Objective
To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson
disease (PD) in the risk of isolated REM sleep behavior disorder (iRBD).
Methods
We fully sequenced 25 genes previously identified in GWASs of PD in a total of 1,039 patients with iRBD and
1,852 controls. The role of rare heterozygous variants in these genes was examined with burden tests. The
contribution of biallelic variants was further tested. To examine the potential effect of rare nonsynonymous
BST1 variants on the protein structure, we performed in silico structural analysis. Finally, we examined the
association of common variants using logistic regression adjusted for age and sex.
Results
We found an association between rare heterozygous nonsynonymous variants in BST1 and iRBD (p = 0.0003 at
coverage >50× and 0.0004 at >30×), driven mainly by 3 nonsynonymous variants (p.V85M, p.I101V, and
p.V272M) found in 22 (1.2%) controls vs 2 (0.2%) patients. All 3 variants seem to be loss-of-function variantswith a
potential effect on the protein structure and stability. Rare noncoding heterozygous variants in LAMP3 were also
associated with iRBD (p = 0.0006 at >30×).We found no association between rare heterozygous variants in the rest
of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD.
Conclusion
Our results suggest that rare coding variants in BST1 and rare noncoding variants in LAMP3 are associated with
iRBD. Additional studies are required to replicate these results and to examine whether loss of function of BST1
could be a therapeutic target.
