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Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample

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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.3803OG -> 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.
Keywords
APOLIPOPROTEIN-E, PRECURSOR PROTEIN GENE, MISSENSE MUTATIONS, TYPE-4 ALLELE, DEMENTIA, ROTTERDAM, RISK, PRESENILIN-1, SUBSTITUTION, HISTORY

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Chicago
Rademakers, Rosa, Marc Cruts, Kristel Sleegers, Bart Dermaut, Jessie Theuns, Yurii Aulchenko, Stefan Weckx, et al. 2005. “Linkage and Association Studies Identify a Novel Locus for Alzheimer Disease at 7q36 in a Dutch Population-based Sample.” American Journal of Human Genetics 77 (4): 643–652.
APA
Rademakers, Rosa, Cruts, M., Sleegers, K., Dermaut, B., Theuns, J., Aulchenko, Y., Weckx, S., et al. (2005). Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample. AMERICAN JOURNAL OF HUMAN GENETICS, 77(4), 643–652.
Vancouver
1.
Rademakers R, Cruts M, Sleegers K, Dermaut B, Theuns J, Aulchenko Y, et al. Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample. AMERICAN JOURNAL OF HUMAN GENETICS. 2005;77(4):643–52.
MLA
Rademakers, Rosa, Marc Cruts, Kristel Sleegers, et al. “Linkage and Association Studies Identify a Novel Locus for Alzheimer Disease at 7q36 in a Dutch Population-based Sample.” AMERICAN JOURNAL OF HUMAN GENETICS 77.4 (2005): 643–652. Print.
@article{3200577,
  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.3803OG -> 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.},
  author       = {Rademakers, Rosa and Cruts, Marc and Sleegers, Kristel and Dermaut, Bart and Theuns, Jessie and Aulchenko, Yurii and Weckx, Stefan and De Pooter, Tim and Van den Broeck, Marleen and Corsmit, Ellen and De Rijk, Peter and Del-Favero, Jurgen and van Swieten, John and van Duijn, Cornelia M and Van Broeckhoven, Christine},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keywords     = {APOLIPOPROTEIN-E,PRECURSOR PROTEIN GENE,MISSENSE MUTATIONS,TYPE-4 ALLELE,DEMENTIA,ROTTERDAM,RISK,PRESENILIN-1,SUBSTITUTION,HISTORY},
  language     = {eng},
  number       = {4},
  pages        = {643--652},
  title        = {Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample},
  url          = {http://dx.doi.org/10.1086/491749},
  volume       = {77},
  year         = {2005},
}

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