IEU Seminar - Peter Joshi, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh

Title: Genomic underpinnings of lifespan allow prediction and reveal basis in modern risks

Abstract: We use a multi-stage genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near GADD45G, KCNK3, LDLR, POM121C, ZC3HC1, and ABO. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and tissue-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer, but not other cancers, explain the most variance, possibly reflecting modern susceptibilities, whilst cancer may act through many rare variants, or the environment. Resultant polygenic scores predict a mean lifespan difference of around five years of life across the deciles.

Biography: 

Chancellor's Fellow, Usher Institute of Population Health and Informatics, University of Edinburgh. Education/Academic Qualifications: Bachelor of Science (Mathematics), PhD, University of Edinburgh. 

Professional Qualifications: Fellow of the Faculty of Actuaries, FFA

Current Research Interests: I am interested in fundamental questions on the architecture of complex traits, particularly the components of evolutionary fitness and dominance. Related to this I am interested in the bio-medical basis of human lifespan and the genetic variation that effects it, despite most human mortality being post reproductive age.

Key Publications:

Joshi, P.K. et al. Directional dominance on stature and cognition in diverse human populations. Nature 523, 459-62 (2015).

Joshi, P.K. et al. Variants near CHRNA3/5 and APOE have age- and sex-related effects on human lifespan. Nat Commun 7, 11174 (2016)*.

Joshi, P. K. et al. Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity. Nat Commun 8, 910, doi:10.1038/s41467-017-00934-5 (2017).

Joshi, P.K. et al. Local exome sequences facilitate imputation of less common variants and increase power of genome wide association studies. PLoS One 8, e68604 (2013)

Chair:  Jack Bowden

All welcome