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January 2014

From Genome-Wide Association Studies to Next-Generation Sequencing: Lessons From the Past and Planning for the Future

Author Affiliations
  • 1Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany
  • 2Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany
JAMA Neurol. 2014;71(1):5-6. doi:10.1001/jamaneurol.2013.3682

The question whether common or rare variants will eventually help us understand the genetic architecture of complex diseases, including neurodegenerative disorders, is currently being debated. Recently published studies of Alzheimer disease (AD) and Parkinson disease (PD) are suggesting the role of common and rare variants in both disorders.

“Are we ready for genome-wide association studies?” This question was asked in 2006 to raise issues about genome-wide association studies (GWAS).1 Since then, more than 9000 studies have been published, which led to the discovery and replication of many novel loci for diverse phenotypes, highlighting the success of GWAS, and lending support to the “common disease–common variant” (CDCV) hypothesis. The CDCV hypothesis postulates that a significant proportion of phenotypic variance in a population is due to common variants, suggesting that susceptibility for a given trait is largely due to common variants. Typically, the variants included in standard arrays for GWAS are single-nucleotide polymorphisms (SNPs), selected for having minor allele frequencies greater than 5%. They are thought to detect most of the genetic risk for a given disease contributed by common variants. However, despite the success of GWAS in defining robust risk factors for complex diseases, this approach explains still only a fraction of the heritability of these common diseases, even when very large sample sizes are analyzed.2