More than one in four Singaporeans will suffer from a neurological condition within their lifetime. The prevalence of neurological disorders such as dementia and Parkinson’s disease is expected to rise further with the increasing life expectancy and an ageing population. These trends signify an urgent need to reduce disease burden and improve quality of life, through innovative research into the genetics and genomics underlying neurological disorders. Some projects in neurological disease at GIS are:
Parkinson’s disease genetics in East Asians
We are studying the genetics of Parkinson’s disease in East Asian populations in collaboration with the National Neuroscience Institute with whom we co-lead the Asia Parkinson’s disease Genetics consortium. We have collected ~7,000 cases and 25,000 controls which were analysed in a genome-wide association study to identify common genetic risk variants influencing Parkinson’s disease (Foo et al JAMA Neurol 2020). We are also doing whole exome sequencing of up to 5000 cases 5000 controls to identify genes with rare, high-penetrance variants influencing Parkinson’s disease risk. Disease-associated variants are being modelled in human pluripotent stem cell models including midbrain organoid models (Jo et al Cell Stem Cell 2016, Ann Neurol 2021).
Somatic mosaicism in Parkinson’s disease brains
We are applying single cell genomics technology at GIS to study somatic mosaicism in post-mortem human brain tissue. This is a collaboration with Imperial College and Parkinson’s UK brain bank which provides access to up to 500 post-mortem brain tissue from Parkinson’s disease patients. We are working on methods for single cell DNA sequencing to identify age-accumulated and postzygotic somatic mutations that may contribute to neurodegeneration.
Genetics of Vascular Dementia and Alzheimer’s disease
Alzheimer’s disease (AD) and vascular dementia (VaD) represent the two most common causes of dementia worldwide, frequently co-occurring and contributing jointly to cognitive decline in aging populations. Existing genome-wide association studies (GWAS) in AD and VaD have identified multiple susceptibility loci, yet these discoveries have largely been derived from clinically diagnosed cases and overwhelmingly from cohorts of European ancestry, limiting their relevance for diverse populations. As the field transitions from syndromic, symptom-based diagnosis to biologically grounded definitions incorporating biomarkers, such as p-tau217, and neuroimaging markers, including white matter hyperintensities, it has become increasingly clear that genomic studies must align with this biological precision. For Asian populations where AD and VaD pathology frequently coexist, there is an urgent need for GWAS anchored in biomarker proven disease. Studying genetic associations with specific AD and VaD pathologies rather than broad clinical labels offers a novel opportunity to dissect shared and distinct mechanisms linking neurodegeneration and cerebrovascular injury. By integrating WGS-based genomic discovery with quantitative biomarkers of AD pathology and small-vessel disease, our research aims to illuminate convergent pathways driving mixed dementia, ultimately enabling the identification of new therapeutic targets tailored to the biological complexity of AD–VaD in Asian populations.
Single-cell Spatial Omics
The emergence of single-cell and spatial omics has transformed our ability to map the molecular and cellular organisation of the human brain, providing increasingly comprehensive reference atlases of brain cell types, states and their spatial organisation. The next challenge is to move beyond cataloguing this complexity to understand how these molecular programmes shape brain function, disease susceptibility and progression. At GIS, we integrate single-cell and spatial omics with human brain tissue, patient-derived models and experimental systems to investigate the molecular mechanisms underlying neurological disease. We seek to identify disease-associated cell states and molecular programmes, determine how cells interact and transition between states, and distinguish causal mechanisms from consequences of disease. By combining high-resolution spatial profiling with functional perturbation and orthogonal experimental validation, we aim to translate insights from brain atlases into mechanistic understanding and, ultimately, new opportunities for intervention.
Contact:
Prof Liu Jian Jun
liuj3@gis.a-star.edu.sg