No Association between CALHM1 and Alzheimer's Disease Risk

In a recent paper in Cell, Dreses-Wer-ringloer et al. (2008) reported the identification and functional characterization of a new Alzheimer's disease (AD) gene, CALHM1, encoding calcium homeostasis modulator 1. CALHM1 (formerly annotated as FAM26C) represents a compelling candidate gene for late-onset AD as it is located on chromosome 10q24, a consistently replicated AD linkage region (Bertram et al., 2007), is highly expressed in the hippocampus, which is severely affected by AD-related pathology, and is involved in calcium ion homeostasis, which may be disrupted in AD. In view of these converging leads, Dreses-Werrin-gloer et al. (2008) sequenced the open reading frame of CALHM1 in a small sample of AD patients and healthy controls and identified a nonsynonymous poly-morphism (Pro86Leu, rs2986017) whose minor leucine allele showed a higher frequency in the AD patients. Followup analyses in four additional independent samples of ~3400 DNAs revealed a consistent overrepresentation of the same allele in AD cases compared to controls in each dataset. From the combined analyses the authors estimated that inheritance of the leucine allele modestly, but significantly , elevated the risk for AD by ~40% (p value = 2 × 10 −10). Their genetics findings were supported by data generated in a large number of functional genomics and biochemical experiments showing evidence that the risk-associated leucine allele leads to a loss of protein function, including attenuated permeability to calcium ions and reduced cytosolic calcium ion levels, which, in turn, were associated with an increase in the pathogenic pep-tide, amyloid-β (Aβ). Here, we present an independent assessment of the potential association between AD and the Pro-86Leu single-nucleotide polymorphism (SNP) in CALHM1 in more than 8100 subjects from several independent data-sets comprised of AD families—including those in which the original chromosome 10q24 linkage signal was identified (Ber-tram et al., 2000)—as well as unrelated cases and controls, and we find no evidence of a genetic association in these samples. The family-based datasets (CAG, NIA, NIMH, NCRAD) tested in this project are of self-reported European (Caucasian) ancestry collected in the US for the study of genetic factors in AD (see Table S1, available online, for a summary of sample characteristics). All samples were primarily sibships and lacked parental genotypes. With the exception of the CAG sample, the majority of pedigrees analyzed here were nuclear families ascertained on the basis of multiple affected individuals. In addition to containing at least one affected relative pair, many pedigrees also had …