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. 2023 Apr 1;34(4):607-618.
doi: 10.1681/ASN.2022060725. Epub 2022 Oct 27.

Genomic Disorders in CKD across the Lifespan

Miguel Verbitsky  1 , Sarathbabu Krishnamurthy  1 , Priya Krithivasan  1 , Daniel Hughes  2 , Atlas Khan  1 , Maddalena Marasà  1 , Natalie Vena  1 , Pavan Khosla  1 , Junying Zhang  1 , Tze Y Lim  1 , Joseph T Glessner  3 , Chunhua Weng  4 , Ning Shang  1   4 , Yufeng Shen  5 , George Hripcsak  4 , Hakon Hakonarson  3 , Iuliana Ionita-Laza  6 , Brynn Levy  7 , Eimear E Kenny  8   9 , Ruth J F Loos  10   11 , Krzysztof Kiryluk  1 , Simone Sanna-Cherchi  1 , David R Crosslin  12 , Susan Furth  13 , Bradley A Warady  14 , Robert P Igo Jr  15 , Sudha K Iyengar  15 , Craig S Wong  16 , Afshin Parsa  17 , Harold I Feldman  18   19   20 , Ali G Gharavi  1
Affiliations

Genomic Disorders in CKD across the Lifespan

Miguel Verbitsky et al. J Am Soc Nephrol. .

Abstract

Significance statement: Pathogenic structural genetic variants, also known as genomic disorders, have been associated with pediatric CKD. This study extends those results across the lifespan, with genomic disorders enriched in both pediatric and adult patients compared with controls. In the Chronic Renal Insufficiency Cohort study, genomic disorders were also associated with lower serum Mg, lower educational performance, and a higher risk of death. A phenome-wide association study confirmed the link between kidney disease and genomic disorders in an unbiased way. Systematic detection of genomic disorders can provide a molecular diagnosis and refine prediction of risk and prognosis.

Background: Genomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility.

Methods: We examined the prevalence of GDs among participants in the Chronic Kidney Disease in Children (CKiD) cohort II ( n =248), Chronic Renal Insufficiency Cohort (CRIC) study ( n =3375), Columbia University CKD Biobank (CU-CKD; n =1986), and the Family Investigation of Nephropathy and Diabetes (FIND; n =1318) compared with 30,746 controls. We also performed a phenome-wide association analysis (PheWAS) of GDs in the electronic MEdical Records and GEnomics (eMERGE; n =11,146) cohort.

Results: We found nine out of 248 (3.6%) CKiD II participants carried a GD, replicating prior findings in pediatric CKD. We also identified GDs in 72 out of 6679 (1.1%) adult patients with CKD in the CRIC, CU-CKD, and FIND cohorts, compared with 199 out of 30,746 (0.65%) GDs in controls (OR, 1.7; 95% CI, 1.3 to 2.2). Among adults with CKD, we found recurrent GDs at the 1q21.1, 16p11.2, 17q12, and 22q11.2 loci. The 17q12 GD (diagnostic of renal cyst and diabetes syndrome) was most frequent, present in 1:252 patients with CKD and diabetes. In the PheWAS, dialysis and neuropsychiatric phenotypes were the top associations with GDs. In CRIC participants, GDs were associated with lower serum magnesium, lower educational achievement, and higher mortality risk.

Conclusion: Undiagnosed GDs are detected both in children and adults with CKD. Identification of GDs in these patients can enable a precise genetic diagnosis, inform prognosis, and help stratify risk in clinical studies. GDs could also provide a molecular explanation for nephropathy and comorbidities, such as poorer neurocognition for a subset of patients.

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Conflict of interest statement

A.G. Gharavi reports having consultancy agreements with Actio Biosciences, AstraZeneca Center for Genomics Research, Goldfinch Bio, Natera, Novartis, and Travere; reports having an ownership interest in Actio Biosciences; reports receiving research funding from Natera and the Renal Research Institute; reports receiving honoraria from Alnylam and Sanofi; and reports having an advisory or leadership role with the editorial boards of JASN and the Journal of Nephrology. A. Parsa reports having an advisory or leadership role with the National Institutes of Health (NIH). B. Levy reports having consultancy agreements with Igenomix, Myome, Myriad, and Natera; reports having an ownership interest in Natera; and reports having an advisory or leadership role with American College of Medical Genetics Foundation, College of American Pathologists Cytogenetics committee, Cancer Genomics Consortium, International Society for Prenatal Diagnosis, and Wiley Prenatal Diagnosis. B.A. Warady reports having consultancy agreements with Amgen, Bayer, Lightline Medical Reata, Relypsa, and UpToDate; reports receiving research funding from Baxter Healthcare; reports receiving honoraria from Amgen, Bayer, Reata, Relypsa, and UpToDate; and reports having an advisory or leadership role with Midwest Transplant Network Governing Board, National Kidney Foundation, North American Pediatric Renal Trials and Collaborative Studies, and NTDS Board of Directors. C.S. Wong reports having an advisory or leadership role with the Steering Committee for National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)–funded CKiD study, participated in the past year on the ad hoc advisory committee to the National Kidney Foundation, board of the New Mexico Pediatric Society in Albuquerque, NM; and reports having other interests or relationships with a contract with NephCure International as part of the CurGN study (participating site). D.R. Crosslin reports having consultancy agreements with UnitedHealth Group; reports having an ownership interest in SoundBiology LLC; reports receiving research funding from UnitedHealth Group; and reports having an advisory or leadership role with the UnitedHealth Group. A.Khan received funding from NIH National Center for Advancing Translational Sciences grant UL1TR001873 and NIH NIDDK grant K25DK128563. E.E. Kenny reports having consultancy agreements with and Forsite Labs Inc. and Galatea Inc.; reports having an ownership interest in Galatea Inc, and Forsite Labs Inc.; reports receiving honoraria from 23&Me, Illumina Inc., and Regeneron Pharmaceuticals; reports having an advisory or leadership role with the editorial boards of American Journal of Human Genetics, Cell Genomics, Frontiers in Ecology and Evolution, and G3; reports being on the Advisory Boards of the American Society of Human Genetics (un-paid), Forsite Labs Inc. (paid), and Galatea Inc., Chair of Science Foundation Ireland Center for Research Training in Genomics Data Science Board (un-paid); and reports receiving speakers bureau from 23&Me, Illumina Inc, and Regeneron, Inc. H.I. Feldman reports having consultancy agreements with Kyowa Hakko Kirin and the National Kidney Foundation; reports receiving honoraria from InMed Inc.; reports having an advisory or leadership role as the American Journal of Kidney Disease Editor in Chief, Member of Advisory Board of the National Kidney Foundation, and Steering Committee Chair of the CRIC Study; and reports receiving speakers bureau from InMed, Inc. K. Kiryluk reports having consultancy agreements with Calvariate, and HiBio; and reports receiving research funding from Aevi Genomics, AstraZeneca, Bioporto, Vanda, and Visterra. Mr. Pavan Khosla reports previous employment with Basepair Inc., and reports having an ownership interest in BioNano Genomics Inc., Canopy Growth Corp., GrowGeneration Corp., GSK PLC (formerly GlaxoSmithKline PLC), Pfizer Inc., Pacific Biosciences of California Inc., Nokia Oyj., and 10X Genomics Inc. R.J.F. Loos reports having consultancy agreements with Regeneron; and reports having an advisory or leadership role as Board member of the European Association of the Study of Diabetes. Dr. Simone Sanna-Cherchi reports receiving research funding from NIH/NIDDK, US Department of Defense; reports receiving honoraria from Travere Therapeutics; and reports having an advisory or leadership role with the editorial boards, with no royalties received, from Acta Biomedica, Kidney International, Journal of Nephrology, and Negative Results. Y. Shen reports having an advisory or leadership role with the Scientific Reports. All remaining authors have nothing to disclose. Funding for the CRIC study was obtained under a cooperative agreement from the NIDDK through grants U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902, and U24DK060990). The eMERGE Network was initiated and funded by National Human Genome Research Institute through grants: U01HG006828 (Cincinnati Children's Hospital Medical Center and Boston Children's Hospital), U01HG006830 (Children's Hospital of Philadelphia), U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation, and Pennsylvania State University), U01HG006382 (Geisinger Clinic), U01HG006375 (Group Health Cooperative and the University of Washington), U01HG006379 (Mayo Clinic), U01HG006380 (Icahn School of Medicine at Mount Sinai), U01HG006388 (Northwestern University), U01HG006378 (Vanderbilt University Medical Center), and U01HG006385 (Vanderbilt University Medical Center serving as the coordinating center). Participation of Columbia University in the eMERGE network was supported by National Human Genome Research Institute grant U01HG008680 (to C. Weng, A.G. Gharavi, and G. Hripcsak). The CKiD study was conducted by the CKiD Investigators and supported by the NIDDK, with additional funding from the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute (U01-DK-66143, U01-DK-66174, U01DK-082194, U01-DK-66116). The data and biospecimens from the CKiD study reported here were supplied by the NIDDK Central Repository. The FIND study was supported by grants U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, and U01DK57304 from the NIDDK and, in part, by the Intramural Research Program of the NIDDK; support was also received from the National Heart, Lung and Blood Institute grants U01HL065520, U01HL041654, and U01HL041652; this project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400 and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research; this work was also supported by the National Center for Research Resources for the General Clinical Research Center grants: Case Western Reserve University, M01-RR-000080, Wake Forest University, M01-RR-07122, Harbor-University of California, Los Angeles Medical Center, M01-RR-00425, College of Medicine, University of California, Irvine, M01-RR-00827–29, University of New Mexico, HSC M01-RR-00997, and Frederic C. Bartter, M01-RR-01346. Because A.G. Gharavi is an editor of the Journal of the American Society of Nephrology, he was not involved in the peer review process for this manuscript. A guest editor oversaw the peer review and decision-making process for this manuscript.

Figures

None
Graphical abstract
Figure 1
Figure 1
GD in CKD across the lifespan. GD frequency (n GD carriers/n subjects×100) distribution by age (years) of enrollment among patients with CKD in the combined CKiD I and II, FIND, CRIC, and CU-CKD cohorts (n=7346). The youngest and oldest GD carriers were 2 and 78 years old, respectively.
Figure 2
Figure 2
GD phenotypic associations in the CRIC cohort. Lower serum Mg++ concentrations (A) (P=2.22×10−3), lower Modified Mini Mental State Exam scores. (B) (P=1.42×10−2), a smaller proportion of higher education level. (C) (P=7.50×10−4), and a higher rate of death. (D) (P=3.11×10−2) in GD carriers compared with noncarriers in the CRIC cohort (n=3375).
Figure 3
Figure 3
GDs pheWAS in eMERGE. Manhattan plot of association tests between GD carrier status and 1487 phenotypes in 11,146 eMERGE participants. The −log(P value) as a function of phenotypic code is shown. Only top signals are annotated.
See this image and copyright information in PMC

Comment in

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