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Genetic variation in a haplotype block spanning IDE influences Alzheimer disease†

  1. Jonathan A. Prince1,
  2. Lars Feuk1,
  3. Harvest F. Gu1,
  4. Boo Johansson2,
  5. Margaret Gatz3,
  6. Kaj Blennow4,
  7. Anthony J. Brookes1,*

Article first published online: 24 SEP 2003

DOI: 10.1002/humu.10282

Issue

Human Mutation

Human Mutation

Volume 22, Issue 5, pages 363–371, November 2003

Additional Information

How to Cite

Prince, J. A., Feuk, L., Gu, H. F., Johansson, B., Gatz, M., Blennow, K. and Brookes, A. J. (2003), Genetic variation in a haplotype block spanning IDE influences Alzheimer disease. Human Mutation, 22: 363–371. doi: 10.1002/humu.10282

Author Information

  1. 1

    Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden

  2. 2

    Department of Psychology, University of Göteborg, Göteborg, Sweden

  3. 3

    Department of Psychology, University of Southern California, Los Angeles, California

  4. 4

    Department of Clinical Neuroscience and Transfusion Medicine, University of Göteborg, Sahlgren's University Hospital, Göteborg, Sweden

*Center for Genomics and Bioinformatics, Karolinska Institute, Berzelius väg 35, S-171 77 Stockholm, Sweden

  1. †

    Communicated by Richard G. H. Cotton

Publication History

  1. Issue published online: 25 SEP 2003
  2. Article first published online: 24 SEP 2003
  3. Manuscript Accepted: 29 AUG 2003
  4. Manuscript Received: 11 AUG 2003

Funded by

  • Pharmacia Corporation
  • Swedish Medical Research Council
  • Swedish Foundation for Strategic Research
  • Knut and Alice Wallenberg Foundation
  • AMF Jubileum Fund
  • Tore Nilsons Foundation
  • Loo and Hans Ostermans Foundation
  • Swedish Old Servants Foundation (Gamla Tjänarinnor)
  • Captain Arthur Erikssons Foundation
  • Åke Wibergs Foundation
  • Torsten and Ragnar Söderbergs Foundation
  • Fredrik and Ingrid Thurings Foundation
  • Swedish Alzheimer Foundation (Alzheimerfonden)
  • NIA. Grant Numbers: R01-AG08724, AG08861

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Keywords:

  • Alzheimer, AD;
  • linkage disequilibrium;
  • association;
  • IDE;
  • haplotype, SNP;
  • KNSL1;
  • HHEX;
  • MAPT

Abstract

Linkage studies have identified a large (>60-Mb) region on chromosome 10q that segregates with Alzheimer Disease (AD). Within the region, the gene for insulin degrading enzyme (IDE) represents a notable biological candidate given that it degrades amyloid β-protein (one of the major constituents of senile plaques) and the intracellular amyloid precursor protein (APP) domain released by γ-secretase processing. We have used a single nucleotide polymorphism (SNP) genetic association strategy to investigate AD in relation to a 480-kb region encompassing IDE. A 276-kb linkage disequilibrium block was revealed that spans three genes (IDE, KNSL1, and HHEX). Assessing this block in several independent sets of case-control materials (early- and late-onset AD) and focusing also upon quantitative measures that are pertinent to AD diagnosis and severity (MMSE scores, microtubule-associated protein Tau [MAPT] levels in CSF, degree of brain pathology, and age-at-onset) produced extensive evidence for significant AD association. Signals (p-values ranging from 0.05 to <1×10−9) were generally stronger when examining haplotypes rather than individual SNPs, and quantitative trait tests most uniformly revealed the detected associations. Consistent risk alleles and haplotypes were apparent across the study, with effects in some cases as large as that of the ϵ4 allele of APOE. A subsequent mutation screen of exons in all three suspect genes provided no evidence for common causative mutations. These results provide substantial evidence that genetic variation within or extremely close to IDE impacts both disease risk and traits related to the severity of AD. Hum Mutat 22:363–371, 2003. © 2003 Wiley-Liss, Inc.

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