Identification of risk loci by genome-wide association study in individuals with a positive family history of premature death in UK Biobank
C G Joenck, I P Thierry, J D Andersen, R Jabbari, J Tfelt-Hansen, C GlingeAbstract
Introduction
Early parental death may be a sign of genetic vulnerability to Sudden Death and increased risk of cardiovascular disease. Identifying genetic susceptibility loci will increase our knowledge of biological and functional pathways underlying premature death.
Purpose
This study aimed to identify common genetic variants - single nucleotide polymorphisms (SNPs), that predispose individuals to premature death and provide insights into its molecular underpinnings.
Methods
The UK Biobank was utilized to conduct a genome-wide association study (GWAS) to identify variants associated with premature death. We included participants of non-adopted, white British ancestry with available parental age data. Cases were defined as individuals with ≥1 parent deceased before the age of 50 years, while controls were participants with the father and the mother surviving beyond 80, and 85 years respectively. Standard GWAS quality control and imputation procedures were applied. The association of each SNP with a family history of premature death was evaluated using logistic regression model assuming an additive genetic model with adjustment for age, sex, and the first ten principal components.
Results
A total of 62,176 individuals were included (29,515 cases and 32,661 controls). The distribution of P values for the associations of SNPs with family history of premature death is shown in figure 1, and SNPs displaying the strongest associations (chr. 19 and chr. 15) are presented in figure 2. We found two novel genetic loci associated with premature death in parent. On chr.19 the most robust association was found for rs429358 which is associated with the APOE gene (odds ratio = 1.15 per T allele, 95 % CI 1.14–1.17, P = 3.12435 × 10−18). APOE plays a multifunctional role in lipid metabolism and emerges as a critical factor for both normal and pathological ageing. On chr.15 the most robust association was found for rs56390833 which is located near CHRNA5 and ADAMTS7 (odds ratio = 1.08 per C allele, 95 % CI 1.07–1.09, P = 7.34318 × 10−10). CHRNA5 plays a role in nicotine addiction and the development of smoking related diseases and schizophrenia. ADAMTS7 is known as a potential new drug target in atherosclerosis.
Conclusions
In conclusion, two novel genetic loci were linked to family history of premature death. Our discovered loci may help to elucidate genetic susceptibility and the biological mechanisms underlying premature death.Manhattan plotLocusZoom plot