Further examination of the candidate genes in chromosome 12p13 locus for late-onset Alzheimer disease.
A broad region on chromosome 12p13 has been intensely investigated for novel genetic variants associated with Alzheimer disease (AD). We examined this region with 23 microsatellite markers using 124 North European (NE) families and 209 Caribbean Hispanic families with late-onset AD (FAD). Significant evidence for linkage was present in a 5-cM interval near 20 cM in both the NE FAD (LOD = 3.5) and the Caribbean Hispanic FAD (LOD = 2.2) datasets. We further investigated these families and an independent NE case-control dataset using 14 single nucleotide polymorphisms (SNPs). The initial screening of the region at approximately 20 cM in the NE case-control dataset revealed significant association between AD and seven SNPs in several genes, with the strongest result for rs2532500 in TAPBPL (p = 0.006). For rs3741916 in GAPDH, the C allele, rather than the G allele as was observed by Li et al. (Proc Natl Acad Sci U S A 101(44):15688-15693, 2004), was the risk allele. When the two family datasets were examined, none of the SNPs were significant in NE families, but two SNPs were associated with AD in Caribbean Hispanics: rs740850 in NCAPD2 (p = 0.0097) and rs1060620 in GAPDH (p = 0.042). In a separate analysis combining the Caribbean Hispanic families and NE cases and controls, rs740850 was significant after correcting for multiple testing (empirical p = 0.0048). Subsequent haplotype analyses revealed that two haplotype sets-haplotype C-A at SNPs 6-7 within NCAPD2 in Caribbean Hispanics, and haplotypes containing C-A-T at SNPs 8-10 within GAPDH in Caribbean Hispanic family and NE case-control datasets-were associated with AD. Taken together, these SNPs may be in linkage disequilibrium with a pathogenic variant(s) on or near NCAPD2 and GAPDH.
Lee
Joseph H
JH
Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.
Cheng
Rong
R
Rogaeva
Ekaterina
E
Meng
Yan
Y
Stern
Yaakov
Y
Santana
Vincent
V
Lantigua
Rafael
R
Medrano
Martin
M
Jimenez-Velazquez
Ivonne Z
IZ
Farrer
Lindsay A
LA
St George-Hyslop
Peter
P
Mayeux
Richard
R
D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D017691:Caribbean Region; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D030541:Databases, Genetic; D005060:Europe; D005260:Female; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide