The genetic analysis of complex behavioural traits has taught us that the phenotype
definition is most critical in establishing genotype-phenotype relationships. Global
behavioural variables are not directly related to their molecular genetic determinants
as many modifying factors are operating. However, neurobiological phenotypes are closer
to the impacting molecular genetic variants, and genotype-phenotype relationships
can be detected more easily and consistently.
Thus, defining the phenotype in pharmacogenetics by changes in psychopathologically
based rating scales might produce inconsistent results with only small effect sizes.
Using pharmacologically changes in brain functions as phenotypes might produce more
robust results.
In a highly standardized pharmacological treatment protocol (fixed doses, monotherapy
with citalopram) in 80 patients with unipolar depression and homogeneous background
we selected a series of neurobiological indicators of clinical efficacy as targeted
phenotypes. We report on two neurobiological indicators: Antidepressant-induced changes
(a) in the regulation of the hypothalamus-pituitary axis (HPA) measured by the DEX-CRH
test, and (b) in cognitive functions (memory). We focus on candidate genes which are
a priori likely to influence these selected phenotypes (e.g., glucocorticoid- and
mineralocorticoid-receptor genes). Haplotype analysis is used to increase the information
content of markers. This more hypothesis-driven, standardized approach is able to
produce meaningful genotype-phenotype relationships.
