Investigating Rare Genetic Drivers of Fatty Liver Disease in British South Asians

Code: BC-DTP_2026_16

Title: Investigating Rare Genetic Drivers of Fatty Liver Disease in British South Asians

Primary Supervisor: Dr Elena G Bochukova 

Email: e.bochukova@qmul.ac.uk

Institute: Blizard Institute 

Secondary Supervisor: Professor Kenneth Linton 

Email: k.j.linton@qmul.ac.uk

Institute: Blizard Institute

Lay Summary:

We aim to study genetics of Fatty Liver Disease in British South Asians from East London, a population at heightened risk for development of the disease. Genetic research in European populations has failed to fully explain this risk, suggesting that rare, population-specific mutations are critical drivers in South Asians. Our approach uses the Genes & Health cohort, which is enriched for British Bangladeshi and Pakistani individuals, to find these high-impact genetic variants. We have recently identified rare, damaging mutations in two genes: APOB (involved in fat transport) and SHANK2 (an intracellular scaffolding protein) in fatty liver disease patients. We propose to genetically dissect the effect of these mutations by expanding the studies across other populations; describe the detailed clinical presentation; and perform cellular and metabolic investigation in hepatic stem cell derived models carrying the mutations in order to gain insight into the disease mechanisms. This project aims to uncover novel genetic causes of fatty liver disease in South Asians, ultimately leading to improved genetic screening for high-risk South Asian individuals and the identification of new drug targets for treating the disease.

Aims:

Our Primary Aim is to validate the association between rare mutations in APOB and SHANK2 and fatty liver disease in the Genes & Health cohort, and to mechanistically characterize the impact of SHANK2 variants on hepatocyte function in stem-cell derived cellular models. Three core Objectives will be pursued:

1. Genetic Validation: Precisely quantify the association and estimate the penetrance of rare APOB and SHANK2 variants with quantitative fatty liver phenotypes across the full ELGH dataset. Findings will be validated in external cohorts like the Million Veterans Programme (MVP) and UK Biobank (UKB).
2. Phenotype Deep-Diving using PheWAS: Characterize the metabolic and clinical profiles of variant carriers to define the specific MASLD sub-phenotype associated with each gene.
3. Mechanistic Dissection (In vitro) of SHANK2 Loss of Function Mutations: Functionally test the impact of identified rare mutations using CRISPR-edited induced pluripotent stem cell (iPSC)-derived 2D hepatocytes and 3D liver organoids. Determine the specific cellular mechanistic pathways perturbed (e.g., VLDL secretion, fat accumulation, cellular stress, and bile duct integrity) within these advanced cellular models.

References:

• Chen, S., et al. (2024). Cells, 13(6).
• Chen, Y., et al. (2023). Nat Genet, 55(10), 1640-1650.
• Finer, S et al. (2020). International Journal of Epidemiology, 49(1), 20-21i.
• Gaziano JM et al. (2016). J Clin Epidemiol. 70:214-23.
• Jamialahmadi, O et al. (2021). Gastroenterology, 160(5), 1634-1646 e1637.
• Jamialahmadi O. et al., (2024) Nature Medicine (30), p3614–
• Li, J et al. (2024). Aging (Albany NY), 16(5), 4591-4608.
• Li, W., et al. (2021). Clin Gastroenterol Hepatol, 19(8), 1698-1707 e1613.
• Mbatchou, J. et al. (2021). Nature Genetics, 53(7), 1097-1103.
• Medine, C. Net al. (2011). J Vis Exp(56), e2969. https://doi.org/10.3791/2969
• Molk, N et al. (2023). Front Med (Lausanne), 10, 1106441.
• Mun, S. Jet al.(2023). Sci Rep, 13(1), 22935.
• Pei, Y., & Goh, G. B. (2025). Gut Liver, 19(1), 8-18.
• Teng, M. L. Pet al. (2023). Clinical and Molecular Hepatology, 29, S32-S42.
• The Tabula Sapiens Consortium. (2022). Science, 376(6594), 715-723.
• Yoo, I., et al. (2024). Mol Cells, 47(8), 100095.
• Xu, L., Li, P. et al. Protein Cell 12, 174–193 (2021).