A comprehensive screening of copy number variability in dementia with Lewy bodies.
Kun-Rodrigues C., Orme T., Carmona S., Hernandez DG., Ross OA., Eicher JD., Shepherd C., Parkkinen L., Darwent L., Heckman MG., Scholz SW., Troncoso JC., Pletnikova O., Dawson T., Rosenthal L., Ansorge O., Clarimon J., Lleo A., Morenas-Rodriguez E., Clark L., Honig LS., Marder K., Lemstra A., Rogaeva E., St George-Hyslop P., Londos E., Zetterberg H., Barber I., Braae A., Brown K., Morgan K., Troakes C., Al-Sarraj S., Lashley T., Holton J., Compta Y., Van Deerlin V., Serrano GE., Beach TG., Lesage S., Galasko D., Masliah E., Santana I., Pastor P., Diez-Fairen M., Aguilar M., Tienari PJ., Myllykangas L., Oinas M., Revesz T., Lees A., Boeve BF., Petersen RC., Ferman TJ., Escott-Price V., Graff-Radford N., Cairns NJ., Morris JC., Pickering-Brown S., Mann D., Halliday GM., Hardy J., Trojanowski JQ., Dickson DW., Singleton A., Stone DJ., Guerreiro R., Bras J.
The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.