Having chosen an appropriate phenotype upon which to build a specific hypothesis, it is then necessary to consider the potential for a range of temporal and other para-genetic factors to influence gene expression and effect. These include the potential for genes to act at critical periods during different developmental stages, the effect that age related fat accretion will have on phenotype and sexual dimorphism of lipid storage (e.g. ‘gynoid versus android’ distributions and total body fat differences between males and females).
Epistasis between genes, whereby the effect of one gene may be modified by other genes and interactions between genes and environment may further complicate the picture.
Conversely, ‘phenocopies’ of obesity may exist without possessing the genotype sought by any particular study hypothesis thus reducing the power to detect genetic influence.
Thus, despite the fascinating physiological (and pharmacological) insights into the pathways involved in body weight regulation provided by unravelling the aetiology of some forms of monogenic obesity, it is increasingly clear that ultimate genetic understanding of common forms of human obesity will rely upon dissection of many small effects of multiple genetic variants superimposed on a permissive environment.
Many of these principals are illustrated by recent progress in understanding the genetics of Bardet–Biedl syndrome (BBS). First, more accurate phenotyping has permitted this syndrome to be separated from the Lawrence–Moon syndrome, which appears to be a distinct entity. Second, it is apparent that more than one genetic abnormality may be responsible for the observed abnormalities in this condition; at the time of writing, at least six loci (BBS 1–6) on different chromosomes have been identified with subtly different effects on phenotype such as stature, body weight or pattern of polydactyly (Iannello et al., 2002).
Third, in at least some forms of the disease, it may be necessary to have up to three distinct mutations (tri-allelic inheritance) for full disease expression, illustrating the principle of epistasis between disease alleles (Katsanis et al., 2001).
Warden CH and Fisler JS
Katsanis N, Beales PL, Woods MO