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Approved Research

The Role of Rare Variants on NOTCH3 in Brain White Matter Hyperintensities and Cerebral Small Vascular Disease in UK Biobank Participants

Principal Investigator: Dr Yi-Cheng Zhu
Approved Research ID: 87582
Approval date: January 16th 2023

Lay summary

Cerebral small vessel disease (CSVD) is a common chronic disease affecting older adults and increasing the risk of dementia and stroke. It is diagnosed by examining the abnormalities in magnetic resonance imaging (MRI) of the brain. Previous studies have suggested CSVD as well as abnormalities in MRI are associated with genetic variants. The Neurogenic locus notch homolog protein 3 (NOTCH3) gene is involved in vascular function and its common variants have been found to be associated with CSVD. However, studies on rare variants of NOTCH3 are lacking. In our previous research in a Chinese cohort, we found carriers of rare variants of NOTCH3 increase the risk of aging-related CSVD.

Therefore, in this 36-months research project, we would like to explore whether carrying rare variants of NOTCH3 would contribute to an increased risk of CSVD and MRI abnormalities in a more diverse population using UK Biobank.

To clarify this issue, we would identify carriers with rare variants of NOTCH3 using the whole-exome sequencing data in UK Biobank. Then, we would group the carriers and non-carriers and compare their risk of CSVD and MRI abnormalities. We would also identify individuals carrying rare variants that are related to the EGFr domain, which is considered to impact the function of NOTCH3 gene directly. In addition, we would also like to describe the clinical characteristics of carriers of rare NOTCH3 variants and explore the functions of those variants, so we can better understand how the variants contribute to the development of CSVD.

This project would lead to a better understanding of the etiology of CSVD. As CSVD is chronic and progressive, identification of genetic markers of high-risk populations would also help early detection and management of the disease, and lead to better health outcomes.