What is a functional locus? Understanding the genetic basis of complex phenotypic traits.

A multitude of results from genome-wide association studies have been published in recent years in relation to different human diseases and phenotypic traits. However, the identified polymorphisms explain just a small fraction of the variability of the traits and they are poor predictors of occurrence of disease. Although part of the missing variability may be found in still to be identified rare genetic variants, the present work proposes that a major part of the problem is due to our conceptual limitations regarding functional loci and its variants. Functional variants are currently defined in absolute positional terms; they are just sequence variations in fixed positions along the DNA molecule. In the present study is postulated that functional loci may include different positions in the DNA sequence. As consequence, variants of the same functional locus may be located in different physical positions along the genome and, the observed effect of any particular genetic variant will be then reduced compared to its true effect. The differential use of regulatory regions such as gene promoters and enhancers would be a particular case of the proposed hypothesis. The hypothesis makes predictions that can be tested, offering potential paths of research to elucidate the genetic basis of complex human traits.