Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.

TitleInteraction between variants in CLU and MS4A4E modulates Alzheimer's disease risk.
Publication TypeJournal Article
Year of Publication2016
AuthorsEbbert MTW, Boehme KL, Wadsworth ME, Staley LA, Mukherjee S, Crane PK, Ridge PG, Kauwe JSK
Corporate AuthorsAlzheimer's Disease Neuroimaging Initiative, Alzheimer's Disease Genetics Consortium
JournalAlzheimers Dement
Volume12
Issue2
Pagination121-129
Date Published2016 Feb
ISSN1552-5279
KeywordsAlleles, Alzheimer Disease, Apolipoprotein E4, Clusterin, Epistasis, Genetic, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Membrane Proteins, Risk Factors, Sialic Acid Binding Ig-like Lectin 3
Abstract

INTRODUCTION: Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest data set for an epistasis study.

METHODS: We tested interactions using 3837 cases and 4145 controls from Alzheimer's Disease Genetics Consortium using meta-analyses and permutation analyses. We repeated meta-analyses stratified by apolipoprotein E (APOE) ε4 status, estimated combined odds ratio (OR) and population attributable fraction (cPAF), and explored causal variants.

RESULTS: Results support the CLU-MS4A4E interaction and a dominant effect. An association between CLU-MS4A4E and APOE ε4 negative status exists. The estimated synergy factor, OR, and cPAF for rs11136000-rs670139 are 2.23, 2.45, and 8.0, respectively. We identified potential causal variants.

DISCUSSION: We replicated the CLU-MS4A4E interaction in a large case-control series and observed APOE ε4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer's disease locus except APOE ε4, APP, and TREM2. We estimated an 8% decrease in Alzheimer's disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.

DOI10.1016/j.jalz.2015.08.163
Alternate JournalAlzheimers Dement
PubMed ID26449541
PubMed Central IDPMC4744542
Grant ListMH60451 / MH / NIMH NIH HHS / United States
UL1 TR001445 / TR / NCATS NIH HHS / United States
R01AG21136 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
R01 AG17917 / AG / NIA NIH HHS / United States
AG041232 / AG / NIA NIH HHS / United States
AG07562 / AG / NIA NIH HHS / United States
U01 AG10483 / AG / NIA NIH HHS / United States
P30 AG10133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 AG031581 / AG / NIA NIH HHS / United States
R01AG042611 / AG / NIA NIH HHS / United States
P50 AG016577 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
R01 AG042611 / AG / NIA NIH HHS / United States
R01 AG 042437 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
AG02365 / AG / NIA NIH HHS / United States
P50 AG016575 / AG / NIA NIH HHS / United States
/ / Medical Research Council / United Kingdom
AG05128 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
1R01AG035137 / AG / NIA NIH HHS / United States
P01 AG03991 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
AG010491 / AG / NIA NIH HHS / United States
P30 AG08051 / AG / NIA NIH HHS / United States
NS39764 / NS / NINDS NIH HHS / United States
AG041718 / AG / NIA NIH HHS / United States
5R01AG022374 / AG / NIA NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
R01AG33193 / AG / NIA NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
U24 AG026390 / AG / NIA NIH HHS / United States
1RC2AG036502 / AG / NIA NIH HHS / United States
M01RR00096 / RR / NCRR NIH HHS / United States
AG030653 / AG / NIA NIH HHS / United States
AG025688 / AG / NIA NIH HHS / United States
AG027944 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
AG05144 / AG / NIA NIH HHS / United States
R01 CA129769 / CA / NCI NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
R01AG31272 / AG / NIA NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01AG11380 / AG / NIA NIH HHS / United States
5R01AG012101 / AG / NIA NIH HHS / United States
R01 AG30146 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
5R01AG013616 / AG / NIA NIH HHS / United States
P50 AG016576 / AG / NIA NIH HHS / United States
AG019757 / AG / NIA NIH HHS / United States
P50 AG033514 / AG / NIA NIH HHS / United States
AG021547 / AG / NIA NIH HHS / United States
UL1RR02777 / RR / NCRR NIH HHS / United States