title: Genome-wide and gene-based association implicates FRMD6 in Alzheimer disease.
abstract: 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 marker-specific meta-analysis.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Mun-Gwan
authors.initials: MG
authors.lastname: Hong
authors.forename: Chandra A
authors.initials: CA
authors.lastname: Reynolds
authors.forename: Adina L
authors.initials: AL
authors.lastname: Feldman
authors.forename: Mikael
authors.initials: M
authors.lastname: Kallin
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Prince
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C504793:FRMD6 protein, human; C490895:GAB2 protein, human; D008565:Membrane Proteins