Variation in SWI/SNF Chromatin Remodeling Complex Proteins is Associated with Alcohol Dependence and Antisocial Behavior in Human Populations

Abstract

Background Testing for direct gene/SNP replication of association across studies may not capture the true importance of a candidate locus; rather, we suggest that relevant replication across studies may be found at the level of a biological process. We previously observed that variation in two members of the SWI/SNF chromatin remodeling complex is associated with alcohol dependence (AD) in the Irish Affected Sib Pair Study for Alcohol Dependence. Here, we tested for association with alcohol-related outcomes using a set of genes functioning in the SWI/SNF complex in two independent samples. Methods We used a set-based analysis to examine the 29 genes of the SWI/SNF complex for evidence of association with (1) AD in the adult Collaborative Study on the Genetics of Alcoholism (COGA) case/control sample and (2) antisocial behavior, hypothesized to be a genetically-related developmental precursor, in a younger population sample (Spit for Science). Results We found evidence for association of the SWI/SNF complex with AD in COGA (p=0.0435) and more general antisocial behavior in Spit for Science (p=0.00026). The genes that contributed most strongly to the signal in COGA were SS18L1, SMARCD1, BRD7, SMARCB1 and BCL11A. In the Spit for Science sample, ACTB, ARID2, BCL11A, BCL11B, BCL7B, BCL7C, DPF2, and DPF3 all contributed strongly to the signal. Conclusions We detected associations between the SWI/SNF complex and AD in an adult population selected from treatment-seeking probands and antisocial behavior in an adolescent population sample. This provides strong support for a role for SWI/SNF in the development of alcohol-related problems.

The Emerging Role of ATP-Dependent Chromatin Remodeling in Memory and Substance Use Disorders

“…Alcohol has also been demonstrated to establish long-lasting changes in BAF CRC function. Recently Mathies et al (2017) identified several SNP clusters within BAF-genes that correlate with alcohol use disorder in humans, including Baf47 , Baf60a , and Crest [ 141 ]. Lastly, ethanol exposure during neuronal development induces expression of Baf53b , Baf57 , Baf60 , Baf200 , and Crest [ 142 ].…”

SWI/SNF complexes act through CBP-1 histone acetyltransferase to regulate acute functional tolerance to alcohol

“…In worms, most SWI/SNF complex members were involved in regulating acute ethanol response behaviors, but different SWI/SNF complexes affected different behaviors: BAF subunits were required for normal initial sensitivity to ethanol, while PBAF subunits were required for acute functional tolerance to ethanol [ 10 ]. We found that allelic variation in several SWI/SNF complex members was associated with alcohol dependence in different adult human populations [ 10 , 14 ]. Allelic variation in different SWI/SNF complex members was also associated with antisocial behavior in adolescents, a phenotype that is strongly predictive of future alcohol use problems [ 14 ].…”

“…We found that allelic variation in several SWI/SNF complex members was associated with alcohol dependence in different adult human populations [ 10 , 14 ]. Allelic variation in different SWI/SNF complex members was also associated with antisocial behavior in adolescents, a phenotype that is strongly predictive of future alcohol use problems [ 14 ].…”

Intrinsic Disorder of the BAF Complex: Roles in Chromatin Remodeling and Disease Development

“…Alterations in the human BCL7C gene are associated with the Sézary syndrome, which is a leukemic form of cutaneous T-cell lymphoma [191]. BCL7C (together with several other genes encoding subunits of the SWI/SNF complex, such as ACTB , ARID2 , BCL11A , BCL11B , BCL7B , BRD7 , DPF2 , DPF3 , SMARCB1 , SMARCD1 , and SS18L1 ) was also linked to the development of alcoholism and alcohol-related problems [192].…”