title: Covariate analysis of late-onset Alzheimer disease refines the chromosome 12 locus.
abstract: Alzheimer disease (AD) is a progressive neurodegenerative disorder of later life with a complex etiology and a strong genetic component. Several genomic screens have suggested that a region between chromosome 12p13 and 12q22 contains at least one additional locus underlying the susceptibility of AD. However, localization of this locus has been difficult. We performed a 5 cM microsatellite marker screen across 74 cM on chromosome 12 with 15 markers in 585 multiplex families consisting of 994 affected sibpairs and 213 other affected relative pairs. Analyses across the entire data set did not reveal significant evidence of linkage. However, suggestive linkage was observed in several subsets. In the 91 families where no affected individuals carry an ApoE varepsilon4 allele, an HLOD score of 1.55 was generated at D12S1042. We further examined the linkage data considering the proposed linkages to chromosome 9 (D9S741) and chromosome 10 (alpha-catenin gene). There was a modest (P=0.20) increase in the LOD score for D12S368 (MLOD=1.70) when using the D9S741 LOD scores as a covariate and a highly significant (P<0.001) increase in the MLOD score (4.19) for D12S1701 in autopsy-confirmed families (n=228) when using alpha-catenin LOD scores as a covariate. In both cases, families with no evidence of linkage to D9S741 or alpha-catenin demonstrated most of the evidence of linkage to chromosome 12, suggesting locus heterogeneity. Taken together, our data suggest that the 16 cM region between D12S1042 and D12S368 should be the subject of further detailed genomic efforts for the disease.
authors.affiliation: Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: X
authors.initials: X
authors.lastname: Liang
authors.forename: N
authors.initials: N
authors.lastname: Schnetz-Boutaud
authors.forename: S J
authors.initials: SJ
authors.lastname: Kenealy
authors.forename: L
authors.initials: L
authors.lastname: Jiang
authors.forename: J
authors.initials: J
authors.lastname: Bartlett
authors.forename: B
authors.initials: B
authors.lastname: Lynch
authors.forename: P C
authors.initials: PC
authors.lastname: Gaskell
authors.forename: H
authors.initials: H
authors.lastname: Gwirtsman
authors.forename: L
authors.initials: L
authors.lastname: McFarland
authors.forename: M L
authors.initials: ML
authors.lastname: Bembe
authors.forename: P
authors.initials: P
authors.lastname: Bronson
authors.forename: J R
authors.initials: JR
authors.lastname: Gilbert
authors.forename: E R
authors.initials: ER
authors.lastname: Martin
authors.forename: M A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: J L
authors.initials: JL
authors.lastname: Haines
mesh_terms: D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics*; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D002881:Chromosomes, Human, Pair 12; D002899:Chromosomes, Human, Pair 9; D005190:Family; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008126:Lod Score; D008297:Male; D035781:Siblings
chemical_list: D005819:Genetic Markers