Trans-ethnic genome-wide association study of blood metabolites in the Chronic Renal Insufficiency Cohort (CRIC) study

CKD Biomarkers Consortium and the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators

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11 Scopus citations

Abstract

Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate analyses in 822 White and 687 Black study participants. Trans-ethnic meta-analysis was then applied to improve fine-mapping of potential causal variants. Mean estimated glomerular filtration rate was 44.4 and 41.5 mL/min/1.73m2 in the White and Black participants, respectively. There were 45 significant metabolite associations at 19 loci, including novel associations at PYROXD2, PHYHD1, FADS1-3, ACOT2, MYRF, FAAH, and LIPC. The strength of associations was unchanged in models additionally adjusted for estimated glomerular filtration rate and proteinuria, consistent with a direct biochemical effect of gene products on associated metabolites. At several loci, trans-ethnic meta-analysis, which leverages differences in linkage disequilibrium across populations, reduced the number and/or genomic interval spanned by potentially causal single nucleotide polymorphisms compared to fine-mapping in the White participant cohort alone. Across all validated associations, we found strong concordance in effect sizes of the potentially causal single nucleotide polymorphisms between White and Black study participants. Thus, our study identifies novel genetic determinants of blood metabolites in chronic kidney disease, demonstrates the value of diverse cohorts to improve causal inference in metabolomics GWAS, and underscores the shared genetic basis of metabolism across race.

Original languageEnglish (US)
Pages (from-to)814-823
Number of pages10
JournalKidney international
Volume101
Issue number4
DOIs
StatePublished - Apr 2022

Funding

The authors acknowledge the following: Alan S. Go, MD; James P. Lash, MD; Robert G. Nelson, MD, PhD, MS; Mahboob Rahman, MD; Vallabh O Shah, PhD, MS; Raymond R. Townsend, MD; and Mark L. Unruh, MD, MS. The opinions presented herein do not necessarily represent those of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institutes of Health (NIH), the Department of Health and Human Services (DHHS), or the US government. This study was supported by the CKD Biomarkers Consortium, including U01 DK106981 (principal investigator [PI]: EPR) and U01 DK085689 (PI: JC); additional funding was provided by R01DK108803 and R01DK124399 (PI: MEG). Funding for the Chronic Renal Insufficiency Cohort (CRIC) study was obtained under a cooperative agreement from the NIDDK (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902 and U24DK060990). In addition, this work was supported in part by the following: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR000003; Johns Hopkins University UL1 TR-000424; University of Maryland General Clinical Research Center (GCRC) M01 RR-16500; Clinical and Translational Science Collaborative of Cleveland; UL1TR000439 from the NCATS component of the NIH and NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433; University of Illinois at Chicago Clinical and Translational Science Award (CTSA) UL1RR029879; Tulane Center of Biomedical Research Excellence (COBRE) for Clinical and Translational Research in Cardiometabolic Diseases P20 GM109036; Kaiser Permanente NIH/National Center for Research Resources (NCRR) University of California San Francisco–Clinical & Translational Science Institute (UCSF-CTSI) UL1 RR-024131, Department of Internal Medicine; and University of New Mexico School of Medicine, Albuquerque, NM R01DK119199. The authors acknowledge the following: Alan S. Go, MD; James P. Lash, MD; Robert G. Nelson, MD, PhD, MS; Mahboob Rahman, MD; Vallabh O Shah, PhD, MS; Raymond R. Townsend, MD; and Mark L. Unruh, MD, MS. The opinions presented herein do not necessarily represent those of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institutes of Health (NIH), the Department of Health and Human Services (DHHS), or the US government. This study was supported by the CKD Biomarkers Consortium , including U01 DK106981 (principal investigator [PI]: EPR) and U01 DK085689 (PI: JC); additional funding was provided by R01DK108803 and R01DK124399 (PI: MEG). Funding for the Chronic Renal Insufficiency Cohort (CRIC) study was obtained under a cooperative agreement from the NIDDK ( U01DK060990 , U01DK060984 , U01DK061022 , U01DK061021 , U01DK061028 , U01DK060980 , U01DK060963 , U01DK060902 and U24DK060990 ). In addition, this work was supported in part by the following: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH / National Center for Advancing Translational Sciences (NCATS) UL1TR000003 ; Johns Hopkins University UL1 TR-000424 ; University of Maryland General Clinical Research Center (GCRC) M01 RR-16500 ; Clinical and Translational Science Collaborative of Cleveland ; UL1TR000439 from the NCATS component of the NIH and NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433 ; University of Illinois at Chicago Clinical and Translational Science Award (CTSA) UL1RR029879 ; Tulane Center of Biomedical Research Excellence (COBRE) for Clinical and Translational Research in Cardiometabolic Diseases P20 GM109036 ; Kaiser Permanente NIH /National Center for Research Resources ( NCRR) University of California San Francisco–Clinical & Translational Science Institute (UCSF-CTSI) UL1 RR-024131 , Department of Internal Medicine ; and University of New Mexico School of Medicine, Albuquerque, NM R01DK119199 .

Keywords

  • GWAS
  • metabolomics
  • trans-ethnic meta-analysis

ASJC Scopus subject areas

  • Nephrology

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