Novel associations of BST1 and LAMP3 with rapid eye movement sleep behavior disorder

Abstract

AbstractIsolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) is a parasomnia, characterized by loss of muscle atonia and dream enactment occurring during REM sleep phase. Since a large subgroup of iRBD patients will convert to Parkinson’s disease, and since previous genetic studies have suggested common genes, it is likely that there is at least a partial overlap between iRBD and Parkinson’s disease genetics. To further examine this potential overlap and to identify genes specifically involved in iRBD, we fully sequenced 25 genes previously identified in genome-wide association studies of Parkinson’s disease. The genes were captured and sequenced using targeted next-generation sequencing in a total of 1,039 iRBD patients and 1,852 controls of European ancestry. The role of rare heterozygous variants in these genes was examined using burden tests and optimized sequence Kernel association tests (SKAT-O), adjusted for age and sex. The contribution of biallelic (homozygous and compound heterozygous) variants was further tested in all genes. To examine the association of common variants in the target genes, we used logistic regression adjusted for age and sex. We found a significant association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p=0.0003 at coverage >50X and 0.0004 at >30X), mainly driven by three nonsynonymous variants (p.V85M, p.I101V and p.V272M) found in a total of 22 (1.2%) controls vs. two (0.2%) patients. Rare non-coding heterozygous variants in LAMP3 were also found to be associated with reduced iRBD risk (p=0.0006 at >30X). We found no statistically significant association between rare heterozygous variants in the rest of genes and risk of iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD patients vs. controls. To examine the potential impact of the rare nonsynonymous BST1 variants on the protein structure, we performed in silico structural analysis. All three variants seem to be loss-of-function variants significantly affecting the protein structure and stability. Our results suggest that rare coding variants in BST1 and rare non-coding variants in LAMP3 are associated with iRBD, and additional studies are required to replicate these results and examine whether loss-of-function of BST1 could be a therapeutic target.