei D Hector Emily C EC Young Erica E Ganel Liron L Das Indraniel I Abel Haley H Erdos Michael R MR Bonnycastle Lori L LL Kuusisto Johanna J Stitziel Nathan O NO Hall Ira M IM Wagner Gregory R GR Kang Jian J Morrison Jean J Burant Charles F CF Collins Francis S FS Ripatti Samuli S Palotie Aarno A Freimer Nelson B NB Mohlke Karen L KL Scott Laura J LJ Wen Xiaoquan X Fauman Eric B EB Laakso Markku M Boehnke Michael M

Nature communications 20220328 1

Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. ...[more]

PMID: 35347128

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Project description:Plants synthesize specialized metabolites to facilitate environmental and ecological interactions. During evolution, plants diversified in their potential to synthesize these metabolites. Quantitative differences in metabolite levels of natural Arabidopsis (Arabidopsis thaliana) accessions can be employed to unravel the genetic basis for metabolic traits using genome-wide association studies (GWAS). Here, we performed metabolic GWAS on seeds of a panel of 315 A. thaliana natural accessions, including the reference genotypes C24 and Col-0, for polar and semi-polar seed metabolites using untargeted ultra-performance liquid chromatography-mass spectrometry. As a complementary approach, we performed quantitative trait locus (QTL) mapping of near-isogenic introgression lines between C24 and Col-0 for specific seed specialized metabolites. Besides common QTL between seeds and leaves, GWAS revealed seed-specific QTL for specialized metabolites, indicating differences in the genetic architecture of seeds and leaves. In seeds, aliphatic methylsulfinylalkyl and methylthioalkyl glucosinolates associated with the ALKENYL HYDROXYALKYL PRODUCING loci (GS-ALK and GS-OHP) on chromosome 4 containing alkenyl hydroxyalkyl producing 2 (AOP2) and 3 (AOP3) or with the GS-ELONG locus on chromosome 5 containing methylthioalkyl malate synthase (MAM1) and MAM3. We detected two unknown sulfur-containing compounds that were also mapped to these loci. In GWAS, some of the annotated flavonoids (kaempferol 3-O-rhamnoside-7-O-rhamnoside, quercetin 3-O-rhamnoside-7-O-rhamnoside) were mapped to transparent testa 7 (AT5G07990), encoding a cytochrome P450 75B1 monooxygenase. Three additional mass signals corresponding to quercetin-containing flavonols were mapped to UGT78D2 (AT5G17050). The association of the loci and associating metabolic features were functionally verified in knockdown mutant lines. By performing GWAS and QTL mapping, we were able to leverage variation of natural populations and parental lines to study seed specialized metabolism. The GWAS data set generated here is a high-quality resource that can be investigated in further studies.

Dataset Information

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci.

Publications

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci.

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