Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities

Area of Science:

• Neurogenetics
• Neuroimaging
• Genomics

Background:

• White matter hyperintensities (WMH) are classified as periventricular (PVWMH) or deep (DWMH).
• These classifications suggest differing underlying causes.
• Previous research has not fully elucidated their distinct genetic architectures.

Purpose of the Study:

• To conduct genome-wide association analyses (GWAS) for PVWMH and DWMH.
• To determine if these WMH phenotypes share or have distinct genetic underpinnings.
• To identify novel genetic loci associated with PVWMH and DWMH.

Main Methods:

• GWAS were performed on 26,654 participants from CHARGE, ENIGMA, and UK Biobank cohorts.
• Regional and cross-trait genetic correlations were investigated using pairwise GWAS and LDSC.
• Discovery, replication, and meta-analyses were conducted for PVWMH and DWMH.

Main Results:

• Genome-wide significant associations for PVWMH were identified on chromosomes 2, 6, 7, 10, 13, 16, and 17q23.1.
• A shared locus at 17q25.1 was significant for both DWMH and PVWMH.
• PVWMH showed stronger genetic correlations with small vessel ischemic stroke, while DWMH loci were implicated in vascular, astrocyte, and neuronal functions.

Conclusions:

• PVWMH and DWMH possess distinct, yet partially shared, genetic architectures.
• Genetic factors influencing PVWMH are more strongly associated with ischemic stroke.
• The study identified novel candidate genes for PVWMH, reinforcing their distinct neuroimaging classifications.