How are the Causes of Complex Disease Distributed in the Human Genome

The advent of very large, richly-phenotyped and high-quality human genomics datasets, together with the development of models that allow joint analyses of all GWAS test statistics, have led to big advances in understanding the genomic architecture of complex traits. However, models for the analysis of genome-wide SNPs, particularly for analyses based on association test statistics rather than individual genotype data, often rest on simplistic assumptions about the distribution of causal variation across the genome. Different approaches have led to discordant results about the genomic architecture of complex traits. I will review recent progress in genome-wide models of the heritability of complex human traits. In particular we look at the relationship between heritability and a range of genome annotation features, as well as linkage disequilibrium and minor allele fraction (MAF). The relationship between MAF and heritability is informative about the effects of negative or purifying selection, for different traits and in different genome regions. I will also discuss how the heritability models that arise from our work can be used to improve genomic prediction. This work leads to improved insights into the genomic architecture of complex traits.

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About David Balding

David Balding was trained in mathematics: B Math (Newcastle, Australia) and D Phil (Oxford, UK). Since graduating, he has worked to apply mathematical, computational, and statistical innovations in population, evolutionary, medical and forensic genetics. He held academic posts in and around London, initially in Mathematics (Queen Mary) but transitioning through Applied Statistics (Reading), Epidemiology and Public Health (Imperial) to the UCL Genetics Institute. He has given expert evidence in many court cases, mostly about interpretation of DNA profile evidence which is the topic of his monograph ‘Weight-of-Evidence for Forensic DNA Profiles’ (Wiley, 2nd ed 2015). He is lead editor of the Handbook of Statistical Genomics, (4th ed, 2019), with co-editors Ida Moltke (Copenhagen) and John Marioni (Cambridge). After 30 years in the UK, he returned to Australia in 2014 where he was Professor of Statistical Genetics at the University of Melbourne and Director of Melbourne Integrative Genomics (MIG). He took early retirement in 2021, but is continuing his research in an honorary capacity. He is President of the International Genetic Epidemiology Society for 2022 and Section Editor for Methods at PLOS Genetics.