Consisting of approximately three billion nucleotides, the DNA code of our genome is about 99.9% identical between any two individuals. It is the small differences—the genetic variants—in the remaining 0.1% that make us different from one another.
My research focuses on identifying the genetic variations that underlie our susceptibility to certain diseases. In particular, my lab aims to understand the biological basis of neurodegenerative diseases that result in cognitive deficits like those we see in Alzheimer’s disease, or movement disorders like those experienced in Parkinson’s disease (Figure 1).
Affecting about one in ten and predominantly striking in older age, neurodegenerative diseases are becoming a major healthcare burden in Singapore and many other countries with fast ageing populations.
Parkinson’s disease in Asian populations
Working together with researchers at the National Neuroscience Institute, we use genomics as a tool to study neurodegenerative diseases in Singaporean and East Asian populations.
Genome-wide association studies (GWAS) allow us to survey common genetic variations—those that occur in more than 1% of the population—for association with disease risk. Previous GWAS on nearly 40,000 Parkinson’s disease patients have identified about 90 genetic variants that seem to affect one’s risk of getting the disease. Unfortunately, over 90% of the studied patients have European ancestry, leaving a gap in our understanding of genetic variations and associated disease risk in other populations.
My lab has been working on building a corresponding large Asian sample collection. In collaboration with research groups in seven Asian regions, including Singapore, Malaysia, Hong Kong, Taiwan, China, South Korea and Japan, we are assembling a collection of genomic DNA from 10,000 Parkinson’s disease patients of East Asian heritage (Figure 2).
Preliminary findings of our GWAS show that genetic risk variants in Asian patients with Parkinson’s disease are overall very similar to those identified in the European cohort. However, there are also important differences. In particular, we identified two novel genetic variants that may play a role in Parkinson’s disease in Asians (Figure 3). The study’s findings of Asian disease-associated variants already improved our ability to identify at-risk individuals in the Singapore population, long before symptoms appear.
Sequencing “human knockouts”
While studies of knockout mice (mice with specific genes inactivated) provide insight into the function of each gene in the mouse, identifying naturally occurring “human knockouts” allows us to study what each gene does in humans.
To identify rare knockout variants, which are often unique to an individual and his or her closest relatives, we are sequencing the protein-encoding parts of genomes from the Asian Parkinson’s disease cohort, using an approach called whole-exome sequencing.
Comparing gene sequences derived from patients with those of healthy controls allows us to identify genes inactivated by knockout variants. These disease gene candidates are then studied further as potential treatment targets for Parkinson’s disease.
A step towards precision medicine
In our search for genetic knockout variants with strong effects on health, we have until recently neglected another class of genetic variants known as somatic variants, which arise during early embryonic development or accumulate with age. Recent studies have shown that the brain is in fact a genetic mosaic, whereby the DNA of each cell slightly differs from the DNA in a neighbouring cell.
We recently started to study somatic genetic variants in post-mortem brain tissue from the Multiple Sclerosis and Parkinson’s Tissue Bank at Imperial College London, UK. To study brain samples representative of Asian patients, NTU’s Lee Kong Chian School of Medicine—in collaboration with Singapore’s National Neuroscience Institute and National Healthcare Group—is establishing the Brain Bank Singapore, which will collect post-mortem brain tissue locally for studies on brain diseases.
To observe the effects of genetic variants on gene and cell function in vitro and in vivo, we will subsequently carry out disease modelling studies in the lab, including functional studies in zebrafish, mice and brain organoids (lab-grown miniature brain-resembling organs) (Figure 4). We will also monitor patients over long periods to correlate genetic variants with disease subtypes, prognosis and drug response.
Human genetics has the potential to bridge and integrate basic and translational neuroscience, which will lead us towards two important goals in the future of medicine—precision medicine and biological insight.