TY - JOUR
T1 - Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample
AU - Rademakers, Rosa
AU - Cruts, Marc
AU - Sleegers, Kristel
AU - Dermaut, Bart
AU - Theuns, Jessie
AU - Aulchenko, Yurii
AU - Weckx, Stefan
AU - De Pooter, Tim
AU - Van Den Broeck, Marleen
AU - Corsmit, Ellen
AU - De Rijk, Peter
AU - Del-Favero, Jurgen
AU - Van Swieten, John
AU - Van Duijn, Cornelia M.
AU - Van Broeckhoven, Christine
N1 - Funding Information:
We are grateful to the family members for their cooperation in this study. We also acknowledge Gerwin Roks and Hilda Kornman, for their contributions to the genealogy and ascertainment of family 1270; Sebastiaan Engelborghs, for expert second opinion on the clinical diagnoses; and the Flanders Interuniversity Institute for Biotechnology (VIB8) Genetic Service Facility, for genetic analyses. The research was funded by the Special Research Fund of the University of Antwerp; the Fund for Scientific Research Flanders (FWO-F); Interuniversity Attraction Poles program P5/19 of the Belgian Science Policy Office; the International Alzheimer Research Foundation, Belgium; EU contract LSHM-CT-2003-503330 (APOPIS); and the Netherlands Organization for Scientific Research. R.R., M.C., and J.T. are postdoctoral fellows of the FWO-F.
PY - 2005/10
Y1 - 2005/10
N2 - 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.
AB - 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.
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U2 - 10.1086/491749
DO - 10.1086/491749
M3 - Article
C2 - 16175510
AN - SCOPUS:25444507964
SN - 0002-9297
VL - 77
SP - 643
EP - 652
JO - American journal of human genetics
JF - American journal of human genetics
IS - 4
ER -