Evidence of linkage and association on chromosome 20 for late-onset Alzheimer disease

Neurogenetics - Tập 5 - Trang 121-128 - 2004
Katrina A. B. Goddard1,2, Jane M. Olson1, Haydeh Payami3,4, Monique van der Voet5, Helena Kuivaniemi5,6, Gerard Tromp5
1Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, USA
2Department of Epidemiology and Biostatistics, Wolstein Research Building, Cleveland, USA
3Department of Neurology, Oregon Health Sciences University, Portland, USA
4Division of Genetic Disorders, Wadsworth Center, Albany, USA
5Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, USA
6Department of Surgery, Wayne State University School of Medicine, Detroit, USA

Tóm tắt

Recently, we reported evidence of linkage on chromosome 20 for Alzheimer disease (AD) using a novel statistical approach to incorporate covariates (e.g., age, ApoE genotype) into the analysis. These results suggest that very elderly subjects (>85 years), and individuals who carry an ε2 allele at the ApoE locus are more likely to be linked to this candidate region. The region on chromosome 20 includes a strong candidate gene, cystatin C (CST3), which has previously been associated with AD in case-control studies. We investigated these findings further by genotyping additional markers to narrow the candidate region, and to identify evidence of linkage disequilibrium as additional support for a susceptibility locus on chromosome 20. We selected 43 elderly sibships (89 subjects) from the NIMH AD Genetics Initiative based on current age older than 84 years, and identified 129 unrelated control subjects who were older than 84 years from the Oregon Brain Aging Study to conduct linkage and association studies in this region. Fourteen additional markers were evaluated, including 4 markers located within or near CST3. We narrowed the candidate region on chromosome 20 to an 11.8-cM region between markers D20S174 and D20S471, which includes the CST3 candidate gene. In addition, we observed evidence of association for markers located near the CST3 candidate gene, with P values between 0.002 and 0.08 for two-locus haplotypes. These results support the presence of a susceptibility locus for AD in the vicinity of CST3 for very elderly subjects with AD.

Tài liệu tham khảo

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