, 1997]) and impaired corticosteroid receptor signaling (Holsboer, 2000), more recent hypotheses include the involvement of neurotrophins (Samuels and Hen, 2011), fibroblast growth factors (both ligands and receptors) (Turner et al., 2012), GABAergic deficits (Luscher et al., 2011), and epigenetic changes, specifically alterations in methylation and acetylation profiles at the promoters of glucocorticoid receptors and brain-derived neurotrophic factor (McGowan et al., this website 2009). Genetics does not support the primacy of one theory over another; indeed as our Review of the candidate gene
literature indicates, genetics does not support any of the biological theories put forward to date. Our Review indicates two pathways forward. First, there is no reason to suppose that undifferentiated MD is intractable to GWAS, but success will require very large sample sizes (Figure 3). However, interpreting the results of such a study is likely to be challenging. We have seen that MD is highly comorbid with anxiety, and etiologically heterogeneous, at both genetic and environmental levels. Without information on comorbidity, known risk factors, and clinical phenotypes, the role of each locus will be unclear. Some will be sex specific, some will act only in situations of environmental stress, and others will predispose to anxiety. Genetic selleck studies will need to include
an extensive amount of phenotypic information if we are to make sense of hard-won mapping results. Second, our Review indicates that we should not abandon attempts to concentrate
on subtypes of MD. So far, studies using recurrent and early-onset MD have been no more successful than those that examine undifferentiated MD, but this may be due to lack of power. If we consider MD as part of all a quantitative trait (representing liability to depression), then using a sample of more extreme cases would be equivalent to analyzing a rare disease (as Figure 3 demonstrates). Even a small improvement in genetic tractability could result in a large saving in the number of samples that need to be analyzed (reducing from 50,000 to 20,000, for example). The problem is that we do not know for sure how to determine the scale on which severity is measured: is it the number of episodes of MD, the length of episodes, the number of symptoms, or some other feature or combination of features? Furthermore, the severity scale needs to differentiate cases with higher genetic risk, not those cases resulting largely from environmental adversities. Alternatively, subdividing MD on the basis of one or more clinical features (e.g., typical versus atypical vegetative features, standard versus postpartum onset), sensitivity to environmental stress, or sex, might identify a rarer, or at least a more genetically homogenous, subtype. At present, deciding which features to investigate is likely to be an ad hoc enterprise.
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