Abstract 58: Multi-Ancestry Genome-Wide Association Study of Age-at-Onset in Heart Failure
Authors: Sun Yan V , Hui Qin , Linchangco Gregorio V , Rahafrooz Maryam , Liu Chang , Gaziano John Michael , Wilson Peter W ,   the Million Veteran Program, Phillips Lawrence , Joseph Jacob 
Published: May 2024

Background:
Heart failure (HF) is a life-threatening syndrome with growing impact on the global population. It is estimated that >8 million people in the US will be living with HF by 2030. Aging is a major risk factor for HF. Age-at-onset (AAO) is one of the critical traits in cohort studies of age-related diseases. Large-scale genome-wide association studies (GWAS) of HF AAO can provide insights into genetic effects on disease progression and transitions to severe stages.

Methods:
The multi-ancestry study consisted of a discovery cohort from the Million Veteran Program (MVP) including 67845, 17687, 4936, and 527 HF patients in European, African, Hispanic, and Asian Americans, respectively. HF AAO was determined by the first HF diagnosis date with a measured left ventricle ejection fraction within 90 days. Within each group, a GWAS of AAO was conducted using common SNPs (minor allele frequency>1%) imputed to the 1000 Genome Project panel, adjusted for sex and top 10 ancestry-specific principal components (PCs) of genome-wide SNPs. A meta-analysis of GWAS summary statistics was performed to identify genome-wide significant (GWS, p<5x10
-8
) loci. In the replication study, 20453 HF patients of European ancestry from the UK Biobank (UKB) study were identified using HF diagnosis codes extracted from in-patient Hospital Episode Statistics and National Death Registry. The age at the first use of a HF diagnosis code was used to approximate the AAO in the GWAS adjusted for sex and top 10 PCs. The sentinel SNPs of GWS locus from the discovery phase were examined for replication in the UKB cohort.

Results:
From the multi-ancestry GWAS of HF AAO in MVP, four GWS loci were identified in chromosomes 3 (3:49862418, p=3.41x10
-11
), 9 (9:22124744, p=1.18x10
-11
), 15 (15:78868398, p=1.60x10
-9
) and 19 (19:45411941, p=4.15x10
-38
). All but the chromosome 19 locus were replicated in the UKB, with the most significant replication in the chromosome 3 locus (p=8.74x10
-5
). The chromosome 3 locus has been associated with multiple phenotypes including metabolic diseases, inflammation, and lung function. The 9p21 locus is a well-established locus of coronary heart disease, which is a key antecedent of HF. The chromosome 15 locus maps to the
CHRNA
gene cluster, which is associated with pulmonary function and disease, as well as aging. The chromosome 19 locus is located within the
APOE
gene, which plays an important role in aging, Alzheimer’s disease, and lipid metabolism. The allelic effects of younger HF AAO are in the same direction of elevated disease risk at corresponding loci (e.g., younger AAO and higher CAD risk for 9p21).

Conclusion:
The significant genetic associations with AAO of HF revealed the pathways and mechanisms regulating HF progression and transition into clinical stages. They may lead to novel targets for treatment and prevention which could eventually reduce the burden of HF among the aging population in the US.