Insights into CKD from Metabolite GWAS

Liu, Lili; Kiryluk, Krzysztof

doi:10.1681/asn.2018030291

Cited by 3 publications

(4 citation statements)

References 10 publications

(14 reference statements)

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“…20 Participants 18-74 years of age at their baseline examination were recruited through a stratified multistage area probability sample design from four communities (San Diego, California; Chicago, Illinois; The Bronx, New York, New York; and Miami, Florida). Overall, 16,415 participants, representing major self-reported US Hispanic/Latino background groups (Mexicans, Puerto Ricans, Cubans, Central Americans, Dominicans, and South Americans), took part in baseline examinations that occurred in June 2008-July 2011. Second visits were performed in 2014-2017, and the completion of third visits began in 2020 and is ongoing.…”

Section: Hchs/solmentioning

confidence: 99%

“…We conducted a network-based analysis to identify modules of genes whose combined effect was overrepresented in GWASs by using the previously developed dense module searching for GWASs (dmGWAS, version 2.7). 43 Specifically, we performed our analysis by using two protein-protein interaction networks: one from PathwayCommons (PC) 44 (16,332 genes and 369,895 interactions) and the other from in-house curation with 21,137 genes and 413,492 interactions. In brief, dmGWAS implements a dense module searching algorithm to search for modules in the reference network with a goal of achieving a maximum module score.…”

Section: Pathway Analysismentioning

confidence: 99%

“…13 The resulted findings have illuminated mechanisms underlying human metabolism and provided insights relevant to common complex diseases. [14][15][16] For example, in the early GWAS era, one single intronic variant, rs174548 (FADS1), was shown to affect serum glycerophospholipids, which were involved in cholesterol metabolism. Prior analyses showed that rs174548 was also associated with blood lipids-known cardio-vascular disease risk factors.…”

Section: Introductionmentioning

confidence: 99%

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A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos

Feofanova

Chen

Dai

et al. 2020

The American Journal of Human Genetics

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Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variantmetabolite pairs (p value < 1.2 3 10 À10 , minor allele frequency R 1%, proportion of variance explained [PEV] mean ¼ 3.4%, PEV range ¼ 1%-22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.

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Section: Hchs/solmentioning

confidence: 99%

Section: Pathway Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos

Feofanova

Chen

Dai

et al. 2020

The American Journal of Human Genetics

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“…Although genome-wide association study (GWAS) may indicate risk for disease, it does not clearly explain the underlying cause. Thus, other research groups have performed an integrated analysis of GWAS with other fields such as metabolomics, proteomics, and transcriptomics to overcome the limitations of GWAS [ 26 , 27 ]. To the best of our knowledge, metabolite GWAS (mGWAS) for IDO activity associated with CKD has not been reported yet.…”

Section: Introductionmentioning

confidence: 99%

Metabolite Genome-Wide Association Study for Indoleamine 2,3-Dioxygenase Activity Associated with Chronic Kidney Disease

Kim

Jin

Eom

2021

Genes

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Chronic kidney disease (CKD) causes progressive damage to kidney function with increased inflammation. This process contributes to complex amino acid changes. Indoleamine 2,3-dioxygenase (IDO) has been proposed as a new biomarker of CKD in previous studies. In our research, we performed a metabolite genome-wide association study (mGWAS) to identify common and rare variants associated with IDO activity in a Korean population. In addition, single-nucleotide polymorphisms (SNPs) selected through mGWAS were further analyzed for associations with the estimated glomerular filtration rate (eGFR) and CKD. A total of seven rare variants achieved the genome-wide significance threshold (p < 1 × 10−8). Among them, four genes (TNFRSF19, LOC105377444, LOC101928535, and FSTL5) associated with IDO activity showed statistically significant associations with eGFR and CKD. Most of these rare variants appeared specifically in an Asian geographic region. Furthermore, 15 common variants associated with IDO activity were detected in this study and five novel genes (RSU1, PDGFD, SNX25, LOC107984031, and UBASH3B) associated with CKD and eGFR were identified. This study discovered several loci for IDO activity via mGWAS and provided insight into the underlying mechanisms of CKD through association analysis with CKD. To the best of our knowledge, this is the first study to suggest a genetic link between IDO activity and CKD through comparative and integrated analysis.

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Mass spectrometry-based metabolomics for an in-depth questioning of human health

Alvès¹,

Paris²,

Rathahao‐Paris³

2020

Advances in Clinical Chemistry

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Insights into CKD from Metabolite GWAS

Cited by 3 publications

References 10 publications

A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos

A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos

Metabolite Genome-Wide Association Study for Indoleamine 2,3-Dioxygenase Activity Associated with Chronic Kidney Disease

Mass spectrometry-based metabolomics for an in-depth questioning of human health

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