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Epistatic Genetic Effects among Alzheimer’s Candidate Genes

BACKGROUND: Novel risk variants for late-onset Alzheimer’s disease (AD) have been identified and replicated in genome-wide association studies. Recent work has begun to address the relationship between these risk variants and biomarkers of AD, though results have been mixed. The aim of the current s...

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Autores principales: Hohman, Timothy J., Koran, Mary Ellen, Thornton-Wells, Tricia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832488/
https://www.ncbi.nlm.nih.gov/pubmed/24260488
http://dx.doi.org/10.1371/journal.pone.0080839
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author Hohman, Timothy J.
Koran, Mary Ellen
Thornton-Wells, Tricia
author_facet Hohman, Timothy J.
Koran, Mary Ellen
Thornton-Wells, Tricia
author_sort Hohman, Timothy J.
collection PubMed
description BACKGROUND: Novel risk variants for late-onset Alzheimer’s disease (AD) have been identified and replicated in genome-wide association studies. Recent work has begun to address the relationship between these risk variants and biomarkers of AD, though results have been mixed. The aim of the current study was to characterize single marker and epistatic genetic effects between the top candidate Single Nucleotide Polymorphisms (SNPs) in relation to amyloid deposition. METHODS: We used a combined dataset across ADNI-1 and ADNI-2, and looked within each dataset separately to validate identified genetic effects. Amyloid was quantified using data acquired by Positron Emission Tomography (PET) with (18)F-AV-45. RESULTS: Two SNP-SNP interactions reached significance when correcting for multiple comparisons, BIN1 (rs7561528, rs744373) x PICALM (rs7851179). Carrying the minor allele in BIN1 was related to higher levels of amyloid deposition, however only in non-carriers of the protective PICALM minor allele. CONCLUSIONS: Our results support previous research suggesting these candidate SNPs do not show single marker associations with amyloid pathology. However, we provide evidence for a novel interaction between PICALM and BIN1 in relation to amyloid deposition. Risk related to the BIN1 minor allele appears to be mitigated in the presence of the PICALM protective variant. In that way, variance in amyloid plaque burden can be better classified within the context of a complex genetic background. Efforts to model cumulative risk for AD should explicitly account for this epistatic effect, and future studies should explicitly test for such effects whenever statistically feasible.
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spelling pubmed-38324882013-11-20 Epistatic Genetic Effects among Alzheimer’s Candidate Genes Hohman, Timothy J. Koran, Mary Ellen Thornton-Wells, Tricia PLoS One Research Article BACKGROUND: Novel risk variants for late-onset Alzheimer’s disease (AD) have been identified and replicated in genome-wide association studies. Recent work has begun to address the relationship between these risk variants and biomarkers of AD, though results have been mixed. The aim of the current study was to characterize single marker and epistatic genetic effects between the top candidate Single Nucleotide Polymorphisms (SNPs) in relation to amyloid deposition. METHODS: We used a combined dataset across ADNI-1 and ADNI-2, and looked within each dataset separately to validate identified genetic effects. Amyloid was quantified using data acquired by Positron Emission Tomography (PET) with (18)F-AV-45. RESULTS: Two SNP-SNP interactions reached significance when correcting for multiple comparisons, BIN1 (rs7561528, rs744373) x PICALM (rs7851179). Carrying the minor allele in BIN1 was related to higher levels of amyloid deposition, however only in non-carriers of the protective PICALM minor allele. CONCLUSIONS: Our results support previous research suggesting these candidate SNPs do not show single marker associations with amyloid pathology. However, we provide evidence for a novel interaction between PICALM and BIN1 in relation to amyloid deposition. Risk related to the BIN1 minor allele appears to be mitigated in the presence of the PICALM protective variant. In that way, variance in amyloid plaque burden can be better classified within the context of a complex genetic background. Efforts to model cumulative risk for AD should explicitly account for this epistatic effect, and future studies should explicitly test for such effects whenever statistically feasible. Public Library of Science 2013-11-18 /pmc/articles/PMC3832488/ /pubmed/24260488 http://dx.doi.org/10.1371/journal.pone.0080839 Text en © 2013 Hohman et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Hohman, Timothy J.
Koran, Mary Ellen
Thornton-Wells, Tricia
Epistatic Genetic Effects among Alzheimer’s Candidate Genes
title Epistatic Genetic Effects among Alzheimer’s Candidate Genes
title_full Epistatic Genetic Effects among Alzheimer’s Candidate Genes
title_fullStr Epistatic Genetic Effects among Alzheimer’s Candidate Genes
title_full_unstemmed Epistatic Genetic Effects among Alzheimer’s Candidate Genes
title_short Epistatic Genetic Effects among Alzheimer’s Candidate Genes
title_sort epistatic genetic effects among alzheimer’s candidate genes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832488/
https://www.ncbi.nlm.nih.gov/pubmed/24260488
http://dx.doi.org/10.1371/journal.pone.0080839
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