Search

Background Despite the high heritability of alcohol dependence ( AD), the genes found to be associated with it account for only a small proportion of its total variability. The goal of this study was to identify and analyze phenotypes based on homogeneous classes of individuals to increase the power to detect genetic risk factors contributing to the risk of AD. Methods The 7 individual DSM- IV criteria for AD were analyzed using latent class analysis ( LCA) to identify classes defined by the pattern of endorsement of the criteria. A genome-wide association study was performed in 118 extended European American families ( n = 2,322 individuals) densely affected with AD to identify genes associated with AD, with each of the 7 DSM- IV criteria, and with the probability of belonging to 2 of 3 latent classes. Results Heritability for DSM- IV AD was 61% and ranged from 17 to 60% for the other phenotypes. A single nucleotide polymorphism (SNP) in the olfactory receptor OR51L1 was significantly associated (7.3 × 10−8) with the DSM- IV criterion of persistent desire to, or inability to, cut down on drinking. LCA revealed a 3-class model: the 'low-risk' class (50%) rarely endorsed any criteria and none met criteria for AD; the 'moderate-risk' class (33%) endorsed primarily 4 DSM- IV criteria and 48% met criteria for AD; and the 'high-risk' class (17%) manifested high endorsement probabilities for most criteria and nearly all (99%) met criteria for AD. One SNP in a sodium leak channel NALCN demonstrated genome-wide significance with the high-risk class ( p = 4.1 × 10−8). Analyses in an independent sample did not replicate these associations. Conclusions We explored the genetic contribution to several phenotypes derived from the DSM- IV AD criteria. The strongest evidence of association was with SNPs in NALCN and OR51L1. [ABSTRACT FROM AUTHOR]

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.