SNP-SNP interactions dominate the genetic architecture of candidate genes associated with left ventricular mass in African-Americans of the GENOA study.
BACKGROUND
Left ventricular mass (LVM) is a strong, independent predictor of heart disease incidence and mortality. LVM is a complex, quantitative trait with genetic and environmental risk factors. This research characterizes the genetic architecture of LVM in an African-American population by examining the main and interactive effects of individual candidate gene single nucleotide polymorphisms (SNPs) and conventional risk factors for increased LVM.


METHODS
We used least-squares linear regression to investigate 1,878 SNPs from 234 candidate genes for SNP main effects, SNP-risk factor interactions, or SNP-SNP interactions associated with LVM in 1,328 African-Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We reduced the probability of false positive results by implementing three analytic criteria: 1) the false discovery rate, 2) cross-validation, and 3) testing for internal replication of results.


RESULTS
We identified 409 SNP-SNP interactions passing all three criteria, while no SNP main effects or SNP-risk factor interactions passed all three. A multivariable model including four SNP-SNP interactions explained 11.3% of the variation in LVM in the full GENOA sample and 5.6% of LVM variation in independent test sets.


CONCLUSIONS
The results of this research underscore that context dependent effects, specifically SNP-SNP interactions, may dominate genetic contributions to variation in complex traits such as LVM.
Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin, USA.
Kristin J
KJ
Meyers
Jian
J
Chu
Thomas H
TH
Mosley
Sharon L R
SL
Kardia
D001741:Black or African American / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000208:ethnology / Q000235:genetics*; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors