Genome‐wide association studies of cerebral white matter lesion burden

Abstract

Objective White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)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. WMH 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 (GWAS) 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 one locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (Pdiscovery= 4.0×10−9; Preplication =1.3×10−7; Pcombined =4.0×10−15). Other SNPs in this region also reaching genome-wide significance are 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.

Heterogeneity in age-related white matter changes

“…Genome-wide association studies are another way to identify pathways involved in white matter lesion development. The CHARGE Consortium [25] provided the first meta-analysis of genome-wide association data from 9,361 individuals of European descent and identified novel genetic associations with white matter hyperintensity burden. Six SNPs mapping to a locus on chromosome 17q25 reached genome-wide significance, of which five were in strong linkage disequilibrium (r 2 [ 0.8).…”

Thrombogenic microvesicles and white matter hyperintensities in postmenopausal women

“…First, there may be several mechanisms underlying the pathophysiology of WMH, which were not addressed in this study, such as Table 2 Adjusted regression coefficients of associations of white matter hyperintensity load and progression of white matter hyperintensity with baseline platelet characteristics, numbers of microvesicles, and measures of atherosclerosis genetic modifiers of WMH load and progression. 11,38 Second, the Mayo Clinic KEEPS consisted of healthy, well-educated women, most of whom were nonsmokers, and may not reflect the general population of recently menopausal women. However, an advantage of a homogeneous population is that findings may reflect physiologic processes without the confounding effect of manageable cardiovascular risk factors.…”

Blood and CSF biomarkers in brain subcortical ischemic vascular disease: Involved pathways and clinical applicability

“…106 Later, authors from the Rotterdam Scan study replicated these associations within the 17q25 locus and more recently, the first replication for the same locus in a non-European population was published. 107,108 Finally, this locus was related with WMHs in a cohort of subjects with acute ischemic stroke, although on the contrary to what should be expected regarding etiology, lacunar stroke was not associated.…”