Abstract
Introduction: Cerebral white matter lesions (WML) increase the risk of stroke and dementia. WML burden is highly heritable, but few genetic variants have been identified to date, which explain a small proportion of the trait variance. To identify novel genetic loci for cerebral white matter lesions, we conducted a trans-ethnic meta-analysis of genome-wide association studies. Methods: We included 21,079 people of European (N=17,936), Afro-American (N=1,943), Hispanic (N=795), Chinese (N=204) and Malay (N=201) descent from 22 population-based cohorts in the middle-aged and elderly. People with dementia or stroke were excluded. WML burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study was imputed to the 1000 Genomes reference panel. We investigated the relationship between each SNP and WML burden with linear regression models, adjusted for age, sex and intracranial volume. A fixed-effects meta-analysis was conducted using a z-score based method for each ethnicity separately and for the total sample. Results: In the European sample, we confirmed a previously known locus on chr17q25 (p=3.9E-19) and identified two novel loci: on chr2p21 (p=4.1E-08) and chr10q24 (p=9.4E-10). Two additional loci, on chr1q22 (p=4.6E-08) and chr2p16 (p=1.6E-08), were identified in the trans-ethnic meta-analysis. The novel loci contain genes that are involved in the extracellular matrix (chr2p16), ubiquitination (chr1q22) and apoptosis (chr10q24) and have been implicated in Huntington’s disease (chr2p21), multiple sclerosis (chr2p21), medulloblastoma (chr10q24) and glioma (chr10q24, chr2p16). Suggestive associations (p<10-6) include loci on chr2q33 containing a gene involved in gliomas, and chr7q31 containing a gene implicated in autism and schizophrenia. Conclusions: We identified four novel loci for WML burden in a trans-ethnic meta-analysis of genome-wide association studies and confirmed a previously identified locus.
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