Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRICLINICAL PERSPECTIVE

Benjamin F.J. Verhaaren, Stéphanie Debette, Joshua C. Bis, Jennifer A. Smith, M. Kamran Ikram, Hieab H. Adams, Ashley H. Beecham, Kumar B. Rajan, Lorna M. Lopez, Sandra Barral, Mark A. van Buchem, Jeroen van der Grond (+90 others)
2015 Circulation: Cardiovascular Genetics  
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
more » ... nd 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 by guest Verhaaren et al Multiethnic GWAS of Cerebral WMH 399 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. (Circ Cardiovasc Genet. 2015;8:398-409. C erebral white matter hyperintensities (WMH) are common in the aging population and are associated with an increased risk of stroke, vascular cognitive impairment, dementia, and death. 1 The prevalence and severity of WMH increase with advancing age and the presence of vascular risk factors, notably hypertension. 2 The pathophysiology of WMH is poorly understood but likely reflects ischemic or degenerative damage to the small vessels of the brain, leading to chronic cerebral hypoperfusion and myelin rarefaction. 3 Perivascular inflammation is a prominent pathological feature in WMH, 4 and WMH burden has been associated with circulating biomarkers of inflammation, including high-sensitivity C-reactive protein, interleukin-6, lipoprotein-associated phospholipase A2, and myeloperoxidase. 5,6 Statistical Analyses and Meta-Analysis Statistical analyses were performed similar to the previous meta-GWAS on WMH burden. 8 Analyses were performed separately by Clinical Perspective on p 409 by guest on November 10, 2017 http://circgenetics.ahajournals.org/ Downloaded from Loci with corresponding P value are given for the association with white matter hyperintensities burden. The sign indicates the direction of the effect of the risk allele. Multiple single-nucleotide polymorphisms at the same locus indicate independent associations.
doi:10.1161/circgenetics.114.000858 pmid:25663218 pmcid:PMC4427240 fatcat:k7cdljyqnnhnrnelnsqkpkbfn4