Table 2 Alternative explanations for small genetic effects in association studies of ADHD. This table lists potential explanations for small effect sizes in ADHD that range between 1.1 and 2.0. Studies to include or exclude each of these possibilities have yet to be completed, so the true size of the genetic effects remains unknown at this time.
From: The IMAGE project: methodological issues for the molecular genetic analysis of ADHD
Multiple genes of small effect | Main effect sizes of individual genes are small. Genetic influences consist mainly of common alleles, each making a small additive contribution to genetic effects. |
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Allelic heterogeneity | Average effect sizes of individual causal variants are small. The average effect size could be contributed by common variants, each conferring a small genetic effect and/or one or more rare variants conferring larger genetic effects. |
Tagging markers (indirect association) | Strength of the observed association is proportional to the correlation between the genotyped marker(s) and the causal variant(s). This arises since not all the markers investigated are necessarily causal variants themselves, but may be tagging nearby functional genetic variants. The strength of the association will decrease with decreasing correlation between the tagging marker and functional variant. |
Tagging phenotype | Strength of association is proportional to the correlation between the measured phenotype and underlying genetic liability. This arises since we do not know the best way to measure underlying genetic liability for a disorder. Phenotypic measurements are proxy variables that serve to tag the assumed underlying distribution of genetic risk. The strength of the association will decrease with decreasing correlation between the phenotypic measures and genetic liability |
Interactions between adjacent loci | Variants within a gene may interact with each to alter gene function. This can arise since genetic variants may have functional consequences that depend on variation at a second variable site. An example that has been proposed is an interaction between the intro 8 and 3'UTR variants in the dopamine transporter gene (described in text). |
Higher-order interactions | Main effects of individual genes may make little or no contribution to phenotypic variance. Genetic effects may be mediated by interaction with environment risks (gene by environment interactions) or other genetic loci (gene by gene interactions, referred to as epistasis). |