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NPC1 variants are not associated with Parkinson's disease, REM-sleep behaviour disorder or Dementia with Lewy bodies in European cohorts.

Somerville, E. N.; Krohn, L.; Yu, E.; Rudakoua, U.; Senkevich, K.; Ruskey, J. A.; Asayesh, F.; Ahmad, J.; Spiegelman, D.; Dauvilliers, Y.; Arnulf, I.; Hu, M. T. M.; Montplaisir, J. Y.; Gagnon, J.-F.; Desautels, A.; Ibrahim, A.; Stefani, A.; Hogl, B.; Gigli, G. L.; 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.; Cochen De Cock, V.; Ferini-Strambi, L.; Heibreder, A.; Monaca, C. C.; Abril, B.; Dijkstra, F.; Viaene, M.; Boeve, B. F.; Postuma, R. B.;

2022-11-08 genetic and genomic medicine
10.1101/2022.11.08.22281508 medRxiv
Show abstract

NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Nieman-Pick disease type C, 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 Parkinsons disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement (REM)-sleep behavior disorder (RBD). We analyzed common and rare variants from three cohorts of European descent: 1,084 RBD cases and 2,945 controls, 2,852 PD cases and 1,686 controls, and 2,610 DLB cases and 1,920 controls. Logistic regression models were used to assess common variants while optimal sequence Kernel association tests (SKAT-O) 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.

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