Abstract
Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10−7) and MAPT H1c (17q21; rs242557; P=7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
Highlights
Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy
Replication stage samples included 67 autopsy-proven CBD cases (Mayo Clinic Florida Brain Bank, 6 CBD cases that failed quality control and 61 new CBD cases collected since the genome-wide association study (GWAS) genotyping was performed) and 457 control individuals collected from Mayo Clinic Florida, all of which were clinically diagnosed as being free of any neurological disorder
Two different quantitative PCR (qPCR) assays targeting TCONS_00014956 were designed, one targeting exon 1 and the other for exon 2, which showed good correlation upon comparison of expression levels using the two different primer sets (R2 1⁄4 0.97). This identified a statistical trend for greater lnc-KIF13B-1 expression with the minor risk allele (Supplementary Fig. 6). This first CBD GWAS on 152 autopsy-proven CBD patients and 3,311 control individuals has a clear limitation in terms of sample size
Summary
Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. First described in 1968 by Rebeiz and colleagues, three CBD cases were identified to have a distinct movement disorder and neuropathologic profile[2] These patients presented with what is termed corticobasal syndrome (CBS) where patients can exhibit levodopa-unresponsive parkinsonism, asymmetric akinesia and rigidity, accompanied by ideomotor apraxia, dystonia, and myoclonus. Autopsy-confirmed CBD cases can often present with several different clinical syndromes[3], which are frequently associated with other underlying neurodegenerative disorders such as PSP, AD, and frontotemporal dementia[4]. This phenotypic variability results in o50% of patients with CBS having CBD at autopsy[5,6,7]. These findings highlight the genetic similarities and differences between CBD and PSP and suggest that the two disorders may, at least in part, share common disease processes
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