A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium

Numerical solutions to the rate equations governing the simultaneous release of electrons and holes during thermoluminescence and isothermal decay

The usual, simple model for the analysis of thermoluminescence (TL) curves deals with just one trapping level and one recombination level and assumes that only one recombination pathway exists for the production of luminescence (e.g., the thermal release of trapped electrons to recombine with thermally stable, trapped holes). In this paper we examine a more complex model which allows for the thermal release of both charge carriers in the same temperature range. Known as the Schön-Klasens model, this charge-transfer scheme has been often suggested as a cause of the thermal quenching of luminescence in insulators. The set of four simultaneous differential equations which describe the flow of charge between the energy levels in the Schön-Klasens model is solved numerically without the use of approximations. The TL curve shapes so generated are then analyzed with use of the usual Randall-Wilkins, Garlick-Gibson, or general-order formalisms i.e., the so-called three-parameter form of equations. In the cases examined, good fits between the generated TL curves and the curves expected using these approximate formulations were obtained. We conclude that a fit of an experimental glow curve to a three-parameter form of equation cannot be used to indicate that the simple three-parameter model is necessarily valid. Additional to curve fitting, the curves were also analyzed using the conventional initial-rise and heating-rate methods. The parameters calculated from these analyses were compared with the original parameters inserted into the model and conclusions drawn regarding the interpretations of the calculated values. Finally, with use of these calculated parameters the isothermal stabilities of the TL curves were predicted and compared with the stabilities calculated from the numerical solution to the differential equations. We conclude that a three-parameter type of analysis is not a reliable means of estimating the thermal stability of the TL when the Schön-Klasens model is applicable. © 1985 The American Physical Society

Thermoluminescence kinetics for multipeak glow curves produced by the release of electrons and holes

A model is described for the calculation of multipeak glow curves. A set of (km+jm+2) equations are presented which describe the flow of electrons and holes between km different electron trapping levels, jm different hole trapping levels and the conduction and valence bands. The model can be applied to complex cases where glow curves result from both electron and hole transport. A computer program has been written to solve the system of equations numerically. Calculated glow curves for a number of interesting cases are presented and some other applications of the model are briefly discussed