Susceptibility Locus for Alzheimer's Disease on Chromosome 10

Myers, Amanda; Holmans, Peter Alan; Marshall, Helen; Kwon, Jennifer M.; Meyer, David J.; Ramic, Dzanan; Shears, Shantia; Booth, Jeremy; DeVriéze, Fabienne Wavrant; Crook, Richard; Hamshere, Marian L.; Abraham, Richard; Tunstall, Nigel; Rice, Frances; Carty, Stephanie; Lillystone, Sara; Kehoe, Patrick Gavin; Rudrasingham, Varuni; Jones, Lesley; Lovestone, Simon; Pérez‐Tur, Jordi; Williams, Julie; Owen, Michael John; Hardy, John; Goate, Alison M.

doi:10.1126/science.290.5500.2304

Cited by 359 publications

(184 citation statements)

References 7 publications

Supporting

Mentioning

165

Contrasting

Unclassified

Order By: Relevance

“…Our results show no evidence of association between any of these markers and disease phenotype, neither in the sample as a whole nor in subsamples stratified by APOE e4-genotype or onset age. These negative findings are consistent with linkage analyses performed on the same sample 5 and also with other independent linkage studies, [6][7][8] suggesting that the putative chromosome 10 AD gene(s) is located considerably further distal (q-ter).…”

supporting

confidence: 90%

“…At least four linkage studies have implicated regions on chromosome 10 as likely to harbor an AD susceptibility gene [5][6][7][8] ; however, all reported linkage peaks map considerably distal to D10S1423 (440 cM). In an attempt to clarify these conflicting results, we have tested D10S1423 as well as two adjacent markers (D10S2325 and D10S1426) for association with AD in a large and well characterized sample of multiplex AD families using familybased methodologies.…”

mentioning

confidence: 99%

“…2 Finally, the fourth analysis, with the greatest number of cases, failed to replicate these findings altogether. 4 Of note, several research groups using varying samples and various methods of linkage and/or association analysis [5][6][7][8]11 have implicated chromosome 10 as harboring a novel AD locus. However, only one of these studies has reported a signal on the short arm of chromosome 10, 11 whereas all other reports localize the putative AD gene on chromosome 10 at least 40-90 Mb downstream towards the long arm.…”

mentioning

confidence: 99%

See 2 more Smart Citations

No association between marker D10S1423 and Alzheimer's disease

et al. 2003

View full text Add to dashboard Cite

supporting

confidence: 90%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

No association between marker D10S1423 and Alzheimer's disease

et al. 2003

View full text Add to dashboard Cite

“…Recently, four independent AD linkage studies have highlighted a broad region of chromosome 10q [Bertram et al, 2000;Ertekin-Taner et al, 2000;Myers et al, 2000;Li et al, 2002] within which one or more ADinfluencing genes potentially reside (see AD6; MIM# 605526). The linkage peaks from these different studies are not perfectly superimposed, and together cover a wide genomic domain of 460 Mb within which some 100 or more genes are located.…”

Section: Introductionmentioning

confidence: 99%

Genetic variation in a haplotype block spanningIDE influences Alzheimer disease

Prince

Feuk

et al. 2003

Hum. Mutat.

View full text Add to dashboard Cite

Communicated by Richard G. H. CottonLinkage studies have identified a large (460-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 b-protein (one of the major constituents of senile plaques) and the intracellular amyloid precursor protein (APP) domain released by c-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 o1 Â 10 À9 ) 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 e4 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.

show abstract

“…O) This evidence supports the possibility that Ap is pathogenetic. Genome scanning for AD disclosed a novel risk locus at the long arm of chromosome 10,11,12) which is enrolled as the AD6 locus in Online Mendelian Inheritance in Man (OMIM, http://www3.ncbi.nlm.nih.gov/omiml). This locus is also mapped by a genome screening for the ageat-onset of AD.'"…”

Section: Among Mutations Of the P Amyloid Protein Precursor (App)mentioning

confidence: 99%

Apolipoproteins and β Amyloid Transport Pathway

et al. 2002

View full text Add to dashboard Cite

Cholesterol metabolism has been viewed as an important step in the development of Alzheimer's disease, since it was shown that the ~4 allele of apolipoprotein E (APO€) gene is a genetic risk and modifies age-at-onset of Alzheimer's disease. Although the knowledge of the effect of cholesterol in the neuronal cell has been recently accumulated, the link between systemic and brain cholesterol metabolism remains to be elucidated. Lipoproteins in cerebrospinal fluid (CSF) are fractionated only to high-density lipoprotein (HDL), and contain apolipoprotein (apo) A-I, E, A-11, and J. Whereas apoE is produced in the brain, apoA-I and apoA-II in cerebrospinal fluid, the major components of plasma HDL cholesterol, originate from plasma. Plasma HDL is thought to act in reverse cholesterol transport, and in vitro experiments indicated that these apolipoproteins and albumin show a high affinity binding to p amyloid. In patients with Alzheimer's disease, plasma apoA-I and apoA-I1 levels are significantly decreased, which is possibly related to the deposition of p amyloid in the brain, and to the p amyloid transport pathway.

show abstract

Susceptibility Locus for Alzheimer's Disease on Chromosome 10

Cited by 359 publications

References 7 publications

No association between marker D10S1423 and Alzheimer's disease

No association between marker D10S1423 and Alzheimer's disease

Genetic variation in a haplotype block spanningIDE influences Alzheimer disease

Apolipoproteins and β Amyloid Transport Pathway

Contact Info

Product

Resources

About