Background: Thyroid disorders are associated with an increased risk of cognitive impairment and Alzheimer's disease. Both small vessel disease and neurodegeneration have a role in the pathogenesis of cognitive impairment and Alzheimer's disease. Thyroid hormone receptor alpha (TR?) is the predominant TR in brain. The circadian clock gene REV-ERB? overlaps with the TR? gene and interferes with TR? expression. Limited data are available on the role of the TR?/REV-ERB? locus in small vessel disease and neurodegeneration. We therefore studied genetic variation in the TR?/REV-ERB? locus in relation to brain imaging data, as early markers for small vessel disease and neurodegeneration. Methods: Fifteen polymorphisms, covering the TR?/REV-ERB? locus, were studied in relation to white matter lesion (WML), total brain, and hippocampal volumes in the Rotterdam Study I (RS-I, n=454). Associations that remained significant after multiple testing correction were subsequently studied in an independent population for replication (RS-II, n=607). Results: No associations with total brain or hippocampal volumes were detected. A haplotype block in REV-ERB? was associated with WML volumes in RS-I. Absence of this haplotype was associated with larger WML volumes in women (0.38%±0.18% [?±SE], p=0.007), but not in men (0.04%±0.11%, p=0.24), which was replicated in RS-II (women: 0.15%±0.05%, p=0.04; men: 0.05%±0.07%, p=0.80). Meta-analysis of the two populations showed that women lacking this haplotype have a 1.9 times larger WML volume (p=0.001). Conclusion: Our results suggest a role for REV-ERB? in the pathogenesis of WMLs.