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Assessing Cortical Cerebral Microinfarcts on High Resolution MR Images
Published on: November 20, 2015
Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI
Background:
The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.
Methods And Results:
We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).
Conclusions:
We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
Insights
Researchers identified four new genetic loci linked to white matter hyperintensities (WMH), a risk factor for stroke and dementia. These findings highlight inflammatory and glial pathways in WMH development, expanding our understanding of brain health genetics.
Area of Science:
- Genetics and Genomics
- Neuroscience
- Medical Research
Background:
- Cerebral white matter hyperintensities (WMH) increase the risk of stroke, dementia, and mortality.
- WMH are highly heritable, but their genetic basis is not fully understood.
- Identifying genetic variants is crucial for understanding WMH pathogenesis.
Purpose of the Study:
- To identify novel genetic variants associated with white matter hyperintensity (WMH) burden.
- To conduct a comprehensive meta-analysis of multiethnic genome-wide association studies for WMH.
Main Methods:
- A meta-analysis of genome-wide association studies involving 21,079 individuals from 29 population-based cohorts.
- Participants were middle-aged to elderly, free of dementia and stroke, and of diverse ethnic backgrounds.
- WMH burden was quantified using MRI, and genotype data were imputed for analysis.
Main Results:
- Confirmed a known locus on chr17q25 and identified novel loci on chr10q24 and chr2p21 in European descent samples.
- Discovered two additional loci on chr1q22 and chr2p16 in the multiethnic meta-analysis.
- Novel loci contain genes associated with Alzheimer's disease, intracerebral hemorrhage, neuroinflammation, and glioma.
Conclusions:
- Identified four novel genetic loci influencing white matter hyperintensity (WMH) burden.
- These loci implicate inflammatory and glial proliferative pathways in WMH development.
- Findings expand beyond previously proposed ischemic mechanisms for WMH.
