BackgroundSeveral articles suggest that DNA methylation levels in blood relate to Parkinson’s disease (PD) but there is a need for a large-scale study that involves suitable population based controls. The purposes of the study were: (1) to study whether PD status is associated with DNA methylation levels in blood/saliva; (2) to study whether observed associations relate to blood cell types; and (3) to characterize genome-wide significant markers (“CpGs”) and clusters of CpGs (co-methylation modules) in terms of biological pathways.MethodsIn a population-based case control study of PD, we studied blood samples from 335 PD cases and 237 controls and saliva samples from another 128 cases and 131 controls. DNA methylation data were generated from over 486,000 CpGs using the Illumina Infinium array. We identified modules of CpGs (clusters) using weighted correlation network analysis (WGCNA).ResultsOur cross-sectional analysis of blood identified 82 genome-wide significant CpGs (including cg02489202 in LARS2 p = 8.3 × 10–11 and cg04772575 in ABCB9 p = 4.3 × 10–10). Three out of six PD related co-methylation modules in blood were significantly enriched with immune system related genes. Our analysis of saliva identified five significant CpGs. PD-related CpGs are located near genes that relate to mitochondrial function, neuronal projection, cytoskeleton organization, systemic immune response, and iron handling.ConclusionsThis study demonstrates that: (1) PD status has a profound association with DNA methylation levels in blood and saliva; and (2) the most significant PD-related changes reflect changes in blood cell composition. Overall, this study highlights the role of the immune system in PD etiology but future research will need to address the causal structure of these relationships.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0466-5) contains supplementary material, which is available to authorized users.
An improved understanding of etiological mechanisms in Parkinson's disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.
Background: Lifestyle factors may contribute to the development of Parkinson’s disease, but little is known about factors that influence progression. The objective of the current study was to examine whether caffeine or alcohol consumption, physical activity, or cigarette smoking is associated with progression and survival among PD patients. Methods: We assessed lifelong coffee, tea, and alcohol consumption, smoking, and physical activity in a prospective community-based cohort (n = 360). All patients were passively followed for mortality (2001–2016); 244 were actively followed on average ± SD 5.3 ± 2.1 years (2007–2014). Movement disorder specialists repeatedly assessed motor function (Hoehn & Yahr) and cognition (Mini-Mental State Exam). We used Cox proportional hazards models and inverse probability weights to account for censoring. Results: Coffee, caffeinated tea, moderate alcohol consumption, and physical activity were protective against at least 1 outcome. Smoking and heavy alcohol consumption were associated with increased risks. Coffee was protective against time to Hoehn & Yahr stage 3 (hazard ratio, 0.52; 95% confidence interval, 0.28–1.01), cognitive decline (hazard ratio, 0.23; 95% confidence interval, 0.11,0.48), and mortality (hazard ratio, 0.47; 95% confidence interval, 0.32–0.69). Relative to moderate drinkers, those who never drank liquor and those who drank more heavily were at an increased risk of Hoehn & Yahr 3 (hazard ratio, 3.48; 95% confidence interval, 1.90–6.38; and hazard ratio, 2.16; 95% confidence interval, 1.03, 4.54, respectively). A history of competitive sports was protective against cognitive decline (hazard ratio, 0.46; 95% confidence interval, 0.22–0.96) and Hoehn & Yahr 3 (hazard ratio, 0.42; 95% confidence interval, 0.23–0.79), as was physical activity measured by metabolic-equivalent hours. Current cigarette smoking was associated with faster cognitive decline (hazard ratio, 3.20; 95% confidence interval, 1.02–10.01). Conclusions: This population-based study suggests that lifestyle factors influence PD progression and mortality.
This study finds chronic low-level OP exposure is associated with differential DNA methylation in blood and saliva, both in elderly population controls and PD patients. Our study results suggest that long-term sub-acute OP exposure influences methylation in genes enriched for muscarinic and nicotinic acetylcholine receptor pathways.
Background: DNA methylation studies in Parkinson’s disease (PD) thus far have focused on disease susceptibility but not progression. Objective: In this epigenome-wide association study (EWAS), we aim to identify methylation markers associated with faster cognitive decline or motor progression in PD. Methods: We included 232 PD patients from the Parkinson’s Environment and Gene follow-up study who provided blood samples at enrolment. Information on cognitive and motor function was collected using the Mini-Mental State Examination (MMSE) and Unified Parkinson’s Disease Rating Scale (UPDRS). For EWAS analyses, we used a robust measure of correlation: biweight midcorrelations, t-tests, and Cox proportional hazard models. We also conducted weighted correlation network analysis (WGCNA) to identify CpG modules associated with cognitive decline or motor progression in PD. Results: Among 197 individuals of European ancestry, with our EWAS approach we identified 7 genome-wide significant CpGs associated with a MMSE 4-point decline and 8 CpGs associated with faster motor progression (i.e., rate of UPDRS increase ≥5-point/year). The most interesting CpGs for cognitive decline include cg17445913 in KCNB1 (cor = 0.36, p = 6.85 × 10−7) and cg02920897 in DLEU2 (cor = 0.34, p = 3.23 × 10−6), while for motor progression it was cg01754178 in PTPRN2 (cor = −0.34, p = 2.07 × 10−6). In WGCNA, motor progression related modules were enriched for genes related to neuronal synaptic functions, Wnt signaling pathway, and mitochondrial apoptosis. Conclusions: Our study provides the first epigenetic evidence that differential methylation in genes previously identified as being associated with cognitive impairment, neuronal synaptic function, Wnt signaling pathway, and mitochondrial apoptosis is associated with cognitive and motor progression in PD.
We report the magneto-transport, scattering mechanisms, and effective mass analysis of an ultra-low density two-dimensional hole gas capacitively induced in an undoped strained Ge/Si0.2Ge0.8 heterostructure. This fabrication technique allows hole densities as low as p ∼ 1.1 × 1010 cm−2 to be achieved, more than one order of magnitude lower than previously reported in doped Ge/SiGe heterostructures. The power-law exponent of the electron mobility versus density curve, μ ∝ nα, is found to be α ∼ 0.29 over most of the density range, implying that background impurity scattering is the dominant scattering mechanism at intermediate densities in such devices. A charge migration model is used to explain the mobility decrease at the highest achievable densities. The hole effective mass is deduced from the temperature dependence of Shubnikov-de Haas oscillations. At p ∼ 1.0 × 1011 cm−2, the effective mass m* is ∼0.105 m0, which is significantly larger than masses obtained from modulation-doped Ge/SiGe two-dimensional hole gases.
Even as today's most prominent spin-based qubit technologies are maturing in terms of capability and sophistication, there is growing interest in exploring alternate material platforms that may provide advantages, such as enhanced qubit control, longer coherence times, and improved extensibility. Recent advances in heterostructure material growth have opened new possibilities for employing hole spins in semiconductors for qubit applications. Undoped, strained Ge/SiGe quantum wells are promising candidate hosts for hole spin-based qubits due to their low disorder, large intrinsic spin-orbit coupling strength, and absence of valley states. Here, we use a simple one-layer gated device structure to demonstrate both a single quantum dot as well as coupling 2 between two adjacent quantum dots. The hole effective mass in these undoped structures, m* ~ 0.08 m0, is significantly lower than for electrons in Si/SiGe, pointing to the possibility of enhanced tunnel couplings in quantum dots and favorable qubit-qubit interactions in an industry-compatible semiconductor platform. CONCLUSIONSWe have demonstrated lithographically defined single and double hole quantum dots in high quality strained Ge/SiGe quantum wells. These results strongly suggest that this material system may serve as a viable host for spin-based qubits (compatible with CMOS processing) and enable quantitative comparisons between quantum dots in electron and hole systems. Multi-metal-layer devices, as are commonly used in Si/SiGe, should be directly applicable to Ge/SiGe to increase the sharpness of tunnel barriers and provide more orthogonal control of coupling between adjacent quantum dots. Development of successful qubit architectures will ultimately call for indepth studies of qubit decoherence mechanisms in this system, in particular the impact of charge noise due to the enhanced spin-orbit coupling. AUTHOR INFORMATION
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