penetrance of this biologically functional variant.44 Of note, the 37W variant was not observed in 10 000 control individuals,11 the 1000 Genomes project,61 the NHLBI GO Exome Sequencing Project (ESP), nor any of our 889 control samples. These findings on R37W reinforce the probable importance of this domain for DISC1 subcellular distribution and binding of interacting proteins31, 44 and add to the weight of evidence for other functional studies of DISC1 amino-acid substitutions.41 Each observed amino-acid substitution provides a similar opportunity to tease out the relationships between genotype and phenotype and between structure and function.29, 31 Overall, these results demonstrate a high level of sequence variation in DISC1, a subset of which may contribute to psychiatric disorder in some individuals who will be typically rare in the population precluding classical statistical analysis and requiring biological validation. This predicts a population-specific contribution of rare casual variants to risk.80 Our results indicate the potential value of sequencing non-coding regions of the genome, which may harbour disease-associated regulatory variants. Our findings of both functional and putative regulatory variants nominally associated with depression and cognitive ability merit replication in independent samples and biological exploration.
