A genome-wide association study in multiple system atrophy

Abstract

Objective:To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS).Methods:We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed.Results:We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10−6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA.Conclusions:We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.

Multiple system atrophy and apolipoprotein E

“…These findings are in line with the results of previous small studies (n= 22; 59; 47; 40 and 12) 10–14 and no signal at the APOE locus in the recent genome-wide association study of 331 pathologically-confirmed MSA patients. 15 It also is worth noting that in agreement with these findings, a recent study reported no association between rapid eye movement sleep behavior disorder (which could be a clinical prodromal feature preceding the development of MSA) and risk of MSA. 16 …”

Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

“…25 In MSA, contradicting results have been reported regarding the SNCA locus, and the largest analysis thus far refuted the previously reported association. 26 In the current study, we aimed to thoroughly analyze the SNCA locus in RBD. We used a combination of full SNCA sequencing and comprehensive SNP genotyping in the largest genetic study of iRBD to date, as well as in PD and DLB patients with and without pRBD, to examine SNCA association with RBD risk and phenoconversion from RBD to defined neurodegenerative disease.…”

The neuropathology of multiple system atrophy and its therapeutic implications

“…In light of these observations, it could also be concluded that there may exist a genetic predisposition for oligodendrocytes to develop abnormal α-syn accumulation (Sturm et al, 2016). The genetic risk factors with the most evidence in MSA are variants in the SNCA and COQ2 genes (Collaboration, 2013; Scholz et al, 2009), however genome-wide association studies have failed to find association between common genetic variations in those genes and MSA (Sailer et al, 2016). …”