title: Linkage analysis for plasma amyloid beta levels in persons with hypertension implicates Aβ-40 levels to presenilin 2.
abstract: Plasma concentrations of Aβ40 and Aβ42 rise with age and are increased in people with mutations that cause early-onset Alzheimer's disease (AD). Amyloid beta (Aβ) plasma levels were successfully used as an (endo)phenotype for gene discovery using a linkage approach in families with dominant forms of disease. Here, we searched for loci involved in Aβ plasma levels in a series of non-demented patients with hypertension in the Erasmus Rucphen Family study. Aβ40 and Aβ42 levels were determined in 125 subjects with severe hypertension. All patients were genotyped with a 6,000 single nucleotide polymorphisms (SNPs) illumina array designed for linkage analysis. We conducted linkage analysis of plasma Aβ levels. None of the linkage analyses yielded genome-wide significant logarithm of odds (LOD) score over 3.3, but there was suggestive evidence for linkage (LOD > 1.9) for two regions: 1q41 (LOD = 2.07) and 11q14.3 (LOD = 2.97), both for Aβ40. These regions were followed up with association analysis in the study subjects and in 320 subjects from a population-based cohort. For the Aβ40 region on chromosome 1, association of several SNPs was observed at the presenilin 2 gene (PSEN2) (p = 2.58 × 10(-4) for rs6703170). On chromosome 11q14-21, we found some association (p = 3.1 × 10(-3) for rs2514299). This linkage study of plasma concentrations of Aβ40 and Aβ42 yielded two suggestive regions, of which one points toward a known locus for familial AD.
authors.affiliation: Department of Neurology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. c.ibrahim-verbaas@erasmusmc.nl
authors.forename: Carla A
authors.initials: CA
authors.lastname: Ibrahim-Verbaas
authors.forename: Irina V
authors.initials: IV
authors.lastname: Zorkoltseva
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.forename: Maaike
authors.initials: M
authors.lastname: Schuur
authors.forename: Antonia M W
authors.initials: AM
authors.lastname: Coppus
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.forename: Monique M B
authors.initials: MM
authors.lastname: Breteler
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.forename: Tatiana I
authors.initials: TI
authors.lastname: Axenovich
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Verbeek
authors.forename: John C
authors.initials: JC
authors.lastname: van Swieten
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000097:blood* / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000097:blood* / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010446:Peptide Fragments / Q000097:blood* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053766:Presenilin-2 / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053766:Presenilin-2; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)