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Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium
Myriam Fornage1, Stephanie Debette, Joshua C Bis
1Brown Foundation Institute of Molecular Medicine, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA. Myriam.Fornage@uth.tmc.edu
Insights
Researchers identified a new genetic locus on chromosome 17 associated with white matter hyperintensities (WMH), a marker of brain aging and stroke risk. This discovery offers potential new insights into the causes of cerebral small vessel disease.
Area of Science:
- Neurogenetics
- Neuroimaging
- Vascular Neurology
Background:
- White matter hyperintensities (WMHs) are linked to brain aging, cognitive decline, dementia, and stroke.
- WMHs reflect ischemic damage to small cerebral vessels and have a significant genetic component.
- Identifying genetic loci for WMH burden is crucial for understanding its pathogenesis.
Purpose of the Study:
- To conduct a large-scale genome-wide association study (GWAS) to identify genetic variants associated with WMH burden.
- To replicate significant findings in independent cohorts to confirm their validity.
Main Methods:
- Meta-analysis of GWAS data from 9,361 stroke-free individuals of European descent across 7 community-based cohorts.
- Replication analysis in 3,024 individuals from 2 additional cohorts.
Main Results:
- A novel genetic locus on chromosome 17q25 associated with WMH burden was identified.
- Six novel risk-associated single nucleotide polymorphisms (SNPs) were found within this locus, including rs3744028.
- These variants conferred a small increase in WMH burden (4-8%).
Conclusions:
- This study identifies a new locus on chromosome 17 implicated in WMH burden in European populations.
- Further investigation of this locus may elucidate the mechanisms underlying cerebral white matter hyperintensities.
- The findings contribute to understanding the genetic architecture of small vessel disease.
Objective:
White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
Methods:
We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
Results:
We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).
Interpretation:
This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
