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Genome-wide and gene-based association implicates FRMD6 in alzheimer disease

✍ Scribed by Mun-Gwan Hong; Chandra A. Reynolds; Adina L. Feldman; Mikael Kallin; Jean-Charles Lambert; Philippe Amouyel; Erik Ingelsson; Nancy L. Pedersen; Jonathan A. Prince

Publisher: John Wiley and Sons
Year: 2012
Tongue: English
Weight: 237 KB
Volume: 33
Category: Article
ISSN: 1059-7794
DOI: 10.1002/humu.22009

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✦ Synopsis

Genome-wide association studies (GWAS) that allow for allelic heterogeneity may facilitate the discovery of novel genes not detectable by models that require replication of a single variant site. One strategy to accomplish this is to focus on genes rather than markers as units of association, and so potentially capture a spectrum of causal alleles that differ across populations. Here, we conducted a GWAS of Alzheimer disease (AD) in 2,586 Swedes and performed gene-based meta-analysis with three additional studies from France, Canada, and the United States, in total encompassing 4,259 cases and 8,284 controls. Implementing a newly designed gene-based algorithm, we identified two loci apart from the region around APOE that achieved study-wide significance in combined samples, the strongest finding being for FRMD6 on chromosome 14q (P = 2.6 × 10 -14 ) and a weaker signal for NARS2 that is immediately adjacent to GAB2 on chromosome 11q (P = 7.8 × 10 -9 ). Ontology-based pathway analyses revealed significant enrichment of genes involved in glycosylation. Results suggest that gene-based approaches that accommodate allelic heterogeneity in GWAS can provide a complementary avenue for gene discovery and may help to explain a portion of the missing heritability not detectable with single nucleotide polymorphisms (SNPs) derived from markerspecific meta-analysis.

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