title: Extended kindred with recessive late-onset Alzheimer disease maps to locus 8p22-p21.2: a genome-wide linkage analysis.
abstract: Late-onset Alzheimer disease (LOAD) is a complex genetic disorder. Although genes involved in early-onset forms were discovered more than a decade ago, LOAD research has only been able to point out small effect loci, with the exception of APOE. We mapped the gene predisposing to LOAD in an extended inbred family coming from a genetically isolated region (24 sampled individuals, 12 of whom are affected), completing a genome-wide screen with an Affymetrix10 K single nucleotide polymorphism microarray. Genotyping results were evaluated under model-dependent (dominant and recessive) and model-free analysis. We obtained a maximum nonparametric linkage score of 3.24 (P=0.00006) on chromosome 8p22-p21.2. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) under a recessive model (HLOD=3.04). When we compared the results of the model-dependent analysis, a higher score was obtained in the recessive model (3.04) than in the dominant model (1.0). This is a new locus identified in LOAD, in chromosome 8p22-p21.2 and encompassing several candidate genes, among them CLU and PPP3CC that were excluded by sequencing. The finding of a recessive model of inheritance, consistent with the assumption of inbreeding as a morbidity factor in this population, supports the notion of a role of recessive genes in LOAD.
authors.affiliation: Fundacion Hospital Alcorcon, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Baron
authors.forename: Estrella
authors.initials: E
authors.lastname: Gomez-Tortosa
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Bochdanovits
authors.forename: Isabel
authors.initials: I
authors.lastname: Gobernado
authors.forename: Alberto
authors.initials: A
authors.lastname: Rabano
authors.forename: David G
authors.initials: DG
authors.lastname: Munoz
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: Adriano
authors.initials: A
authors.lastname: Jimenez-Escrig
mesh_terms: D017668:Age of Onset; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000235:genetics; D016678:Genome; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D001057:Apolipoproteins E