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Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease : Nature Neuroscience : Nature Research
(a) Braak-associated DNA methylation scores for the top-ranked cross-cortex DMPs identified using linear regression models in the London discovery cohort (Supplementary Table 9) were significantly correlated with neuropathology-associated differences at the same probes in both cortical regions profiled in the Mount Sinai replication cohort using linear regression models (PFC (n = 142) Braak score: r = 0.64, P = 6.03 × 10−13; STG (n = 144) Braak score: r = 0.63, P = 2.66 × 10−12; PFC amyloid burden: r = 0.65, P = 2.87 × 10−13; STG amyloid burden: r = 0.46, P = 1.09 × 10−6). Shown is data for Mount Sinai PFC Braak score analysis, with the two ANK1 probes (cg11823178 and cg05066959) highlighted in red. (b,c) cg11823178 and cg05066959 were significantly associated with Braak score in the STG (cg11823178: r = 0.28, t142 = 3.62, P = 1.63 × 10−4; cg05066959: r = 0.25, t142 = 3.29, P = 5.78 × 10−4) and PFC (cg11823178: r = 0.24, t140 = 3.14, P = 1.07 × 10−3; cg05066959: r = 0.21, t140 = 2.75, P = 4.00 × 10−3) (b), and amyloid pathology in the STG (cg11823178: r = 0.21, t142 = 2.81, P = 4.99 × 10−4; cg05066959: r = 0.27, t142 = 3.47, P = 5.65 × 10−4) and PFC (cg11823178: r = 0.29, t140 = 3.69, P = 2.35 × 10−4; cg05066959: r = 0.19, t140 = 2.56, P = 9.93 × 10−3) (c). (d) In the Oxford replication cohort, bisulfite-pyrosequencing was used to quantify DNA methylation across eight CpG sites spanning an extended ANK1 region. Linear models, adjusting for age and gender, confirmed significant neuropathology-associated hypermethylation in all three of the cortical regions assessed (Supplementary Fig. 1), most notably in the EC (n = 51), where six of the eight CpG sites showed a significant (amplicon average P = 0.0004) neuropathology-associated increase in DNA methylation (data is represented as mean ± s.e.m., *P [Editor: Admin]
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