Significant Correlation Between White Matter Hyperintensity Volume and Rare NOTCH3 Variants in the General Japanese...

Area of Science:

• Neurology
• Genetics
• Radiology

Background:

• Cerebral small vessel disease (CSVD) is common in the elderly, with white matter hyperintensities (WMH) being a key MRI finding.
• Understanding the genetic underpinnings of CSVD is crucial for identifying at-risk populations and developing targeted interventions.

Purpose of the Study:

• To investigate the contribution of hereditary genes associated with CSVD to MRI findings in a general Japanese population.
• Specifically, to examine the relationship between variants in genes like NOTCH3 and ABCC6 and markers of CSVD, such as WMH and lacunes.

Main Methods:

• Analysis of MRI data and genetic variants from 324 individuals aged 50+ in the Tohoku Medical Megabank (TMM) cohort.
• Focus on variants in NOTCH3, ABCC6, COL4A1, COL4A2, GLA, HTRA1, and TREX1 genes, adjusting for factors like age, sex, hypertension, and diabetes.
• Gene-based association tests (burden test, SKAT) were employed to analyze the relationship between genetic variants and WMH/lacune volume.

Main Results:

• Pathogenic variants were found in the ABCC6 gene (n=20).
• A significant correlation was observed between white matter hyperintensity (WMH) volume and rare NOTCH3 variants using the sequence kernel association test (SKAT) (p=0.027 after full adjustment).
• No significant association was found between intracranial major artery stenosis/occlusion (ICASO) and the RNF213 p.Arg4810Lys variant.

Conclusions:

• The study suggests that NOTCH3 variants may play a role in determining white matter hyperintensity (WMH) volume within the general Japanese population.
• This finding highlights the potential genetic contribution to cerebral small vessel disease (CSVD) pathogenesis.