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

Objective: To examine the role of genes identified through genome-wide
association studies (GWASs) of Parkinson disease (PD) in the risk of
isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD). Methods:
We fully sequenced 25 genes previously identified in GWASs of PD, in a
total of 1,039 iRBD patients and 1,852 controls. The role of rare
heterozygous variants in these genes was examined using burden tests. The
contribution of biallelic variants was further tested. To examine the
potential impact 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
>50X and 0.0004 at >30X), mainly driven by three
nonsynonymous variants (p.V85M, p.I101V and p.V272M) found in 22 (1.2%)
controls vs. two (0.2%) patients. All three variants seem to be
loss-of-function variants with a potential effect on the protein structure
and stability. Rare non-coding heterozygous variants in LAMP3 were also
associated with iRBD (p=0.0006 at >30X). 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 non-coding variants in LAMP3 are
associated with iRBD. Additional studies are required to replicate these
results and examine whether loss-of-function of BST1 could be a
therapeutic target.