Multiple System Atrophy (MSA) is a neurodegenerative disease which presents heterogeneously with symptoms and signs of Parkinsonism, ataxia and autonomic dysfunction. Although MSA typically occurs sporadically, rare pathology-proven MSA families following either autosomal recessive or autosomal dominant patterns have been described, indicating a heritable contribution to the pathogenesis.
Samples from the NINDS Repository were used for this study, which implemented Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable component of MSA due to common coding variability in imputed genotype data of 907 MSA cases and 3866 population-matched controls. GCTA only assesses the effect of putative causal variants in linkage disequilibrium (LD) with all common SNPs on the genotyping platform.
As a result, the estimated heritability among common variants of MSA in pooled cases was 2.09-6.65%, with a wider range of values in geographic and diagnostic subgroups. Meta-analysis of geographic cohorts reveals high between-group heterogeneity. Contributions of single chromosomes were generally negligible. The study suggests that all calculated MSA heritability among common variants could be explained by the presence of misdiagnosed cases in the clinical subgroup based on a Bayesian estimate using literature-derived rates of misdiagnosis.
MSA is a challenging disease to study due to high rates of misdiagnosis and low prevalence. Given the low estimates of heritability, common genetic variation appears to play a less prominent role in risk for MSA than in other complex neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. The success of future gene discovery efforts rests on large pathologically-confirmed case series and an interrogation of both common and rare genetic variants.
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