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.
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