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P3‐199: Multi locus interactions in steroidogenic pathway genes predict Alzheimer's disease
Author(s) -
Basson Jacob J.,
Wilson Andrea C.,
Haasl Ryan J.,
Atwood Craig S.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1765
Subject(s) - linkage disequilibrium , biology , locus (genetics) , single nucleotide polymorphism , allele , genetics , endocrinology , medicine , apolipoprotein e , exon , genotype , gene , disease
Background: Genetic and biochemical studies have shown that the apolipoprotein E (APOE) 4 allele is a major risk factor for late-onset Alzheimer’s disease (AD), however approximately 50% of AD patients do not carry the allele. Since ApoE transports cholesterol for gonadotropin-regulated steroidogenesis, we examined polymorphisms in a number of the components of the steroidogenic pathway, including LH beta-subunit (LHB), its receptor (LHCGR), GnRH ligand, its receptor (GnRHR), follicle-stimulating hormone (FSH), its receptor (FSHR), steroidogenic acute regulatory protein (STAR) and 2-macroglobulin (A2M), for their association with AD. Methods: DNA samples from 100 AD and 100 control patients were scored for APOE genotype and previously reported polymorphisms (according to the NCBI database) in the aforementioned genes. These data were analyzed using a combination of single-factor tests as well as tests for multi-locus interactions: linkage disequilibrium (LD), logistic regression (LR), and multi-factor dimensionality reduction (MDR). Results: A marginally significant effect was observed for a missense single nucleotide polymorphism (snp) in exon 10 of FSHR: in each of the general (p 0.013), male (p 0.018), and female (p 0.034) populations heterozygosity at this locus was determined to be a risk factor. Other marginal effects were found at loci throughout FSHR in the general population (exon 10, p 0.012 and intron 8, p 0.040), in males (exon 10, p 0.023), and in females (intron 8, p 0.043 and p 0.023). Importantly, two locus pairs showed significant association with AD in all the multi-locus association tests. In the general population a synonymous snp in LH and a missense snp in FSHR demonstrated a protective effect (p 0.006, odds ratio: 0.14). In females, an intronic snp in LHR and a synonymous snp in FSH combined to make a strongly deleterious effect (p 0.001, odds ratio: 44.12). Conclusions: These multi-gene interactions support the importance of considering the role that gene-gene interactions play in the etiology of complex biological diseases and demonstrate the importance of using multiple analytic methods to detect well-supported gene-gene interactions.