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O1‐09‐06: Pathway analysis of IGAP GWAS data implicates endocytosis in the aetiology of late‐onset Alzheimer's disease
Author(s) -
Holmans Peter,
Jones Lesley
Publication year - 2012
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.2012.05.256
Subject(s) - genome wide association study , genetic association , biology , kegg , computational biology , genetics , endocytosis , biological pathway , genome , gene , single nucleotide polymorphism , gene ontology , receptor , gene expression , genotype
consistently associated with increased LDL levels. Quantile-quantile plots showed considerable genetic enrichment in AD as a function of significance of association with LDL. Between AD and LDL, the most significant overlap was in SNPs located close to or within the APOE cluster (TOMM40 (rs2075650) showed largest overlap, p 1⁄4 6.18 x 10-264). We also discovered novel pleiotropic signal in ABCA1 (rs12686004)(P 1⁄4 2.54 x 10-9). Conclusions: There is specific and striking genetic pleiotropy between elevated plasma cholesterol levels and dementia risk indicating a fundamental mechanistic relationship between lipid biology and AD pathogenesis that is not mediated via cardiovascular disease-related genetic pathways. These findings have implications for primary and secondary AD prevention trials using lipid-lowering agents. Examining overlap in common genetic variants can inform pathobiology and identify potential therapeutic strategies.