Parsing the genetic heterogeneity of chromosome 12q susceptibility genes for Alzheimer disease by family-based association analysis

• Published in: Neurogenetics Vol. 7; no. 3; pp. 157 - 165
• Main Authors: LIN, Ping-I, MARTIN, Eden R, BROWNING-LARGE, Carrie A, SCHMECHEL, Donald E, WELSH-BOHMER, Kathleen A, MURALI DORAISWAMY, P, GILBERT, John R, HAINES, Jonathan L, PERICAK-VANCE, Margaret A
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.07.2006; Springer Nature B.V
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Autopsies; Biological and medical sciences; Chromosomes; Chromosomes, Human, Pair 12; Comparative analysis; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; General aspects. Genetic counseling; Genes; Genetic Heterogeneity; Genetic Linkage; Genetic Predisposition to Disease; Genetic Testing; Haplotypes; Humans; Linkage Disequilibrium; Medical genetics; Medical sciences; Neurology; Polymorphism; Polymorphism, Single Nucleotide; Proteins; Nervous system diseases; Alzheimer disease; Family study; Association study; Chromosome C12; Genetic diversity; Genetic determinism; Cerebral disorder; Sensitivity; Association; Apolipoprotein E; Central nervous system disease; Predisposition; Molecular epidemiology; Family environment; SNPs; Genetics; Degenerative disease; Single nucleotide polymorphism; APOE; Haplotype
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-006-0047-z

Previous linkage studies have suggested that chromosome 12 may harbor susceptibility genes for late-onset Alzheimer disease (LOAD). No risk genes on chromosome 12 have been conclusively identified yet. We have reported that the linkage evidence for LOAD in a 12q region was significantly increased in autopsy-confirmed families particularly for those showing no linkage to alpha-T catenin gene, a LOAD candidate gene on chromosome 10 [LOD score increased from 0.1 in the autopsy-confirmed subset to 4.19 in the unlinked subset (optimal subset); p<0.0001 for the increase in LOD score], indicating a one-LOD support interval spanning 6 Mb. To further investigate this finding and to identify potential candidate LOAD risk genes for follow-up analysis, we analyzed 99 single nucleotide polymorphisms in this region, for the overall sample, the autopsy-confirmed subset, and the optimal subset, respectively, for comparison. We saw no significant association (p<0.01) in the overall sample. In the autopsy-confirmed subset, the best finding was obtained in the activation transcription factor 7 (ATF7) gene (single-locus association, p=0.002; haplotype association global, p=0.007). In the optimal subset, the best finding was obtained in the hypothetical protein FLJ20436 (FLJ20436) gene (single-locus association, p=0.0026). These results suggest that subset and covariate analyses may be one approach to help identify novel susceptibility genes on chromosome 12q for LOAD.