Complexity in the genetic architecture of leukoaraiosis in hypertensive sibships from the GENOA Study
dc.contributor.author | Smith, Jennifer A | |
dc.contributor.author | Turner, Stephen T | |
dc.contributor.author | Sun, Yan V | |
dc.contributor.author | Fornage, Myriam | |
dc.contributor.author | Kelly, Reagan J | |
dc.contributor.author | Mosley, Thomas H | |
dc.contributor.author | Jack, Clifford R | |
dc.contributor.author | Kullo, Iftikhar J | |
dc.contributor.author | Kardia, Sharon L | |
dc.date.accessioned | 2015-08-07T17:49:58Z | |
dc.date.available | 2015-08-07T17:49:58Z | |
dc.date.issued | 2009-04-07 | |
dc.identifier.citation | BMC Medical Genomics. 2009 Apr 07;2(1):16 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/112925 | en_US |
dc.description.abstract | Abstract Background Subcortical white matter hyperintensity on magnetic resonance imaging (MRI) of the brain, referred to as leukoaraiosis, is associated with increased risk of stroke and dementia. Hypertension may contribute to leukoaraiosis by accelerating the process of arteriosclerosis involving penetrating small arteries and arterioles in the brain. Leukoaraiosis volume is highly heritable but shows significant inter-individual variability that is not predicted well by any clinical covariates (except for age) or by single SNPs. Methods As part of the Genetics of Microangiopathic Brain Injury (GMBI) Study, 777 individuals (74% hypertensive) underwent brain MRI and were genotyped for 1649 SNPs from genes known or hypothesized to be involved in arteriosclerosis and related pathways. We examined SNP main effects, epistatic (gene-gene) interactions, and context-dependent (gene-environment) interactions between these SNPs and covariates (including conventional and novel risk factors for arteriosclerosis) for association with leukoaraiosis volume. Three methods were used to reduce the chance of false positive associations: 1) false discovery rate (FDR) adjustment for multiple testing, 2) an internal replication design, and 3) a ten-iteration four-fold cross-validation scheme. Results Four SNP main effects (in F3, KITLG, CAPN10, and MMP2), 12 SNP-covariate interactions (including interactions between KITLG and homocysteine, and between TGFB3 and both physical activity and C-reactive protein), and 173 SNP-SNP interactions were significant, replicated, and cross-validated. While a model containing the top single SNPs with main effects predicted only 3.72% of variation in leukoaraiosis in independent test samples, a multiple variable model that included the four most highly predictive SNP-SNP and SNP-covariate interactions predicted 11.83%. Conclusion These results indicate that the genetic architecture of leukoaraiosis is complex, yet predictive, when the contributions of SNP main effects are considered in combination with effects of SNP interactions with other genes and covariates. | |
dc.title | Complexity in the genetic architecture of leukoaraiosis in hypertensive sibships from the GENOA Study | |
dc.type | Article | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/112925/1/12920_2008_Article_80.pdf | |
dc.identifier.doi | 10.1186/1755-8794-2-16 | en_US |
dc.language.rfc3066 | en | |
dc.rights.holder | Smith et al. | |
dc.date.updated | 2015-08-07T17:49:58Z | |
dc.owningcollname | Interdisciplinary and Peer-Reviewed |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.