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Phenotype definition
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Unclear definition of phenotype or use of non-standardized definitions can lead to noise in the outcome, which compromises ability to identify corresponding susceptibility variants.
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Genotyping misclassification
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Differential misclassification of genotypes can positively or negatively affect associations depending on the direction of misclassification. Non-differential misclassification of genotypes will bias association toward the null.
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Selection of sample
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Source of cases and controls or participants for analysis of quantitative traits can bias the association; for example, contrasting hospital cases with controls from the general population will inflate the association.
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Confounding by ethnic origin
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If populations from ethnic groups differ in frequency of risk alleles, confounding may occur if the populations are unevenly distributed across comparison groups.
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Multiple testing
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Testing a multitude of genetic variants against a phenotype creates a possibility of finding significant associations by chance (type 1 error).
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Relatedness
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Consanguinity in genetic association studies can distort the genotype-phenotype associations. Even in supposed unrelated populations, some individuals may be related. Relatedness should therefore be investigated with additional methods and adjusted for in the statistical analysis.
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Treatment effects
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The phenotype under investigation may be modified by treatments and hence distort the size of association between genetic variants and the phenotype of interest.
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