The Thyroid Hormone Receptor Alpha Locus and White Matter Lesions: A Role for the Clock Gene REV-ERB alpha

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 alpha) is the predominant TR in brain. The circadian clock gene REV-ERB alpha overlaps with the TR alpha gene and interferes with TR alpha expression. Limited data are available on the role of the TR alpha/REV-ERB alpha locus in small vessel disease and neurodegeneration. We therefore studied genetic variation in the TR alpha/REV-ERB alpha locus in relation to brain imaging data, as early markers for small vessel disease and neurodegeneration. Methods: Fifteen polymorphisms, covering the TR alpha/REV-ERB alpha 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 alpha was associated with WML volumes in RS-I. Absence of this haplotype was associated with larger WML volumes in women (0.38% +/- 0.18% [beta +/- 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 Conclusion: Our results suggest a role for REV-ERB alpha in the pathogenesis of WMLs.