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

Manu Sharma, PhD1,2; Rejko Krüger, MD1; Thomas Gasser, MD1
[+] 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.
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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.

Article InformationCorresponding Author: Manu Sharma, PhD, Hertie Institute of Clinical Brain Research, Department of Neurology, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany (manu.sharma@uni-tuebingen.de).

Published Online: November 4, 2013. doi:10.1001/jamaneurol.2013.3682.

Conflict of Interest Disclosures: None reported.

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Deciphering Missing Heritability of Neurodegenerative Diseases by Combining the CDCV and CDRV Hypotheses

Genome-wide association studies (GWAS) are used to identify common variants with minor allele frequency (MAF) greater than 5%. The common variants identified are most likely not causative themselves but in linkage disequilibrium with causal variants (common disease–common variant [CDCV] hypothesis). Next-generation approaches are now being applied either by performing targeted resequencing of top loci identified by GWAS or whole-exome sequencing in multiple affected cases to identify potential causal variants (common disease–rare variant [CDRV] hypothesis). Triangle indicates gradient change in MAFs from greater than 5% to less than 1%. APP indicates amyloid precursor protein; CLU, clusterin; HLA-DRB5, major histocompatibility complex, class II, DR beta 5; LRRK2, leucine-rich repeat kinase 2; MAPT, microtubule-associated protein tau; SORL1, sortilin-related receptor L; SNCA, synuclein; TREM2, triggering receptor on myeloid cells 2; VPS35, vacuolar protein sorting 35.

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