title: Genome-wide estimate of the heritability of Multiple System Atrophy.
abstract: BACKGROUND
  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.
  
  
  METHODS
  We used 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.
  
  
  RESULTS
  We estimate the heritability among common variants of MSA in pooled cases at 2.09-6.65%, with a wider range of values in geographic and diagnostic subgroups. Meta-analysis of our geographic cohorts reveals high between-group heterogeneity. Contributions of single chromosomes are generally negligible. We suggest 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.
  
  
  CONCLUSIONS
  MSA is a challenging disease to study due to high rates of misdiagnosis and low prevalence. Given our 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.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address: monica.federoff22@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Federoff
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Price
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Sailer
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA; Neurodegenerative Diseases Research Group, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: S
authors.initials: S
authors.lastname: Scholz
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hernandez
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nalls
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Houlden
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D019578:Multiple System Atrophy / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
keywords: Atypical parkinsonisms; Genetics; Multiple System Atrophy