Table 1 Common bias in genetic association studies

Phenotype definition

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.

Genotyping misclassification

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.

Selection of sample

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.

Confounding by ethnic origin

If populations from ethnic groups differ in frequency of risk alleles, confounding may occur if the populations are unevenly distributed across comparison groups.

Multiple testing

Testing a multitude of genetic variants against a phenotype creates a possibility of finding significant associations by chance (type 1 error).

Relatedness

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.

Treatment effects

The phenotype under investigation may be modified by treatments and hence distort the size of association between genetic variants and the phenotype of interest.