Dataset Information

Common variants in Mendelian kidney disease genes and their association with renal function.

ABSTRACT: Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

SUBMITTER: Parsa A

PROVIDER: S-EPMC3839542 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Common variants in Mendelian kidney disease genes and their association with renal function.

Parsa Afshin A Fuchsberger Christian C Köttgen Anna A O'Seaghdha Conall M CM Pattaro Cristian C de Andrade Mariza M Chasman Daniel I DI Teumer Alexander A Endlich Karlhans K Olden Matthias M Chen Ming-Huei MH Tin Adrienne A Kim Young J YJ Taliun Daniel D Li Man M Feitosa Mary M Gorski Mathias M Yang Qiong Q Hundertmark Claudia C Foster Meredith C MC Glazer Nicole N Isaacs Aaron A Rao Madhumathi M Smith Albert V AV O'Connell Jeffrey R JR Struchalin Maksim M Tanaka Toshiko T Li Guo G Hwang Shih-Jen SJ Atkinson Elizabeth J EJ Lohman Kurt K Cornelis Marilyn C MC Johansson Asa A Tönjes Anke A Dehghan Abbas A Couraki Vincent V Holliday Elizabeth G EG Sorice Rossella R Kutalik Zoltan Z Lehtimäki Terho T Esko Tõnu T Deshmukh Harshal H Ulivi Sheila S Chu Audrey Y AY Murgia Federico F Trompet Stella S Imboden Medea M Kollerits Barbara B Pistis Giorgio G Harris Tamara B TB Launer Lenore J LJ Aspelund Thor T Eiriksdottir Gudny G Mitchell Braxton D BD Boerwinkle Eric E Schmidt Helena H Hofer Edith E Hu Frank F Demirkan Ayse A Oostra Ben A BA Turner Stephen T ST Ding Jingzhong J Andrews Jeanette S JS Freedman Barry I BI Giulianini Franco F Koenig Wolfgang W Illig Thomas T Döring Angela A Wichmann H-Erich HE Zgaga Lina L Zemunik Tatijana T Boban Mladen M Minelli Cosetta C Wheeler Heather E HE Igl Wilmar W Zaboli Ghazal G Wild Sarah H SH Wright Alan F AF Campbell Harry H Ellinghaus David D Nöthlings Ute U Jacobs Gunnar G Biffar Reiner R Ernst Florian F Homuth Georg G Kroemer Heyo K HK Nauck Matthias M Stracke Sylvia S Völker Uwe U Völzke Henry H Kovacs Peter P Stumvoll Michael M Mägi Reedik R Hofman Albert A Uitterlinden Andre G AG Rivadeneira Fernando F Aulchenko Yurii S YS Polasek Ozren O Hastie Nick N Vitart Veronique V Helmer Catherine C Wang Jie Jin JJ Stengel Bénédicte B Ruggiero Daniela D Bergmann Sven S Kähönen Mika M Viikari Jorma J Nikopensius Tiit T Province Michael M Colhoun Helen H Doney Alex A Robino Antonietta A Krämer Bernhard K BK Portas Laura L Ford Ian I Buckley Brendan M BM Adam Martin M Thun Gian-Andri GA Paulweber Bernhard B Haun Margot M Sala Cinzia C Mitchell Paul P Ciullo Marina M Vollenweider Peter P Raitakari Olli O Metspalu Andres A Palmer Colin C Gasparini Paolo P Pirastu Mario M Jukema J Wouter JW Probst-Hensch Nicole M NM Kronenberg Florian F Toniolo Daniela D Gudnason Vilmundur V Shuldiner Alan R AR Coresh Josef J Schmidt Reinhold R Ferrucci Luigi L van Duijn Cornelia M CM Borecki Ingrid I Kardia Sharon L R SL Liu Yongmei Y Curhan Gary C GC Rudan Igor I Gyllensten Ulf U Wilson James F JF Franke Andre A Pramstaller Peter P PP Rettig Rainer R Prokopenko Inga I Witteman Jacqueline J Hayward Caroline C Ridker Paul M PM Bochud Murielle M Heid Iris M IM Siscovick David S DS Fox Caroline S CS Kao W Linda WL Böger Carsten A CA

Journal of the American Society of Nephrology : JASN 20130912 12

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidne ...[more]

PMID: 24029420

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Project description:ImportanceLiving kidney donation is associated with increased long-term risk of end-stage renal disease (ESRD). An early postdonation marker of ESRD risk could improve postdonation risk assessment and counseling for kidney donors and allow early intervention for donors at increased risk.ObjectiveTo determine the association between renal function in the first 6 months postdonation and subsequent risk of ESRD in kidney donors.Design, setting, and participantsThis secondary analysis of a prospective national cohort uses a population-based registry of all living kidney donors in the United States between October 26, 1999, and January 1, 2018, with follow-up through December 31, 2018. All kidney donors who had donated in the date range and had serum creatinine measured at 6 months (±3 months) postdonation were included.ExposuresRenal function as measured by estimated glomerular filtration rate 6 months after donation (eGFR6).Main outcomes and measuresEnd-stage renal disease, ascertained via linkage to Centers for Medicare & Medicaid Services data.ResultsA total of 71 468 living kidney donors were included (of 109 065 total donors over this period). Their median (interquartile range) eGFR6 was 63 (54-74) mL/min/1.73 m2. Cumulative incidence of ESRD at 15 years postdonation ranged from 11.7 donors per 10 000 donors with eGFR6 values greater than 70 mL/min/1.73 m2 to 33.1 donors per 10 000 donors with eGFR6 values of 50 mL/min/1.73 m2 or less. Adjusting for age, race, sex, body mass index, and biological relationship, every 10 mL/min/1.73 m2 reduction in eGFR6 was associated with a 28% increased risk of ESRD (adjusted hazard ratio, 1.28 [95% CI, 1.06-1.54]; P = .009). The association between predonation eGFR and ESRD was not significant and was fully mediated by eGFR6 (adjusted hazard ratio, 1.00 [95% CI, 0.86-1.17]; P = .97). The postdonation eGFR value was a better marker of ESRD than eGFR decline after donation or the ratio of eGFR6 to predonation eGFR, as determined by the Akaike information criterion (in which a lower value indicates a better model fit; eGFR6, 1495.61; predonation eGFR - eGFR6, 1503.58; eGFR6 / predonation eGFR, 1502.30).Conclusions and relevanceIn this study, there was an independent association of eGFR6 with subsequent ESRD risk in living kidney donors, even after adjusting for predonation characteristics. The findings support measurement of early postdonation serum creatinine monitoring in living kidney donors, and the use of these data to help identify donors who might need more careful surveillance and early intervention.

Project description:The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a single phenotype of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore the phenotypic expressivity of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population. Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, NOTCH2 FBN1, PTPN1 and RAS-opathy genes, and genes in the 22q11.2 locus) and performed a gene burden test. Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome. Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.

Dataset Information

Common variants in Mendelian kidney disease genes and their association with renal function.

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Common variants in Mendelian kidney disease genes and their association with renal function.

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