Abstract P153: Genetic Linkage and Association of Echocardiographic Measures in the Fels Longitudinal Study

Abstract

Measures of cardiac structure such as left ventricular mass (LVM) have been shown to be significantly heritable. Relative to other complex traits, however, gene variants influencing echocardiographic traits have been less frequently identified. In this study of subjects from the Fels Longitudinal Study, our aim was to perform quantitative trait linkage and genome-wide association (GWA) analyses on LVM, relative wall thickness (RWT), fractional shortening (FS), aortic root diameter (ARD), and LVM index (LVMI; LVM/height 2.7 ). The study sample consisted of 1,060 (467 male, 593 female) whites aged 8-97 years from 131 families. Variables were inverse normal transformed for all analyses. Each subject was genotyped with the Illumina Human 610-Quad BeadChip containing more than 550,000 single nucleotide polymorphism (SNP) markers. Variance-component linkage analyses were conducted using a subset of 17,561 genome-wide SNP markers in genetic equilibrium with each other. GWA analyses were conducted using all SNPs and the measured genotype method implemented in SOLAR, allowing for residual non-independence among relatives After adjusting for covariates of age, sex, BMI, and population stratification, all echocardiograpic traits were significantly heritable (p < 0.00006); h 2 (SE) for LVM, LVMI, RWT, FS, and ARD were 0.28 (0.07), 0.36 (0.07), 0.22 (0.07), 0.27 (0.06), and 0.55 (0.06), respectively. Linkage analyses revealed significant linkage of LVMI to chromosome 1p31 (LOD=3.64 at 96cM) in a region where the LEPR (leptin receptor), PDE4B (phosphodiesterase 4B, cAMP-specific), NEGR1 (neuronal growth regulator 1), and TNNI3K (TNNI3 interacting kinase) genes are located. For ARD, we identified chromosomal region 13q14 (LOD = 3.88 at 45cM) which harbors the FOXO1 (forkhead box O1) and TSC22D1 (TSC22 domain family, member 1) genes. Suggestive (LOD > 2.0) linkages were found on chromosomes 1, 2, 3, 4, 9 and 19 for the various traits. In GWA analyses, significant ( χ 2 >27.85) association was found between LVMI and SNP rs7939215 on chromosome 11p15. For LVM we observed evidence of a suggestive association ( χ 2 >22.70) with rs660464 in the NRG3 (neuregulin 3) gene, which has been associated with hypertrophy among the Amish. Other suggestive associations were found between FS and SNPs rs12485048 and rs5753622 on chromosome 22q12, and SNP rs2993639 chromosome on 3q21. In summary, we identified several significant linkage and association signals for cardiac measures. Future work will include replicating these results in other study populations.