title: Genome-wide analysis of the heritability of amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.
  
  
  OBJECTIVE
  To estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies.
  
  
  METHODS
  We applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland.
  
  
  METHODS
  A linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability.
  
  
  RESULTS
  With our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk.
  
  
  CONCLUSIONS
  We found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS.
authors.affiliation: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland2Department of Biological Anthropology, Temple University, Philadelphia, Pennsylvania.
authors.forename: Margaux F
authors.initials: MF
authors.lastname: Keller
authors.affiliation: Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: Department of Neurology, Helsinki University Central Hospital and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland.
authors.forename: Pentti J
authors.initials: PJ
authors.lastname: Tienari
authors.affiliation: Department of Neurology, Helsinki University Central Hospital and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Laaksovirta
authors.affiliation: Molecular Genetics Unit, Department of Clinical Pathology, ASO OIRM-St Anna, Turin, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Restagno
authors.affiliation: Rita Levi-Montalcini Department of Neuroscience, University of Turin, Turin, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.affiliation: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics