Genetically independent phenotype analysis identifies LPA and VCAM1 as drug targets for human ageing

Timmers, Paul R. H. J.; Tiys, Evgeny S.; Sakaue, Saori; Akiyama, Masato; Kiiskinen, Tuomo T. J.; Zhou, Wei; Hwang, Shih-Jen; Yao, Chen; Deelen, Joris; Levy, Daniel; Ganna, Andrea; Kamatani, Yoichiro; Okada, Yukinori; Joshi, Peter K.; Wilson, James F.; Tsepilov, Yakov A.

The length and quality of life is important to us all, yet identification of promising drug targets for human ageing using genetics has had limited success. Here, we combine six large European-ancestry genome-wide association studies (GWAS) of human ageing traits—healthspan, father and mother lifespan, exceptional longevity, frailty index, and self-rated health—in a principal component framework that maximises their shared genetic architecture. The first principal component (GIP1) is more heritable than the original studies and shows strong genetic correlations with length of life as well as multiple indices of mental and physical wellbeing. We identify 27 genomic regions associated with GIP1, and provide additional, independent evidence for an effect on human ageing for loci near HTT and MAML3 using a study of Finnish and Japanese subject survival. Across the genome, GIP1 associations are enriched in genes involved in haem metabolism and pathways related to transcription, neurogenesis, homeostasis, proteolysis, intracellular signalling, immunity, and the muscle system. Finally, using proteome-wide two-sample Mendelian randomisation and colocalisation, we provide robust evidence for a detrimental effect of blood levels of apolipoprotein(a) (LPA) and vascular cell adhesion molecule 1 (VCAM1) on GIP1. Together, our results demonstrate that combining multiple ageing traits using genetic principal components enhances power to detect biological targets for human ageing.