Dissertations & Theses (Open Access)

Date of Award

Spring 5-2020

Degree Name

Doctor of Philosophy (PhD)

Advisor(s)

Myriam Fornage Phd

Second Advisor

Jan Bressler Phd

Third Advisor

Michael Swartz Phd

Abstract

Cerebral white matter hyperintensities (WMH) on MRI are an indicator of cerebral small vessel disease, a major risk factor for vascular dementia and stroke. DNA methylation may contribute to the molecular underpinnings of WMH, which are highly heritable. We performed a meta-analysis of 11 epigenome-wide association studies in 6,019 middle-aged to elderly subjects, who were free of dementia and stroke and were of African (AA) or European (EA) descent. In each study, association between WMH volume and each CpG was tested within ancestry using a linear mixed model, adjusted for age, sex, total intracranial volume, white blood cell count, technical covariates, BMI, smoking and blood pressure (BP). To detect differentially methylated regions (DMRs), we also calculated region-based p values accounting for spatial correlations among CpGs. No individual CpG reached epigenome-wide significance, but suggestive novel associations were identified with cg17577122 (CLDN5, P=2.39E-7), cg24202936 (LOC441601, P=3.78E-7), cg03116124 (TRIM67, P=6.55E-7), cg04245766 (BMP4, P=3.78E-7) and cg06809326 (CCDC144NL, P=6.14E-7). Gene enrichment analyses implicated pathways involved in regulation of cell development and differentiation, especially of endothelial cells. We identified 11 DMRs (PSidak<0.05) and two were mapped to BP-related genes (HIVEP3, TCEA2). The most significant DMRs were mapped to PRMT1, a protein arginine methyltransferase involved in glioblastomagenesis (P=7.9E-12), and mapped to CCDC144NL-AS1, an antisense transcript of CCDC144NL (P=1.6E-11). Genes mapping to DMRs were enriched in biological processes related to lipoprotein metabolism and transport. Bi-directional Mendelian randomization analysis showed that DNA methylation level at cg06809326 influenced WMH burden (OR [95% CI] = 1.7[1.2-2.5], P=0.001) but not the reverse (P=0.89). Additionally, increased methylation at cg06809326 was associated with lower expression of CCDC144NL (P=3.3E-2), and two-step Mendelian randomization analysis supported its mediating role in the association of cg06809326 and WMH burden. CCDC144NL is known to be associated with diabetic retinopathy and the coiled coil proteins in general promotes integrin-dependent cell adhesion. Integrin-related pathway was further supported by integrative genetic analyses. In conclusion, we identified novel epigenetic loci associated with WMH burden, and further supported the role of cg06809326 in the WMH etiology implicating integrin-mediated pathology.

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