Speaker: David Balding, University of Melbourne & Melbourne Integrative Genomics
Title:Progress and Controversy in Statistical Modelling of the Genomic Architecture of Complex Traits
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. Analysis of summary statistics is effectively unlimited in sample size and number of genetic variants, and avoids confidentiality issues associated with individual-level data. However, the models rest on assumptions that were initially unchallenged but have since become the subject of controversy. A key focus has been to answer detailed questions about how much causal variation lies in specific genomic regions, particularly those with functional annotations. Different approaches have led to very different estimates, giving discordant pictures of the genomic architecture of complex traits. The problem has been different assumptions about how the causal effect of a SNP varies according to genomic properties known a priori, for example minor allele fraction and linkage disequilibrium. I will review recent progress in using genome-wide SNPs to assess the heritability of complex human traits and its distribution across the genome, as well as the effect of confounding on GWAS test statistics. We have also derived improved estimates of selection parameters, leading to new insights into the effects of purifying selection on various traits. I will describe a consensus position that we have recently reached, and our reasons for believing that we are close to robust answers about genomic architecture, even though there remain many avenues for model refinements.
David Balding received a BMath from the University of Newcastle (Australia) and a PhD in Applied Probability from the University of Oxford, UK. He then held academic posts in and around London, initially in Mathematics but transitioning through Applied Statistics and Epidemiology/Public Health to Genetics. His research develops mathematical/ computational/ statistical innovations in population, evolutionary, medical and forensic genetics. 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). His applied research has also encompassed genetics of purebred dogs and crop production, evolutionary and demographic inferences in humans and other species, as well as several human diseases. After 30 years in the UK, he returned to Australia in 2014 where he is Professor of Statistical Genetics at the University of Melbourne, with a joint position in BioSciences and in Mathematics & Statistics. He is also Director of the newly-established Melbourne Integrative Genomics (MIG). He is lead editor of the Handbook of Statistical Genomics, of which the 4th edition has just appeared (Sept 2019), with co-editors Ida Moltke (Copenhagen) and John Marioni (Cambridge).