TY - JOUR
T1 - Genetic association of CTNNA3 with late-onset Alzheimer's disease in females
AU - Miyashita, Akinori
AU - Arai, Hiroyuki
AU - Asada, Takashi
AU - Imagawa, Masaki
AU - Matsubara, Etsuro
AU - Shoji, Mikio
AU - Higuchi, Susumu
AU - Urakami, Katsuya
AU - Kakita, Akiyoshi
AU - Takahashi, Hitoshi
AU - Toyabe, Shinichi
AU - Akazawa, Kohei
AU - Kanazawa, Ichiro
AU - Ihara, Yasuo
AU - Kuwano, Ryozo
N1 - Funding Information:
This study was supported by KAKENHI (Grant-in-Aid for Scientific Research) on Priority Areas, Comprehensive Genomics (R.K.), and a Grant-in-Aid for Scientific Research on Priority Areas (C), Advanced Brain Science Project (Y.I.), from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and a Grant for the Promotion of Niigata University Research Projects, Japan (A.M.).
PY - 2007/12/1
Y1 - 2007/12/1
N2 - Alzheimer's disease (AD), the most common form of dementia in the elderly, was found to exhibit a trend toward a higher risk in females than in males through epidemiological studies. Therefore, we hypothesized that gender-related genetic risks could exist. To reveal the ones for late-onset AD (LOAD), we extended our previous genetic work on chromosome 10q (genomic region, 60-107 Mb), and single nucleotide polymorphism (SNP)-based genetic association analyses were performed on the same chromosomal region, where the existence of genetic risk factors for plasma Aβ42 elevation in LOAD was implied on a linkage analysis. Two-step screening of 1140 SNPs was carried out using a total of 1408 subjects with the APOE-ε3* 3 genotype: we first genotyped an exploratory sample set (LOAD, 363; control, 337), and then genotyped some associated SNPs in a validation sample set (LOAD, 336; control, 372). Seven SNPs, spanning about 38 kb, in intron 9 of CTNNA3 were found to show multiple-hit association with LOAD in females, and exhibited more significant association on Mantel-Haenszel test (allelic P-valuesMH-F = 0.000005945-0.0007658). Multiple logistic regression analysis of a total of 2762 subjects (LOAD, 1313; controls, 1449) demonstrated that one of the seven SNPs directly interacted with the female gender, but not with the male gender. Furthermore, we found that this SNP exhibited no interaction with the APOE-ε4 allele. Our data suggest that CTNNA3 may affect LOAD through a female-specific mechanism independent of the APOE-ε4 allele.
AB - Alzheimer's disease (AD), the most common form of dementia in the elderly, was found to exhibit a trend toward a higher risk in females than in males through epidemiological studies. Therefore, we hypothesized that gender-related genetic risks could exist. To reveal the ones for late-onset AD (LOAD), we extended our previous genetic work on chromosome 10q (genomic region, 60-107 Mb), and single nucleotide polymorphism (SNP)-based genetic association analyses were performed on the same chromosomal region, where the existence of genetic risk factors for plasma Aβ42 elevation in LOAD was implied on a linkage analysis. Two-step screening of 1140 SNPs was carried out using a total of 1408 subjects with the APOE-ε3* 3 genotype: we first genotyped an exploratory sample set (LOAD, 363; control, 337), and then genotyped some associated SNPs in a validation sample set (LOAD, 336; control, 372). Seven SNPs, spanning about 38 kb, in intron 9 of CTNNA3 were found to show multiple-hit association with LOAD in females, and exhibited more significant association on Mantel-Haenszel test (allelic P-valuesMH-F = 0.000005945-0.0007658). Multiple logistic regression analysis of a total of 2762 subjects (LOAD, 1313; controls, 1449) demonstrated that one of the seven SNPs directly interacted with the female gender, but not with the male gender. Furthermore, we found that this SNP exhibited no interaction with the APOE-ε4 allele. Our data suggest that CTNNA3 may affect LOAD through a female-specific mechanism independent of the APOE-ε4 allele.
UR - http://www.scopus.com/inward/record.url?scp=35748957469&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35748957469&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddm244
DO - 10.1093/hmg/ddm244
M3 - Article
C2 - 17761686
AN - SCOPUS:35748957469
VL - 16
SP - 2854
EP - 2869
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 23
ER -