NHMRC Career Development Fellowship (Biomedical; Level 1): Dissecting genetic variation for human complex diseases and traits (2013–2014)
Most human complex diseases and traits such as diabetes, cancers, cognitive ability and mental disorders, are influenced by many genes and the interplay of risk variants within and between genetic loci and with environmental factors. Understanding the genetic architecture of complex diseases is of fundamental importance for disease prevention and diagnosis, discovery of drug targets and personalised medicine. Genome-wide association studies (GWAS) have been successful in identifying genetic variants, genes and gene pathways involved in hundreds of human complex diseases and traits. GWAS have been criticised because the genetic variants identified for a particular disease/trait explain only a fraction of the heritability, the so-called the "missing heritability" problem. Possible explanations to the missing heritability problem include that many genes with small effects remain undetected due to insufficient statistical power, that heritability is over-estimated in pedigree analysis due to the existence of non-additive variation and that rare variants are important. In this project, we will develop novel methods and software tools 1) to estimate and partition genetic variance in unrelated individuals using imputed sequence data, which will quantify the allelic spectrum of causal variants and elucidate the role of rare variants; 2) to directly estimate non-additive genetic variation using genotype data; 3) to predict disease risk of individuals in independent samples using all genetic information simultaneously. The outcomes of this project are the provision of new knowledge to inform strategies and designs for future research in human complex diseases, and the delivery of new user-friendly software tools freely available for public use.