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Evidence for Genetic Linkage of Alzheimer's Disease to Chromosome 10q

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Science  22 Dec 2000:
Vol. 290, Issue 5500, pp. 2302-2303
DOI: 10.1126/science.290.5500.2302

Abstract

Recent studies suggest that insulin-degrading enzyme (IDE) in neurons and microglia degrades Aβ, the principal component of β-amyloid and one of the neuropathological hallmarks of Alzheimer's disease (AD). We performed parametric and nonparametric linkage analyses of seven genetic markers on chromosome 10q, six of which map near the IDE gene, in 435 multiplex AD families. These analyses revealed significant evidence of linkage for adjacent markers (D10S1671, D10S583, D10S1710, and D10S566), which was most pronounced in late-onset families. Furthermore, we found evidence for allele-specific association between the putative disease locus and marker D10S583, which has recently been located within 195 kilobases of the IDE gene.

The deposition and aggregation of β-amyloid (Aβ) in various regions of the brain is one of the key neuropathological hallmarks of AD. Consequently, agents that can inhibit and/or reverse these processes are attractive candidate genes for AD. Recent data suggest a principal role for IDE in the degradation and clearance of Aβ secreted by microglial cells and neurons (1). We performed genetic linkage analyses with six genetic markers close to the presumed location of the IDE gene on chromosome 10q23-q25 in 1426 subjects from 435 multiplex AD families (2, 3). In addition, we genotyped marker D10S1225, which is located 32 to 47 cM proximal to this region and lies closest to a linkage peak identified in a recent whole-genome screen (4, 5) using an overlapping set of families. To test for genetic linkage, we performed parametric [FASTLINK (6, 7)] and nonparametric [GENEHUNTER-PLUS (8) and ASM (9,10)] analyses in the sample as a whole and in subsets stratified by onset age and APOE genotype (11).

Under a dominant model, we found significant evidence for linkage around marker D10S583 (Z max = 3.3) (Table 1) in the full sample and for D10S1671 in the late-onset sample (Z max = 3.4). Results were similar under a recessive model, with a maximum lod score (logarithm of the odds ratio for linkage) of 3.8 for marker D10S1671 in the late-onset sample [Web table 1 (12)]. Although linkage was generally more pronounced in families without the APOE ɛ4/4 genotype, none of the markers had lod scores >3 in this stratum [Web table 2 (12)]. Two-point nonparametric linkage results were consistent with parametric findings, yielding the strongest signals for markers D10S1671, D10S583, and D10S1710 in late-onset families [Web table 3 (12)]. Finally, multipoint nonparametric analyses (13) generated maximum Z scores for the likelihood ratio (Z lr) of 1.9 (P= 0.029, full sample), 2.1 (P = 0.02, late-onset), and 2.15 (P = 0.016, APOE ɛ4/4-negative) at marker D10S1710, which lies between the two markers with the strongest two-point signals [Web table 4 (12)].

Table 1

Autosomal-dominant model, maximum two-point parametric lod scores (Z max), and recombination fractions (θ). Families were considered “late-onset” if all sampled affected individuals had onset ages ≥65 years. Marker locations are in Kosambi cM according to the Marshfield map. Values in bold indicate significant linkage.

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None of the analyses yielded significant findings for marker D10S1225, located ∼40 cM proximal to the linkage peak reported here, in contrast to previous reports in an overlapping sample of National Institute of Mental Health (NIMH) families (4,5). In an effort to understand this difference, we divided our sample into two groups according to whether or not all sampled affected individuals were included in the previous reports (14). Although the distal linkage peak was more pronounced in families included in the previous studies (n = 188), the linkage signal at marker D10S1225 did not increase [Web table 5 (12)]. These discrepancies could be due to a number of factors, including sampling issues [sibling pairs (4, 5) versus full families used here], inclusion criteria (diagnostic and age-of-onset cutoffs), stratification procedures, and analytic methods.

During the course of our investigation, public sequence data became available showing that marker D10S583 and IDE are located on the same ∼195-kb bacterial artificial chromosome (15), leading us to test this marker for allelic association with the disease. As determined with the Family-Based Association Test program (FBAT) (16, 17), the multiallelic test on all 11 alleles was not significant (P = 0.15), but the diallelic test revealed significant association of the 211–base pair allele with AD (nominal P = 0.004, Bonferroni correctedP = 0.04). These preliminary findings suggest that there may be linkage disequilibrium between D10S583 and the putative AD locus on chromosome 10q.

Overall, the findings reported here indicate an AD gene on the long arm of chromosome 10. It remains unclear whether the peak reported here between D10S583 (115 cM) and D10S1671 (127 cM) and the more proximal peak at D10S1225 (81 cM) reported previously (4,5) represent linkage to one or two underlying loci. Recent reports have suggested that chance variation of the location estimates obtained from linkage studies in complex diseases can cover as much as 20 to 30 cM or more, even in relatively large samples (18,19). The identification of the putative AD gene(s) on chromosome 10q will require more detailed studies of linkage disequilibrium to narrow the region of interest as well as a thorough assessment of candidate genes.

  • * To whom correspondence should be addressed at Genetics and Aging Unit, Massachusetts General Hospital–East, 149 13th Street, Charlestown, MA 02129, USA. E-mail: tanzi{at}helix.mgh.harvard.edu

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