Association study of promoter polymorphisms at the dopamine transporter gene in Attention Deficit Hyperactivity Disorder

<p>Abstract</p> <p>Background</p> <p>Attention deficit hyperactivity disorder (ADHD) is a complex neurobehavioral disorder. The dopamine transporter gene (DAT1/<it>SLC6A3</it>) has been considered a good candidate for ADHD. Most association studies with ADHD have investigated the 40-base-pair variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region of DAT1. Only few studies have reported association between promoter polymorphisms of the gene and ADHD.</p> <p>Methods</p> <p>To investigate the association between the polymorphisms -67A/T (rs2975226) and -839C/T (rs2652511) in promoter region of DAT1 in ADHD, two samples of ADHD patients from the UK (n = 197) and Taiwan (n = 212) were genotyped, and analysed using within-family transmission disequilibrium test (TDT).</p> <p>Results</p> <p>A significant association was found between the T allele of promoter polymorphism -67A/T and ADHD in the Taiwanese population (<it>P </it>= 0.001). There was also evidence of preferential transmission of the T allele of -67A/T polymorphism in combined samples from the UK and Taiwan (<it>P </it>= 0.003). No association was detected between the -839C/T polymorphism and ADHD in either of the two populations.</p> <p>Conclusion</p> <p>The finding suggests that genetic variation in the promoter region of DAT1 may be a risk factor in the development of ADHD.</p

Exhaustive prediction of disease susceptibility to coding base changes in the human genome

<p>Abstract</p> <p>Background</p> <p>Single Nucleotide Polymorphisms (SNPs) are the most abundant form of genomic variation and can cause phenotypic differences between individuals, including diseases. Bases are subject to various levels of selection pressure, reflected in their inter-species conservation.</p> <p>Results</p> <p>We propose a method that is not dependant on transcription information to score each coding base in the human genome reflecting the disease probability associated with its mutation. Twelve factors likely to be associated with disease alleles were chosen as the input for a support vector machine prediction algorithm. The analysis yielded 83% sensitivity and 84% specificity in segregating disease like alleles as found in the Human Gene Mutation Database from non-disease like alleles as found in the Database of Single Nucleotide Polymorphisms. This algorithm was subsequently applied to each base within all known human genes, exhaustively confirming that interspecies conservation is the strongest factor for disease association. For each gene, the length normalized average disease potential score was calculated. Out of the 30 genes with the highest scores, 21 are directly associated with a disease. In contrast, out of the 30 genes with the lowest scores, only one is associated with a disease as found in published literature. The results strongly suggest that the highest scoring genes are enriched for those that might contribute to disease, if mutated.</p> <p>Conclusion</p> <p>This method provides valuable information to researchers to identify sensitive positions in genes that have a high disease probability, enabling them to optimize experimental designs and interpret data emerging from genetic and epidemiological studies.</p

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Increased Litterfall in Tropical Forests Boosts the Transfer of Soil CO2 to the Atmosphere

Aboveground litter production in forests is likely to increase as a consequence of elevated atmospheric carbon dioxide (CO2) concentrations, rising temperatures, and shifting rainfall patterns. As litterfall represents a major flux of carbon from vegetation to soil, changes in litter inputs are likely to have wide-reaching consequences for soil carbon dynamics. Such disturbances to the carbon balance may be particularly important in the tropics because tropical forests store almost 30% of the global soil carbon, making them a critical component of the global carbon cycle; nevertheless, the effects of increasing aboveground litter production on belowground carbon dynamics are poorly understood. We used long-term, large-scale monthly litter removal and addition treatments in a lowland tropical forest to assess the consequences of increased litterfall on belowground CO2 production. Over the second to the fifth year of treatments, litter addition increased soil respiration more than litter removal decreased it; soil respiration was on average 20% lower in the litter removal and 43% higher in the litter addition treatment compared to the controls but litter addition did not change microbial biomass. We predicted a 9% increase in soil respiration in the litter addition plots, based on the 20% decrease in the litter removal plots and an 11% reduction due to lower fine root biomass in the litter addition plots. The 43% measured increase in soil respiration was therefore 34% higher than predicted and it is possible that this ‘extra’ CO2 was a result of priming effects, i.e. stimulation of the decomposition of older soil organic matter by the addition of fresh organic matter. Our results show that increases in aboveground litter production as a result of global change have the potential to cause considerable losses of soil carbon to the atmosphere in tropical forests

Complement receptor 1 gene (CR1) intragenic duplication and risk of Alzheimer’s disease

Single nucleotide variants (SNVs) within and surrounding the complement receptor 1 (CR1) gene show some of the strongest genome-wide association signals with late-onset Alzheimer’s disease. Some studies have suggested that this association signal is due to a duplication allele (CR1-B) of a low copy repeat (LCR) within the CR1 gene, which increases the number of complement C3b/C4b-binding sites in the mature receptor. In this study, we develop a triplex paralogue ratio test assay for CR1 LCR copy number allowing large numbers of samples to be typed with a limited amount of DNA. We also develop a CR1-B allele-specific PCR based on the junction generated by an historical non-allelic homologous recombination event between CR1 LCRs. We use these methods to genotype CR1 and measure CR1-B allele frequency in both late-onset and early-onset cases and unaffected controls from the United Kingdom. Our data support an association of late-onset Alzheimer’s disease with the CR1-B allele, and confirm that this allele occurs most frequently on the risk haplotype defined by SNV alleles. Furthermore, regression models incorporating CR1-B genotype provide a better fit to our data compared to incorporating the SNV-defined risk haplotype, supporting the CR1-B allele as the variant underlying the increased risk of late-onset Alzheimer’s disease

Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease

Introduction: There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C. Methods: Ten single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger. Results: Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7). Discussion: Our study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD

A next-generation liquid xenon observatory for dark matter and neutrino physics

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector