Understanding the genetic basis of human diseases and related physiological traits is the main objective of the programme. Many of the disease phenotypes we focus on are complex diseases whose genetic risk factors are multi-factorial and work in concert with a number of environmental forces. Using both hypothesis-driven investigations and unbiased genome-wide interrogations, we are working towards identifying genomic regions or genes whose natural variations influence disease predisposition, progression and treatment outcomes.

Disease Gene Discovery

By building up a common set of high-throughput genotyping and sequencing technologies and statistical methods through collaborative efforts, our investigation of disease inheritance and susceptibility covers diverse disease areas, including cancers (breast cancer, nasopharyngeal carcinoma, non-Hodgkin lymphoma), neuropsychiatric disorders (Parkinson Disease, schizophrenia), infectious diseases (tuberculosis, leprosy, meningococcal disease, Kawasaki disease and dengue), immunity and inflammation diseases (psoriasis, SLE, ankylosing spondylitis, IgA nephropathy, IBD), and eye diseases (age-related macular degeneration, glaucoma, pseudoexfoliation syndrome, and extreme myopia) and optic traits (central corneal thickness, optic nerve heard parameters, and intraocular pressure). We have extensive research programmes on interrogating common risk variants by genome-wide association study (GWAS) and are increasing our efforts on deciphering the contribution of low frequency and rare genetic variants to human diseases by carrying out targeted or whole exome sequencing analysis of patient cohorts, particularly the ones with either severe phenotypes or strong family inheritance. Availability and affordability of high throughput sequencing have made possible the generation of a plethora of sequencing data in a large collection of patients affected with complex and rare diseases, which will help us to achieve a good understanding on the whole spectrum of disease-related genetic variants.

Functionalisation of Disease Risk Loci

We are also interested in understanding biological mechanisms that underlie these genetic risk loci by pinpointing causal variants through fine-mapping analysis and characterising their functional impacts using in vitro and in vivo model systems. By combining comprehensive association analysis and functional annotation of all the variants within the critical region of a disease risk locus, we are searching for functional variants that are the primary driver and thus the causal event of disease association. Our effort has also gone beyond regional fine mapping analysis into whole genome interrogation, for example, by analysing all the genetic variants within various transcriptional binding sites in large clinical cohorts of diseases. The importance of regulatory polymorphisms in disease development has already been clearly suggested by the fact that the disease susceptibility loci discovered by GWAS are enriched for DNA elements regulating transcriptional activities. Intersection between the new genome-wide knowledge of regulatory sequences and the rapid development of high-throughput sequencing and genotyping technologies will allow the comprehensive investigation of the role of regulatory variation in human disease development. In addition, banking on the great number of novel disease risk loci discovered by our genetic studies of common and rare diseases, we are collaborating, with other research
programmes at the GIS, to pursue the functional investigation of these genetic risk loci by building up in vitro cellular models of disease where genetic risk variants are introduced into disease-relevant cells derived from either embryonic stem cells (ES) or induced pluri-potent stem cells (iPS) for functional interrogation. As a complementary effort, we are also collaborating to establish in vivo model animals for the functional investigation of disease risk-associated genes or genetic variants.

Population and Evolutionary Genomics and Statistical Genetics

Since the extent and distribution of disease predisposing genetic variation in the human species today is the result of a long and complicated evolutionary, migratory, and demographic history, we are interested in investigating population and evolutionary processes affecting genetic variations in modern human populations. We have been working on assessing the extent of inter- and intra-population genomic variation and detecting signatures of positive natural selection as well as investigating genomic variation across multiple global and regional populations. In addition, we are also interested in understanding the history of introgression from archaic sister species and their distribution into extant human populations as well as the convergent evolution between domesticated species (e.g. dogs) and human beings. Such population and evolutionary genomic studies provide a unique opportunity to look at disease genetics at a much broader scale. Furthermore, we are also interested in developing novel statistical methodologies to progress beyond searching for disease association in the genome at individual SNP level, to incorporate regional or gene-based evidences and to pursue pathway analysis. To control for population stratification in disease association studies, we have also been developing methods to provide efficient and accurate ancestry estimation for both sequencing (including target sequencing, exome sequencing, and whole genome sequencing) and array-genotyping data as well as exploring novel strategies to control for population stratification and to boost statistical power for rare variant association studies by integrating information from large amounts of existing genetic data, expression data, and functional annotation data.

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