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. 2018 Feb 26;8(1):11.
doi: 10.3390/jpm8010011.

A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans

Huichun Xu  1 , Gerald W Dorn 2nd  2 , Amol Shetty  3 , Ankita Parihar  4 , Tushar Dave  5 , Shawn W Robinson  6 , Stephen S Gottlieb  7 , Mark P Donahue  8 , Gordon F Tomaselli  9 , William E Kraus  10   11 , Braxton D Mitchell  12   13 , Stephen B Liggett  14
Affiliations

A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans

Huichun Xu et al. J Pers Med. .

Abstract

Idiopathic dilated cardiomyopathy (IDC) is the most common form of non-ischemic chronic heart failure. Despite the higher prevalence of IDC in African Americans, the genetics of IDC have been relatively understudied in this ethnic group. We performed a genome-wide association study to identify susceptibility genes for IDC in African Americans recruited from five sites in the U.S. (662 unrelated cases and 1167 controls). The heritability of IDC was calculated to be 33% (95% confidence interval: 19-47%; p = 6.4 × 10-7). We detected association of a variant in a novel intronic locus in the CACNB4 gene meeting genome-wide levels of significance (p = 4.1 × 10-8). The CACNB4 gene encodes a calcium channel subunit expressed in the heart that is important for cardiac muscle contraction. This variant has not previously been associated with IDC in any racial group. Pathway analysis, based on the 1000 genes most strongly associated with IDC, showed an enrichment for genes related to calcium signaling, growth factor signaling, neuronal/neuromuscular signaling, and various types of cellular level signaling, including gap junction and cAMP signaling. Our results suggest a novel locus for IDC in African Americans and provide additional insights into the genetic architecture and etiology.

Keywords: African American; CACNB4; GWAS; calcium channel; heart failure; idiopathic dilated cardiomyopathy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Manhattan plots of the genome-wide association results based on imputed data. The x-axis shows the chromosome number, while y-axis shows the −log (p). A post genome-wide association study (GWAS) filter was applied including imputation quality measure “info” >0.3, Hardy–Weinberg equilibrium (HWE) p > 1.0 × 10−6, minor allele frequencies (MAFs) >1%; (B) Regional association plot with linkage disequilibrium (LD) structure for the novel CACNB4 loci. Genomic coordinates are shown on the x-axis, and –log (p) is shown on the y-axis to the left. The index genetic variant is shown in purple. The r2 values of the remaining genetic variants with the index variant are color-coded as indicated by the color bar to the upper right. The genes in this region are indicated at the bottom.
Figure 2
Figure 2
Kyoto Encyclopedia of Genes and Genomes (KEGG) dilated cardiomyopathy pathway overlaid with the top 1000 genes (in yellow box) indicated in our current genome wide association study of idiopathic dilated cardiomyopathy (IDC) in African Americans. Genes with mutations that have been reported in IDC are colored in red font.
See this image and copyright information in PMC

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