Risk categorization for complex disorders according to genotype relative risk and precision in parameter estimates.
OBJECTIVE
To develop a method of genetic risk categorization based on the risk conferred by genetic variants and the precision with which risks are known.


METHODS
We develop a method for risk assignment based on an "average" member of the population and their genotype, deriving empirical confidence intervals encompassing all relevant sources of variation in disease risk. An individual with risk confidence interval that does not overlap with that of the "average" individual is categorized as having higher or lower disease risk. The method is applied to data sets in Crohn's disease and type 2 diabetes.


RESULTS
The proportion of the population assigned to the average risk category depends on genotype relative risk, allele frequency and sample size of the study used to estimate these parameters. For low genotype relative risks or minor allele frequency, little resolution into different risk categories may be possible.


CONCLUSIONS
The utility of a genetic risk variant for risk categorization depends on both the magnitude of the genotype relative risk and the accuracy with which this, and other elements of risk calculation, are known. Genetic risk calculations should include an assessment of the accuracy of the risk estimation.
Goddard
Graham H M
GH
Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, London, UK.
Lewis
Cathryn M
CM
D016022:Case-Control Studies; D003424:Crohn Disease / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation; D005828:Genetics, Population / Q000706:statistics & numerical data*; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment