Genetic variation in a haplotype block spanning IDE influences Alzheimer disease

• Published in: Human mutation 2003-11, Vol.22 (5), p.363-371
• Main Authors: Prince, Jonathan A., Feuk, Lars, Gu, Harvest F., Johansson, Boo, Gatz, Margaret, Blennow, Kaj, Brookes, Anthony J.
• Format: Article
• Language: English
• Subjects: Aged; Alzheimer; Alzheimer Disease - diagnosis; Alzheimer Disease - genetics; Alzheimer, AD; APOE gene; association; Case-Control Studies; chromosome 10; g-secretase; haplotype; haplotype, SNP; Haplotypes; HHEX; Humans; IDE; Insulysin - genetics; KNSL1; Linkage Disequilibrium; MAPT; Medicin och hälsovetenskap; Middle Aged; Polymorphism, Single Nucleotide; Quantitative Trait Loci; SNP
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.10282

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