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The genetic components of idiopathic nephrolithiasis

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Abstract

Nephrolithiasis is a cause of significant morbidity and medical care expenses worldwide. Its prevalence has increased steadily during the last three decades among both adults and children. This trend suggests that changing environmental factors play a significant role in the risk of developing kidney stones although, conversely, there are many indications that genes play an important role in this condition as well. A limited number of monogenic forms have been identified, but the majority of nephrolithiasis cases are the result of complex, multi-factorial interactions between genetic inheritance and environmental exposure. Scientific evidence indicates that inheritance accounts for about half of the risk of common forms, making these forms suitable for investigation by genetic analysis. Here, we review the numerous studies that have been conducted to establish the role of genes in determining the risk of nephrolithiasis, the differential contribution of genes to this risk, and the confounding influence that environmental variables have on genetic studies.

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  1. Departments of Internal Medicine and Human Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, G5.100, Dallas, TX, 75390, USA

    Massimo Attanasio

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Glossary

Linkage analysis

A technique that allows one to assign to genomic regions identified by unique markers the probability to be causative of an observed phenotype. It is performed by comparing the observed cosegregation of markers and phenotypes within one or more pedigrees to the null hypothesis of no cosegregation.

Effect size

The extent of the effect of a locus in determining a trait. An effect size of 1 would correspond to a full penetrant allele completely determining the trait.

Endo-phenotype

An inheritable trait associated with a disease in the population and co-segregating with the disease in pedigrees that is detectable whether or not the disease phenotype is manifest.

Relative risk (λ)

The ratio of the prevalence of a disease in a risk population to the prevalence of the same disease in the general population (λ = R R /R P ). It is a measure of familiarity for a certain condition when the risk population is represented by the relatives of diseased individuals. Notice that this index is not only influenced by genetic factors but also by any other factor shared in the family.

Heritability (h 2)

The ratio of the variability determined by additive genetic effects on the overall phenotypic variability (h 2 = σ A /σ P ). Heritability is a stricter index of genetic contribution to a trait. It does not exclude the existence of non-inheritable components but can never be higher than the overall genetic risk, representing a better estimate of the genetic substratum. A heritability of 0.5 indicates that at least 50% of the familiarity of a trait is explained by inheritable genetic factors.

Regression

A statistics that quantifies how the variance of a dependent variable is explained by changes in the independent variable.

Twins concordance

The conditional probability of the second twin expressing a trait given that the first twin expresses that trait. The concordance in a phenotype between monozygotic twins (MZ, sharing 100% of their alleles) is expected to be higher than that between dizygotic twins (DZ, sharing 50% of their alleles). The ratio of MZ/DZ concordance for a trait can be used as measure of genetic influence on that trait. Although it is still subject to shared pre- and postnatal environment, it is a more reliable index of genetic contribution. High MZ/DZ concordance is strongly suggestive of the existence of heritable genetic risk.

Penetrance

The probability, from zero to 1, of expressing the phenotype in the presence of the risk allele(s). The probability is 1 for Mendelian alleles with strong effect on the phenotype (fully penetrant). A lower than 1 probability can be explained by the concomitance of other variables.

Quantitative Trait

Any trait measurable as a continuous variable (like height, blood pressure, etc.)

Additive effect

In genetics, it refers to the effect that genes have on a trait based only on the number of inherited alleles, not on genetic interactions between genes or alleles, such as dominance (if one of the allele is present it will per se determine the trait) or gene–gene interactions.

Quantitative linkage analysis

A variant of linkage analysis in which, instead of a dichotomous (affected/non affected) phenotype, the deviation of the value of a quantitative trait in a subject from the population mean is tested for cosegregation with genetic markers.

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Attanasio, M. The genetic components of idiopathic nephrolithiasis. Pediatr Nephrol 26, 337–346 (2011). https://doi.org/10.1007/s00467-010-1562-6

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