, 1994). The important point here is that

Wolfram is a recessive condition. The disease itself (in homozygotes) is characterized by a broad spectrum of psychiatric and neurological disorders, but heterozygote carriers show a purer MD phenotype: in one report, out of 11 individuals carrying a Wolfram mutation, eight Selumetinib clinical trial were hospitalized for major MD, significantly more than the three relatives expected if there were no association between psychiatric hospitalizations and mutations at this locus (Swift and Swift, 2005). The authors argue that “if the population frequency of wolframin mutations that predispose carriers to psychiatric illness is about 1%, with an odds ratio of 7.1, wolframin mutation carriers would be estimated to be about 7% of patients

hospitalized for MD” (Swift and Swift, 2005). Overall, we cannot rule out the possibility that rare large-effect risk alleles exist, but we also cannot extend much hope for their discovery. It is possible that risk alleles with odds ratios between 3 and 4, occurring Neratinib at low frequencies (less than 5%), make a contribution to MD, but their discovery will require either a new generation of genotyping arrays, interrogating rare variants, or the deployment of population-scale sequencing. The second hypothesis to explore is the idea that larger-effect loci might be detected if MD were to be analyzed differently. For example, consider the possibility that MD is not one but two disorders that cannot be differentiated on a clinical basis alone. Suppose that 50 variants contribute to disease through one pathway (leading to one subtype of MD) and 50 to a second pathway (leading to the second subtype). Unbeknownst to investigators, a study contained equal numbers of the two subtypes. Since variation in the first pathway is irrelevant to disease susceptibility in the second subtype, the genetic effect also of loci acting on one pathway is reduced by half, and power is similarly reduced. This point is not merely important

in helping design genetic studies, it is critically important for their interpretation. Without knowledge of the existence of two unrelated mechanisms, it would be difficult, perhaps impossible, to interpret the results of the study. We would be left guessing whether the 100 variants represented one, two, or more mechanistic pathways. Do subforms of genetically homogeneous MD exist? A large literature addresses this issue, not all of it readily summarized; here we tackle two questions that are key to understanding how genetic effects operate in MD: first, how separate is MD from other disorders? Second, is MD one disorder or two, or more? Two disorders that most frequently overlap diagnostically with depressive illness are anxiety and bipolar disorder.