New Alzheimer’s disease locus on chromosome 8

• Published in: Journal of medical genetics Vol. 43; no. 12; pp. 931 - 935
• Main Authors: Giedraitis, V, Hedlund, M, Skoglund, L, Blom, E, Ingvast, S, Brundin, R, Lannfelt, L, Glaser, A
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01-12-2006; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Aged; Alzheimer Disease - genetics; Alzheimer's disease; amyloid precursor protein; APOE; apolipoprotein E; Apolipoproteins E - genetics; APP; Biological and medical sciences; Chromosomes; Chromosomes, Human, Pair 8 - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Mutational Analysis; Family Health; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetic Linkage - genetics; Genetic Predisposition to Disease - genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human - genetics; Genotype; Haplotypes - genetics; Humans; IDE; insulin degrading enzyme; LOD; Lod Score; logarithm of the odds; Male; Medical genetics; Medical sciences; MEDICIN; MEDICINE; Microsatellite Repeats; Middle Aged; Molecular and cellular biology; Mutation; Neurology; Pedigree; Polymorphism, Single-Stranded Conformational; presenilin 1; presenilin 2; PS1; PS2; Short Report; single-strand conformation polymorphism; SSCP; Studies; Sweden; Sweden; Human; Nervous system diseases; Alzheimer disease; Central nervous system disease; Chromosome 8; Genetics; Degenerative disease; Locus; Chromosome C8; Cerebral disorder
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2006.043000

Background: Family history is one of the most consistent risk factors for dementia. Therefore, analysis of families with a distinct inheritance pattern of disease can be a powerful approach for the identification of previously unknown disease genes. Objective: To map susceptibility regions for Alzheimer’s disease. Methods: A complete genome scan with 369 microsatellite markers was carried out in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least one member with age at onset of ⩽65 years. Mutations in known early-onset Alzheimer’s disease susceptibility genes have been excluded. All people were genotyped for APOE, but no clear linkage with the ε4 allele was observed. Results: Although no common disease locus could be found in all families, in two families an extended haplotype was identified on chromosome 8q shared by all affected members. In one of the families, a non-parametric multimarker logarithm of the odds (LOD) score of 4.2 (p = 0.004) was obtained and analysis based on a dominant model showed a parametric LOD score of 2.4 for this region. All six affected members of this family shared a haplotype of 10 markers spanning about 40 cM. Three affected members in another family also shared a haplotype in the same region. Conclusion: On the basis of our data, we propose the existence of a dominantly acting Alzheimer’s disease susceptibility locus on chromosome 8.