title: Alzheimer's Disease Variants with the Genome-Wide Significance are Significantly Enriched in Immune Pathways and Active in Immune Cells.
abstract: The existing large-scale genome-wide association studies (GWAS) datasets provide strong support for investigating the mechanisms of Alzheimer's disease (AD) by applying multiple methods of pathway analysis. Previous studies using selected single nucleotide polymorphisms (SNPs) with several thresholds of nominal significance for pathway analysis determined that the threshold chosen for SNPs can reflect the disease model. Presumably, then, pathway analysis with a stringent threshold to define "associated" SNPs would test the hypothesis that highly associated SNPs are enriched in one or more particular pathways. Here, we selected 599 AD variants (P < 5.00E-08) to investigate the pathways in which these variants are enriched and the cell types in which these variants are active. Our results showed that AD variants are significantly enriched in pathways of the immune system. Further analysis indicated that AD variants are significantly enriched for enhancers in a number of cell types, in particular the B-lymphocyte, which is the most substantially enriched cell type. This cell type maintains its dominance among the strongest enhancers. AD SNPs also display significant enrichment for DNase in 12 cell types, among which the top 6 significant signals are from immune cell types, including 4 B cells (top 4 significant signals) and CD14+ and CD34+ cells. In summary, our results show that these AD variants with P < 5.00E-08 are significantly enriched in pathways of the immune system and active in immune cells. To a certain degree, the genetic predisposition for development of AD is rooted in the immune system, rather than in neuronal cells.
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Mathematics, Harbin Institute of Technology, Harbin, China.
authors.forename: Shuilin
authors.initials: S
authors.lastname: Jin
authors.affiliation: College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
authors.forename: Yongshuai
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Liao
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, China.
authors.forename: Rennan
authors.initials: R
authors.lastname: Feng
authors.affiliation: Department of Statistics, Rice University, Houston, TX, USA.
authors.forename: Liangcai
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. liuguiyou1981@163.com.|Genome Analysis Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Xiqi Dao 32, Tianjin Airport Economic Area, Tianjin, 300308, China. liuguiyou1981@163.com.
authors.forename: Guiyou
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Neurology and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Hao
mesh_terms: D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D030541:Databases, Genetic / Q000706:statistics & numerical data; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007154:Immune System Diseases / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D007111:Immunity, Cellular / Q000235:genetics*
keywords: Alzheimer’s disease; Genome-wide association study; Immune cells; Immune pathways; Pathway analysis