title: Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample.
abstract: We obtained conclusive linkage of Alzheimer disease (AD) with a candidate region of 19.7 cM at 7q36 in an extended multiplex family, family 1270, ascertained in a population-based study of early-onset AD in the northern Netherlands. Single-nucleotide polymorphism and haplotype association analyses of a Dutch patient-control sample further supported the linkage at 7q36. In addition, we identified a shared haplotype at 7q36 between family 1270 and three of six multiplex AD-affected families from the same geographical region, which is indicative of a founder effect and defines a priority region of 9.3 cM. Mutation analysis of coding exons of 29 candidate genes identified one linked synonymous mutation, g.38030G-->C in exon 10, that affected codon 626 of the PAX transactivation domain interacting protein gene (PAXIP1). It remains to be determined whether PAXIP1 has a functional role in the expression of AD in family 1270 or whether another mutation at this locus explains the observed linkage and sharing. Together, our linkage data from the informative family 1270 and the association data in the population-based early-onset AD patient-control sample strongly support the identification of a novel AD locus at 7q36 and re-emphasize the genetic heterogeneity of AD.
authors.affiliation: Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.forename: Bart
authors.initials: B
authors.lastname: Dermaut
authors.forename: Jessie
authors.initials: J
authors.lastname: Theuns
authors.forename: Yurii
authors.initials: Y
authors.lastname: Aulchenko
authors.forename: Stefan
authors.initials: S
authors.lastname: Weckx
authors.forename: Tim
authors.initials: T
authors.lastname: De Pooter
authors.forename: Marleen
authors.initials: M
authors.lastname: Van den Broeck
authors.forename: Ellen
authors.initials: E
authors.lastname: Corsmit
authors.forename: Peter
authors.initials: P
authors.lastname: De Rijk
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
authors.forename: John
authors.initials: J
authors.lastname: van Swieten
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7; D005260:Female; D008040:Genetic Linkage; D005828:Genetics, Population; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide