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Convergent genetic and expression data implicate immunity in Alzheimer's disease.

TitleConvergent genetic and expression data implicate immunity in Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2015
Corporate AuthorsInternational Genomics of Alzheimer's Disease Consortium(IGAP)
JournalAlzheimers Dement
Volume11
Issue6
Pagination658-71
Date Published2015 Jun
ISSN1552-5279
KeywordsAlgorithms, Alzheimer Disease, Brain, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide
Abstract

BACKGROUND: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.

METHODS: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.

RESULTS: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10(-11)), cholesterol transport (P = 2.96 × 10(-9)), and proteasome-ubiquitin activity (P = 1.34 × 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05).

CONCLUSIONS: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.

DOI10.1016/j.jalz.2014.05.1757
Alternate JournalAlzheimers Dement
PubMed ID25533204
PubMed Central IDPMC4672734
Grant ListR01 AG016495 / AG / NIA NIH HHS / United States
N01 HC055019 / HC / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
N01 HC055016 / HC / NHLBI NIH HHS / United States
P30 AG013854 / AG / NIA NIH HHS / United States
N01 HC055022 / HC / NHLBI NIH HHS / United States
MR/K013041/1 / MRC_ / Medical Research Council / United Kingdom
RC2 HL102419 / HL / NHLBI NIH HHS / United States
UL1 TR001445 / TR / NCATS NIH HHS / United States
MC_U123192748 / MRC_ / Medical Research Council / United Kingdom
P30 AG010124 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
UC2 HL103010 / HL / NHLBI NIH HHS / United States
RC2 AG036528 / AG / NIA NIH HHS / United States
P30 AG028377 / AG / NIA NIH HHS / United States
N01 AG012100 / AG / NIA NIH HHS / United States
P50 AG008671 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
P50 AG005128 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 AG031581 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
MC_U123160651 / MRC_ / Medical Research Council / United Kingdom
R01 AG019085 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
167 / ALZS_ / Alzheimer's Society / United Kingdom
P30 AG062421 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
N01 HC055018 / HC / NHLBI NIH HHS / United States
UL1 RR029893 / RR / NCRR NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
U24 AG056270 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
R01 MH080295 / MH / NIMH NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
G0902227 / MRC_ / Medical Research Council / United Kingdom
R01 HL093029 / HL / NHLBI NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
089703 / WT_ / Wellcome Trust / United Kingdom
MR/L501517/1 / MRC_ / Medical Research Council / United Kingdom
P50 AG016573 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
P50 AG016570 / AG / NIA NIH HHS / United States
P30 AG008017 / AG / NIA NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
U54 CA132378 / CA / NCI NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
MR/L023784/1 / MRC_ / Medical Research Council / United Kingdom
R37 AG015473 / AG / NIA NIH HHS / United States
U24 AG026395 / AG / NIA NIH HHS / United States
164 / ALZS_ / Alzheimer's Society / United Kingdom
R01 CA129769 / CA / NCI NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
U01 AG010483 / AG / NIA NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
R01 AG041797 / AG / NIA NIH HHS / United States
N01 HC055015 / HC / NHLBI NIH HHS / United States
N01 HC055021 / HC / NHLBI NIH HHS / United States
R01 AG041232 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
R01 AG020688 / AG / NIA NIH HHS / United States
R01 AG030653 / AG / NIA NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States
R01 AG017173 / AG / NIA NIH HHS / United States
R01 AG025259 / AG / NIA NIH HHS / United States
RF1 AG015473 / AG / NIA NIH HHS / United States
U01 HG004610 / HG / NHGRI NIH HHS / United States
N01 HC055020 / HC / NHLBI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
P50 AG016582 / AG / NIA NIH HHS / United States
R01 AG041718 / AG / NIA NIH HHS / United States
MR/L023784/2 / MRC_ / Medical Research Council / United Kingdom
N01HC85079 / HL / NHLBI NIH HHS / United States
MR/L010305/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL087641 / HL / NHLBI NIH HHS / United States
095317 / WT_ / Wellcome Trust / United Kingdom
100140 / WT_ / Wellcome Trust / United Kingdom
P30 AG028383 / AG / NIA NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
R01 AG026916 / AG / NIA NIH HHS / United States
081864 / WT_ / Wellcome Trust / United Kingdom
R01 NS059873 / NS / NINDS NIH HHS / United States
MC_G1000734 / MRC_ / Medical Research Council / United Kingdom
N01HC85081 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States