Genome-Wide Association Studies in Nephrology Research

doi:10.1053/j.ajkd.2010.05.018

American Journal of Kidney Diseases

Volume 56, Issue 4, October 2010, Pages 743-758

https://doi.org/10.1053/j.ajkd.2010.05.018 Get rights and content

Kidney diseases constitute a serious public health burden worldwide, with substantial associated morbidity and mortality. The role of a genetic contribution to kidney disease is supported by heritability studies of kidney function measures, the presence of monogenic diseases with renal manifestations, and familial aggregation studies of complex kidney diseases, such as chronic kidney disease. Because complex diseases arise from the combination of multiple genetic and environmental risk factors, the identification of underlying genetic susceptibility variants has been challenging. Recently, genome-wide association studies have emerged as a method to conduct searches for such susceptibility variants. They have successfully identified genomic loci that contain variants associated with kidney diseases and measures of kidney function. For example, common variants in the UMOD and PRKAG2 genes are associated with risk of chronic kidney disease; variants in CLDN14 with risk of kidney stone disease; and variants in or near SHROOM3, STC1, LASS2, GCKR, NAT8/ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, FAM122A/PIP5K1B, ATXN2, DACH1, UBE2Q2/FBXO22, and SLC7A9, with differences in glomerular filtration rate. The purpose of this review is to provide an overview of the genome-wide association study method as it relates to nephrology research and summarize recent findings in the field. Results from genome-wide association studies of renal phenotypes represent a first step toward improving our knowledge about underlying mechanisms of kidney function and disease and ultimately may aid in the improved treatment and prevention of kidney diseases.

Section snippets

Background

Kidney diseases pose a significant global disease burden.1, 2 The most common form, chronic kidney disease (CKD), affects an estimated 10% of adults in many countries and the prevalence is increasing.1, 3, 4, 5 Individuals with impaired kidney function are at increased risk of disease progression to end-stage renal disease (ESRD),6, 7 as well as increased risk of cardiovascular morbidity and mortality.8, 9

Differences in known socioeconomic and cardiovascular risk factors for kidney disease,

Case Vignette

Two separate patients both have important known risk factors for the development and progression of CKD: one is a nonsmoking 55-year-old man of European ancestry with a body mass index of 33 kg/m², fasting glucose level of 127.0 mg/dL (7.05 mmol/L), and fasting serum triglyceride level of 131.98 mg/dL (1.49 mmol/L). The other patient is a nonsmoking 58-year-old African American woman with a body mass index of 32 kg/m², fasting glucose level of 96.0 mg/dL (5.33 mmol/L) on chlorpropamide therapy,

Recent Advances

Since 2005, when the first GWAS using a high-throughput single-nucleotide polymorphism (SNP) genotyping array was published,²⁵ a multitude of genetic risk variants for many complex diseases and traits have been identified using this method. By June of 2009, a total of 439 GWAS were published reporting SNP-phenotype associations at P < 5 × 10⁻⁸,²² illustrating the feasibility of this approach.

Association Results With Kidney Diseases

Table 2, Table 3 provide an overview of genomic regions identified in GWAS of kidney diseases and measures of kidney function to date. Table 2 summarizes results for studies with a dichotomous outcome (disease). Several studies were conducted to identify genetic risk variants for diabetic nephropathy. For example, a study of type 1 diabetic nephropathy was conducted in individuals in the GoKinD (Genetics of Kidneys in Diabetes) collection.⁴⁴ Although no SNP showed significant association after

Follow-Up of GWAS Findings, Clinical Utility, and Future Prospects

After initial gene discovery, follow-up on GWAS findings is essential to establish gene function, identify causal variants, characterize the genetic effect in diverse populations and under various exposures, and improve biological insights.

Although it remains to be determined if and how knowledge obtained through GWAS may best be translated into clinical practice, follow-up projects of some of the findings have been initiated with exciting early results. For example, GWAS have led to major

Acknowledgements

Support: The author was supported by the Emmy Noether Programme of the German Research Foundation.

Financial Disclosure: The author declares that she has no relevant financial interests.

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The advent of genome-wide association studies (GWAS) provided an unbiased approach to identify urate-associated genes. GWAS shows correlations between a given condition and common single nucleotide polymorphisms (SNPs), which serve as markers for genomic space [20]. After identifying these genomic regions, additional analyses can be done to identify genes that are most likely to underlie the associated SNPs, sometimes identifying novel causal variants that contribute to disease risk.
Circulation of urate levels is determined by the balance between urate production and excretion, homeostasis regulated by the function of urate transporters in key epithelial tissues and cell types. Our understanding of these physiological processes and identification of the genes encoding the urate transporters has advanced significantly, leading to a greater ability to predict risk for urate-associated diseases and identify new therapeutics that directly target urate transport. Here, we review the identified urate transporters and their organization and function in the renal tubule, the intestinal enterocytes, and other important cell types to provide a fuller understanding of the complicated process of urate homeostasis and its role in human diseases. Furthermore, we review the genetic tools that provide an unbiased catalyst for transporter identification as well as discuss the role of transporters in determining the observed significant gender differences in urate-associated disease risk.
Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
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Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m²/year or more (“Rapid3”; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m² at follow-up among those with eGFRcrea 60 mL/min/1.73m² or more at baseline (“CKDi25”; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Loci associated with genomic damage levels in chronic kidney disease patients and controls
2020, Mutation Research - Genetic Toxicology and Environmental Mutagenesis
Chronic kidney disease (CKD) is a multifactorial disorder with an important genetic component, and several studies have demonstrated potential associations with allelic variants. In addition, CKD patients are also characterized by high levels of genomic damage. Nevertheless, no studies have established relationships between DNA damage, or genomic instability present in CKD patients, and gene polymorphisms. To fill in this gap, the potential role of polymorphisms in genes involved in base excision repair (OGG1, rs1052133; MUTYH, rs3219489; XRCC1, rs25487), nucleotide excision repair (ERCC2/XPD, rs1799793, rs171140, rs13181; ERCC4, rs3136166); phase II metabolism (GSTP1, rs749174; GSTO1, rs2164624; GSTO2, rs156697), and antioxidant enzymes (SOD1, rs17880135, rs1041740, rs202446; SOD2, rs4880; CAT, rs1001179; GPX1, rs17080528; GPX3, rs870406: GPX4, rs713041) were inquired. In addition, some genes involved in CKD (AGT, rs5050; GLO1, rs386572987; SHROOM3, rs17319721) were also evaluated. The genomic damage, the genomic instability, and oxidative damage were evaluated by using the micronucleus and the comet assay in 589 donors (415 CKD patients and 174 controls). Our results showed significant associations between genomic damage and genes directly involved in DNA repair pathways (XRCC1, and ERCC2), and with genes encoding for antioxidant enzymes (SOD1 and GPX1). GSTO2, as a gene involved in phase II metabolism, and MUTYH showed also an association with genomic instability. Interestingly, the three genes associated with CKD (AGT, GLO1, and SHROOM3) showed associations with both the high levels of oxidatively damaged DNA and genomic instability. These results support our view that genomic instability can be considered a biomarker of the CKD status.
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Genetic epidemiology investigates the contribution of germline gene variants to disease etiology. The genetic architecture of many diseases exhibiting Mendelian inheritance patterns was decoded through family-based studies and subsequent functional cloning. Tests for high-penetrance gene variants have clinical utility for individuals, such as in preimplantation, prenatal, or postnatal diagnostics, and in preventive cascade screening of biological relatives. Genome-wide association studies thousands of identified variants associated with complex traits. Yet, the causal variants explaining the replicated statistical associations and their functional effects have rarely been deciphered. A missing heritability gap remains. Genetic testing for complex phenotypes has utility for research and public health rather than individuals. Genetics integrated with other biomarkers and information in the context of large citizen cohorts enables systems epidemiology approaches. The utility of genomic biomarkers is in studying molecular pathways mediating effects of the exposome on the phenome in order to improve causal understanding of modifiable risk factors. The goal is to strengthen the primary prevention of noncommunicable diseases.
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Citation Excerpt :
Namely, common variants in the uromodulin (UMOD) and Protein Kinase AMP-Activated Non-Catalytic Subunit Gamma 2 (PRKAG2) genes were shown to be associated with chronic kidney disease (CKD) (Kottgen, 2010) while variants in Claudin 14 (CLDN14) was linked to kidney stone disease (Thorleifsson et al., 2009). Additionally, heritability of the primary outcome measurement of kidney function, Glomerular Filtration Rate (GFR), was estimated to be 0.33 to 0.82 which means that between 33% and 82% of the phenotypic variations in GFR values can be attributed to genetic factors (Kottgen, 2010). Moreover, heritability of end-stage renal disease (ESRD) was investigated by a group of Swedish scientists who studied ESRD in Swedish-born adopted children as well as their biological and adoptive parents.
Protein misfolding may be the result of a variety of different processes that disrupt the ability of a protein to form a thermodynamically stable tertiary structure that allows it to perform its proper function. In this chapter, we explore the nature of a protein's form that allows it to have a stable tertiary structure, and examine specific mutation that are known to occur in the coding regions of DNA that disrupt a protein's ability to be folded into a thermodynamically stable tertiary structure. We examine the consequences of these protein misfoldings in terms of the endoplasmic reticulum stress response and resulting unfolded protein response. These conditions are specifically related to renal diseases. Further, we explore novel therapeutics, pharmacological chaperones, that are being developed to alleviate the disease burden associated with protein misfolding caused by mutations. These interventions aim to stabilize protein folding intermediates and allow proper folding to occur as well as prevent protein aggregation and the resulting pathophysiological consequences.

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: Originally published online as doi:10.1053/j.ajkd.2010.05.018 on August 23, 2010.

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In TranslationGenome-Wide Association Studies in Nephrology Research

Section snippets

Background

Case Vignette

Recent Advances

Association Results With Kidney Diseases

Follow-Up of GWAS Findings, Clinical Utility, and Future Prospects

Acknowledgements

Kidney Int

BMC Public Health

Am J Kidney Dis

Kidney Int

Genet Med

Lancet

Am J Hum Genet

Kidney Int

Kidney Int

Am J Kidney Dis

Kidney Int

Cell

Am J Hum Genet

Mol Cell Endocrinol

Am J Pathol

Kidney Int

Lancet

J Biol Chem

Chronic kidney disease: the global challenge

Lancet

Prevalence of chronic kidney disease in the United States

JAMA

International comparison of the relationship of chronic kidney disease prevalence and ESRD risk

J Am Soc Nephrol

Combining GFR and albuminuria to classify CKD improves prediction of ESRD

J Am Soc Nephrol

Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization

N Engl J Med

Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population

Circulation

Predictors of new-onset kidney disease in a community-based population

JAMA

Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function

Clin J Am Soc Nephrol

Genomewide linkage analysis to serum creatinine, GFR, and creatinine clearance in a community-based population: the Framingham Heart Study

J Am Soc Nephrol

Familial aggregation of renal disease in a population-based case-control study

J Am Soc Nephrol

Population-based screening for family history of end-stage renal disease among incident dialysis patients

Am J Nephrol

Familial clustering of chronic kidney disease

Semin Dial

A HapMap harvest of insights into the genetics of common disease

J Clin Invest

Genome-wide association studies for complex traits: consensus, uncertainty and challenges

Nat Rev Genet

Genetic mapping in human disease

Science

Potential etiologic and functional implications of genome-wide association loci for human diseases and traits

Proc Natl Acad Sci U S A

Unravelling the genetic basis of renal diseases; from single gene to multifactorial disorders

J Pathol

Susceptibility genes in common complex kidney disease

Curr Opin Nephrol Hypertens

Complement factor H polymorphism in age-related macular degeneration

Science

The future of genetic studies of complex human diseases

Science

Initial sequencing and analysis of the human genome

Nature

The sequence of the human genome

Science

dbSNP: the NCBI database of genetic variation

Nucl Acids Res

The International HapMap Project

Nature

A haplotype map of the human genome

Nature

A second generation human haplotype map of over 3.1 million SNPs

Nature

Principal components analysis corrects for stratification in genome-wide association studies

Nat Genet

In Translation
Genome-Wide Association Studies in Nephrology Research