NPC1 variants are not associated with Parkinson's disease, REM-sleep behavior disorder or dementia with Lewy bodies in European cohorts.
Somerville EN., Krohn L., Yu E., Rudakou U., Senkevich K., Ruskey JA., Asayesh F., Ahmad J., Spiegelman D., Dauvilliers Y., Arnulf I., Hu MTM., Montplaisir JY., Gagnon J-F., Desautels A., Ibrahim A., Stefani A., Högl B., Gigli GL., Valente M., Janes F., Bernardini A., Dusek P., Sonka K., Kemlink D., Plazzi G., Antelmi E., Biscarini F., Mollenhauer B., Trenkwalder C., Sixel-Doring F., Figorilli M., Puligheddu M., De Cock VC., Oertel W., Janzen A., Ferini-Strambi L., Heibreder A., Monaca CC., Abril B., Dijkstra F., Viaene M., Boeve BF., Postuma RB., Rouleau GA., Gan-Or Z.
NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Niemann-Pick disease type C (NPC), a lysosomal storage disorder. The role of NPC1 in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results. This study aimed to evaluate the association of NPC1 variants with the synucleinopathies Parkinson's disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement-sleep behavior disorder (RBD). We analyzed common and rare variants from 3 cohorts of European descent: 1084 RBD cases and 2945 controls, 2852 PD cases and 1686 controls, and 2610 DLB cases and 1920 controls. Logistic regression models were used to assess common variants while optimal sequence Kernel association tests were used to assess rare variants, both adjusted for sex, age, and principal components. No variants were associated with any of the synucleinopathies, supporting that common and rare NPC1 variants do not play an important role in alpha synucleinopathies.