Diversity of Human Clock Genotypes and Consequences - Progress in Molecular Biology and Translational Science - page 73

in a number of the processes implicated by human genetic studies, including
sleep, metabolic syndromes, mood disorders, addiction, and fertility.
It is worthwhile at this point to detail approaches to Mendelian genetics
versus association studies as the distinction between the two is not well
understood by many people who are interested in the current topic. Men-
delian genetics deals with identification of genetic variants of strong effect
and are sufficient to cause a phenotype. For example, genetic studies of
rodents with spontaneous mutations (e.g., the Ck1e

mutant hamster) and
forward genetic screens in model organisms where mutagenesis is performed
and animals are screened for a phenotype (e.g., short/long period or arrhyth-
mia) are focused on identifying the genes and mutations which cause the phe-
notype. Similar studies have been successful in humans where identification
of FASP allowed cloning of causative genes and mutations.
In complex genetics, genetic variants are sought where there is a statis-
tical association of the variant with a phenotype. The variant itself is only
associated with an increased risk of the phenotype. Thus, having the variant
does not mean that the carrier will have the phenotype. Neither does it mean
that one without the variant cannot have the phenotype. Such a finding does
not simply imply that variant is itself causative of the increased risk. Rather, it
suggests that the associated variant and/or a genetic variant in the vicinity of
the associated variant leads to increased risk. Consequently, we must be very
careful when interpreting these data, as many such findings (positive associ-
ations) have (or will turn out to be) false positives. In some cases, a variant in a
genewill be associatedwith the phenotype because that gene is truly linked to
the biology underlying the phenotype of interest. In other cases, a genetic
variant may truly be associated with the phenotype but only because it is
in linkage disequilibrium with a variant in another gene. Mutations in some
clock genes have been generated and result in behavioral and/or physiolog-
ical phenotypes in animal models (such as the mouse studies described earlier
in this chapter). These studies support the argument that the recognized clock
gene associations in humans with similar or related phenotypes occur as a
result of genetic variants in the respective clock genes. To validate whether
these genetic variations found by the association studies lead to phenotypic
changes will require generation and characterization of appropriate animal
models carrying equivalent polymorphisms. Unlike Mendelian traits with
very prominent phenotypes as in the cases of FASP, however, many of the
behavioral and physiological phenotypes observed in association studies are
relatively subtle and may exhibit complex allelic interactions, imposing great
complications and challenges on studies in animal models. Nevertheless, as