Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease

Richard Abraham, Amanda J Myers, Fabienne Wavrant-DeVrieze, Marian L. Hamshere, Hollie V. Thomas, Helen Marshall, Danielle Compton, Gillian Spurlock, Dragana Turic, Bastiaan Hoogendoorn, Jennifer M. Kwon, Ronald C. Petersen, Eric Tangalos, Joanne Norton, John C. Morris, Roger Bullock, Danae Liolitsa, Simon Lovestone, John Hardy, Alison GoateMichael O'Donovan, Julie Williams, Michael J. Owen, Lesley Jones

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including β-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5′-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5′ flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK (P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.

Original languageEnglish
Pages (from-to)646-652
Number of pages7
JournalHuman Genetics
Volume109
Issue number6
DOIs
StatePublished - Dec 1 2001
Externally publishedYes

Fingerprint

Insulysin
Linkage Disequilibrium
Single Nucleotide Polymorphism
Alzheimer Disease
5' Flanking Region
Haplotypes
Untranslated Regions
Chromosomes, Human, Pair 10
Metalloproteases
Amyloid
Gene Frequency
Amino Acid Sequence
Exons
High Pressure Liquid Chromatography
Peptides
Population
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease. / Abraham, Richard; Myers, Amanda J; Wavrant-DeVrieze, Fabienne; Hamshere, Marian L.; Thomas, Hollie V.; Marshall, Helen; Compton, Danielle; Spurlock, Gillian; Turic, Dragana; Hoogendoorn, Bastiaan; Kwon, Jennifer M.; Petersen, Ronald C.; Tangalos, Eric; Norton, Joanne; Morris, John C.; Bullock, Roger; Liolitsa, Danae; Lovestone, Simon; Hardy, John; Goate, Alison; O'Donovan, Michael; Williams, Julie; Owen, Michael J.; Jones, Lesley.

In: Human Genetics, Vol. 109, No. 6, 01.12.2001, p. 646-652.

Research output: Contribution to journalArticle

Abraham, R, Myers, AJ, Wavrant-DeVrieze, F, Hamshere, ML, Thomas, HV, Marshall, H, Compton, D, Spurlock, G, Turic, D, Hoogendoorn, B, Kwon, JM, Petersen, RC, Tangalos, E, Norton, J, Morris, JC, Bullock, R, Liolitsa, D, Lovestone, S, Hardy, J, Goate, A, O'Donovan, M, Williams, J, Owen, MJ & Jones, L 2001, 'Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease', Human Genetics, vol. 109, no. 6, pp. 646-652. https://doi.org/10.1007/s00439-001-0614-1
Abraham, Richard ; Myers, Amanda J ; Wavrant-DeVrieze, Fabienne ; Hamshere, Marian L. ; Thomas, Hollie V. ; Marshall, Helen ; Compton, Danielle ; Spurlock, Gillian ; Turic, Dragana ; Hoogendoorn, Bastiaan ; Kwon, Jennifer M. ; Petersen, Ronald C. ; Tangalos, Eric ; Norton, Joanne ; Morris, John C. ; Bullock, Roger ; Liolitsa, Danae ; Lovestone, Simon ; Hardy, John ; Goate, Alison ; O'Donovan, Michael ; Williams, Julie ; Owen, Michael J. ; Jones, Lesley. / Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease. In: Human Genetics. 2001 ; Vol. 109, No. 6. pp. 646-652.
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T1 - Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease

AU - Abraham, Richard

AU - Myers, Amanda J

AU - Wavrant-DeVrieze, Fabienne

AU - Hamshere, Marian L.

AU - Thomas, Hollie V.

AU - Marshall, Helen

AU - Compton, Danielle

AU - Spurlock, Gillian

AU - Turic, Dragana

AU - Hoogendoorn, Bastiaan

AU - Kwon, Jennifer M.

AU - Petersen, Ronald C.

AU - Tangalos, Eric

AU - Norton, Joanne

AU - Morris, John C.

AU - Bullock, Roger

AU - Liolitsa, Danae

AU - Lovestone, Simon

AU - Hardy, John

AU - Goate, Alison

AU - O'Donovan, Michael

AU - Williams, Julie

AU - Owen, Michael J.

AU - Jones, Lesley

PY - 2001/12/1

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N2 - Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including β-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5′-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5′ flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK (P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.

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