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S1‐04–02: Genetic association studies in Alzheimer's disease
Author(s) -
Tanzi Rudolph E.
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.2008.05.205
Subject(s) - psen1 , genome wide association study , genetics , biology , genetic association , genotyping , apolipoprotein e , candidate gene , single nucleotide polymorphism , locus (genetics) , bonferroni correction , disease , gene , alzheimer's disease , genotype , medicine , presenilin , statistics , mathematics , pathology
expression. Candidates were then tested in additional heterozygous individuals. SNP association with AD was evaluated in case-control series derived from the Mayo-Clinic Jacksonville, Mayo-Clinic Rochester, and the Religious Orders Study. Results: LDLR isoforms lacking exons 2, 4, 11, 12, 15 and/or 16 were readily detected in human hippocampal and cingulate RNA. Modeling predicted that rs688T reduces exon 12 inclusion, a possibility confirmed by in vitro minigene splicing studies. LDLR isoforms lacking exon 12 encode non-functional LDLR. In vivo, the rs688T minor allele was associated with decreased exon 12 inclusion in mRNA from male but not female brains. Moreover, rs688T/T was associated with significantly increased AD risk in males but not females. Unequal allele expression studies identified the minor rs2738464G allele as associated with significantly increased LDLR allelic expression. Although rs2738464G was not associated significantly with AD, we are currently investigating a multi-locus model based on predicted levels of functional LDLR expression, i.e., individuals that splice poorly/express normally (rs688T/T:rs2738464C/C) and splice normally/express highly (rs688C/C: rs2738464C/G) define low and high levels of LDLR expression, respectively, with other genotypes considered intermediate. Conclusions: SNPs associated with function can valuably inform genetic association studies. Specifically, LDLR SNPs associated with decreased functional LDLR in males are associated with increased AD risk in males. Hence, agents that alter LDLR expression may modulate risk for AD.