Genome-wide analysis of the heritability of amyotrophic lateral sclerosis

Margaux F. Keller, Luigi Ferrucci, Andrew B. Singleton, Pentti J. Tienari, Hannu Laaksovirta, Gabriella Restagno, Adriano Chiò, Bryan J. Traynor, Michael A. Nalls

Research output: Contribution to journalArticlepeer-review

Abstract

IMPORTANCE: 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. DESIGN, SETTING, AND PARTICIPANTS: We applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets thatwere 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 phenotypeswebsite (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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: We found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesizemay contain causative risk variants that influence susceptibility to ALS.

Original languageEnglish (US)
Pages (from-to)1123-1133
Number of pages11
JournalJAMA Neurology
Volume71
Issue number9
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology
  • Medicine(all)

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