What molecular mechanisms might underlie how allelic variation in members of the SWI/SNF complex influence antisocial behavior and progression to AD? Because SWI/SNF complexes remodel chromatin structure, they alter gene expression by changing the accessibility of regulatory sequences to the transcriptional machinery. We speculate that allelic variation in these chromatin regulators may result in important changes in their function, either by subtly changing the strength or specificity of protein interactions or enzymatic activity, or by altering the interaction with specific DNA regulatory elements. An alternative mechanism may be that genetic variation may alter the levels of expression of the SWI/SNF component. In any of these cases, such variation could have important effects on the transcriptional regulation of downstream targets of SWI/SNF, either by increasing or decreasing the expression of the target sequences. We anticipate that these targets include the mediators of both of these phenotypes in the brain. Our findings that several SWI/SNF complex members are associated with AD in different human populations and with antisocial behavior in a younger, community sample, that represents a genetically-linked developmental precursor phenotype, argue strongly for efforts to identify the downstream targets of SWI/SNF that are important for mediating these important phenotypes.
