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Genome-wide association studies in pediatric chronic kidney disease

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Abstract

The genome-wide association study (GWAS) has become an established scientific method that provides an unbiased screen for genetic loci potentially associated with phenotypes of clinical interest, such as chronic kidney disease (CKD). Thus, GWAS provides opportunities to gain new perspectives regarding the genetic architecture of CKD progression by identifying new candidate genes and targets for intervention. As such, it has become an important arm of translational science providing a complementary line of investigation to identify novel therapeutics to treat CKD. In this review, we describe the method and the challenges of performing GWAS in the pediatric CKD population. We also provide an overview of successful GWAS for kidney disease, and we discuss the established pediatric CKD cohorts in North America and Europe that are poised to identify genetic risk variants associated with CKD progression.

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Acknowledgments

Jayanta Gupta, Peter A. Kanetsky, Franz Schaefer, and Craig S. Wong were supported by NIH grant number DK082394. Anna Köttgen and Matthias Wüttke were supported by the Emmy Noether Program of the German Research Foundation (KO 3598/2-1). Craig S. Wong received additional support from DK066143. Franz Schaefer received additional support from the European Community 7th Framework Programme (grant 2012–305608, EURenOmics), The KfH Foundation for Preventive Medicine (http://www.kfh-stiftung-praeventivmedizin.de/) and the ERA-EDTA.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, USA

    Jayanta Gupta

  2. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Peter A. Kanetsky

  3. Renal Division, Medical Center - University of Freiburg, Freiburg, Germany

    Matthias Wuttke & Anna Köttgen

  4. Pediatric Nephrology Division, University of Heidelberg, Heidelberg, Germany

    Franz Schaefer

  5. Department of Pediatrics, Division of Nephrology, University of New Mexico Children’s Hospital, MSC10-5590 1 University of New Mexico, Albuquerque, 87131-0001, NM, USA

    Craig S. Wong

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  1. Jayanta Gupta
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Correspondence to Craig S. Wong.

Glossary

Alleles

Alternative DNA sequences at the same physical position on homologous chromosomes.

Ancestry informative markers

Single-nucleotide polymorphisms that have large frequency differences across different continental populations; can be used to infer ancestry and adjust for population stratification in genetic association studies.

Common variant

A genetic variant that is common in the population; frequently defined as one with a population frequency of 1 % or more.

Deep sequencing

The whole genome or a genomic region is sequenced multiple times using high-throughput sequencing (next-generation sequencing) technology to reduce the number of sequencing errors and detect rare genetic variants.

Genomic

Pertaining to the collection of all DNA in an organism.

Genotype

The genetic makeup of an individual, which may refer to the whole genome or to specific genes or regions of genes.

Haplotype

A set of genetic variants (usually clustered together at the same physical position of the genome) that are inherited together.

Imputation

In the context of genetic studies, a statistical procedure that uses linkage disequilibrium (i.e., correlation between individual genetic variants) to infer missing or untyped genotypes in an individual based on a reference panel of several individuals who have been fully genotyped.

Linkage disequilibrium

A non-random association of two or more alleles that are located at different loci.

Loci

Specific positions of genes or genetic markers on a chromosome; the term locus is singular for loci.

Phenotype

Measurable or observable physical characteristic or trait of an organism.

Population stratification

Presence of a systematic difference in allele frequencies between subpopulations in a population, can be introduced by different ancestries.

Principal component analysis

A statistical procedure for reducing high dimensional data into fewer dimensions. Used in population genetics to determine how genetic diversity across the genome varies according to geographical location and race/ethnicity. Widely used to adjust for population stratification in GWAS.

Rare variant

A genetic variant with a population frequency of less than 1 %.

Replication

Validation of a gene-disease association from a discovery genetic association study by a follow-up study in an independent sample of subjects.

Single-nucleotide polymorphisms (SNPs)

DNA sequence variation resulting from a change of a single nucleotide, commonly defined as having a frequency of at least 1 % in a given population.

Tag-SNP

A SNP that is highly correlated with other SNPs and used to serve as a marker for a haplotype block. Tag-SNPs can be utilized for SNP-based genotyping.

Variant

A variation in the DNA sequence, e.g., a SNP. Other forms of genetic variation include structural variations (e.g., deletions and insertions, copy number variations etc.)

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Gupta, J., Kanetsky, P.A., Wuttke, M. et al. Genome-wide association studies in pediatric chronic kidney disease. Pediatr Nephrol 31, 1241–1252 (2016). https://doi.org/10.1007/s00467-015-3235-y

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  • DOI: https://doi.org/10.1007/s00467-015-3235-y

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