Evidence for a gene influencing heart rate on chromosome 5p13-14 in a meta-analysis of genome-wide scans from the NHLBI Family Blood Pressure Program

Abstract

Background: Elevated resting heart rate has been shown in multiple studies to be a strong predictor of cardiovascular disease. Previous family studies have shown a significant heritable component to heart rate with several groups conducting genomic linkage scans to identify quantitative trait loci.

Methods: We performed a genome-wide linkage scan to identify quantitative trait loci influencing resting heart rate among 3,282 Caucasians and 3,989 African-Americans in three independent networks comprising the Family Blood Pressure Program (FBPP) using 368 microsatellite markers. Mean heart rate measurements were used in a regression model including covariates for age, body mass index, pack-years, currently drinking alcohol (yes/no), hypertension status and medication usage to create a standardized residual for each gender/ethnic group within each study network. This residual was used in a nonparametric variance component model to generate a LOD score and a corresponding P value for each ethnic group within each study network. P values from each ethnic group and study network were merged using an adjusted Fisher's combining P values method and the resulting P values were converted to LOD scores. The entire analysis was redone after individuals currently taking beta-blocker medication were removed.

Results: We identified significant evidence of linkage (LOD = 4.62) to chromosome 10 near 142.78 cM in the Caucasian group of HyperGEN. Between race and network groups we identified a LOD score of 1.86 on chromosome 5 (between 39.99 and 45.34 cM) in African-Americans in the GENOA network and the same region produced a LOD score of 1.12 among Caucasians within a different network (HyperGEN). Combining all network and race groups we identified a LOD score of 1.92 (P = 0.0013) on chromosome 5p13-14. We assessed heterogeneity for this locus between networks and ethnic groups and found significant evidence for low heterogeneity (P < or = 0.05).

Conclusion: We found replication (LOD > 1) between ethnic groups and between study networks with low heterogeneity on chromosome 5p13-14 suggesting that a gene in this region influences resting heart rate.

Figure 1

Original Genome Scans for Each Network. Genome scans separated by race for participants not taking β-blocker medication across all three networks. Caucasians and African-Americans are represented in each panel by a solid and a dashed line respectively. A) GenNet B) GENOA C) HyperGEN

Figure 2

Meta-analysis of LOD scores. Meta-analysis of multipoint LOD scores for all genome scans for participants not taking β-blocker medication across all three networks. A) Caucasians B) African-Americans C) Combined

Figure 3

Chromosome 5 meta-analysis of LOD scores. Meta-analysis of multipoint LOD scores on chromosome 5 for resting heart rate for all Caucasians not taking β-blocker medication (Caucasians) and all African-Americans not taking β-blocker medication (African-Americans). Also shown is the combined race meta-analysis for all individuals not taking β-blocker medication (Combined)

Figure 4

Chromosome 10 meta-analysis of LOD scores. Meta-analysis of multipoint LOD scores on Chromosome 10 for resting heart rate for all Caucasians not taking β-blocker medication (Caucasians) and all African-Americans not taking β-blocker medication (African-Americans). Also shown is the combined race meta-analysis for all individuals not taking β-blocker medication (Combined)