Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample.
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.
Rademakers
Rosa
R
Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium.
Cruts
Marc
M
Sleegers
Kristel
K
Dermaut
Bart
B
Theuns
Jessie
J
Aulchenko
Yurii
Y
Weckx
Stefan
S
De Pooter
Tim
T
Van den Broeck
Marleen
M
Corsmit
Ellen
E
De Rijk
Peter
P
Del-Favero
Jurgen
J
van Swieten
John
J
van Duijn
Cornelia M
CM
Van Broeckhoven
Christine
C
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