We recognize a number of limitations to the current study. First, our analyses were limited to European Americans and might not be generalizable to other populations. Replication in other samples is essential. Second, our gene ontology analysis might not be entirely unbiased, since they do not adjust for gene size (Wang et al., 2010): relatively large genes (including many of those expressed in the brain) span more markers than small genes, and are thus more likely to harbor markers meeting our significance criterion by chance alone. Third, our “cases” include individuals who do not meet full DSM-IV criteria for an independent major depressive episode, in that many experienced depressive symptoms under the influence of alcohol or drugs (N=85 females and N=201 males of the total N of 467 cases). It is unclear how such a distinction might influence our results. Previous work suggests that substance-induced and independent depressions might be etiologically distinct (Schuckit et al., 2007); in addition, although the comorbid phenotype might have a heritable component (Nurnberger et al., 2002), the genetics underlying this phenotype could be distinct from
