The development of posttraumatic stress disorder (PTSD) is influenced by genetic factors. Although there have been some replicated candidates, the identification of risk variants for PTSD has lagged ...behind genetic research of other psychiatric disorders such as schizophrenia, autism, and bipolar disorder. Psychiatric genetics has moved beyond examination of specific candidate genes in favor of the genome-wide association study (GWAS) strategy of very large numbers of samples, which allows for the discovery of previously unsuspected genes and molecular pathways. The successes of genetic studies of schizophrenia and bipolar disorder have been aided by the formation of a large-scale GWAS consortium: the Psychiatric Genomics Consortium (PGC). In contrast, only a handful of GWAS of PTSD have appeared in the literature to date. Here we describe the formation of a group dedicated to large-scale study of PTSD genetics: the PGC-PTSD. The PGC-PTSD faces challenges related to the contingency on trauma exposure and the large degree of ancestral genetic diversity within and across participating studies. Using the PGC analysis pipeline supplemented by analyses tailored to address these challenges, we anticipate that our first large-scale GWAS of PTSD will comprise over 10 000 cases and 30 000 trauma-exposed controls. Following in the footsteps of our PGC forerunners, this collaboration-of a scope that is unprecedented in the field of traumatic stress-will lead the search for replicable genetic associations and new insights into the biological underpinnings of PTSD.
We examined concordance of methylation levels across the Illumina Infinium HumanMethylation450 BeadChip and the Infinium MethylationEPIC BeadChip.
We computed the correlation for 145 whole blood DNA ...samples at each of the 422,524 CpG sites measured by both chips.
The correlation at some sites was high (up to r = 0.95), but many sites had low correlation (55% had r < 0.20). The low correspondence between 450K and EPIC measured methylation values at many loci was largely due to the low variability in methylation values for the majority of the CpG sites in blood.
Filtering out probes based on the observed correlation or low variability may increase reproducibility of BeadChip-based epidemiological studies.
While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in ...non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer's Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10
), in ROBO1 (rs11919682, p = 1.63 × 10
), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10
). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10
), CD2AP (rs7738720, p = 1.14 × 10
), and ABCA7 (rs73505251, p = 3.26 × 10
), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.
Functional connectomics from resting-state fMRI Smith, Stephen M; Vidaurre, Diego; Beckmann, Christian F ...
Trends in cognitive sciences,
12/2013, Letnik:
17, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Highlights • Spontaneous fluctuations in brain activity reflect functional brain networks. • We review rfMRI for mapping the functional connectome. • We review methods for functional connectomics ...network analysis. • We describe the WU–Minn Human Connectome Project. • We present exciting new analyses using the latest-released HCP data.
This work describes the development of an intermittently aerated pilot-scale process (V = 0.34 m(3)) operated without oxidized nitrogen recycle and supplemental carbon addition optimized for nitrogen ...removal via nitritation/denitritation. The aeration pattern was controlled using a novel aeration strategy based on set-points for reactor ammonia, nitrite and nitrate concentrations with the aim of maintaining equal effluent ammonia and nitrate + nitrite (NOx) concentrations. Further, unique operational and process control strategies were developed to facilitate the out-selection of nitrite oxidizing bacteria (NOB) based on optimizing the chemical oxygen demand (COD) input, imposing transient anoxia, aggressive solids retention time (SRT) operation towards ammonia oxidizing bacteria (AOB) washout and high dissolved oxygen (DO) (>1.5 mg/L). Sustained nitrite accumulation (NO2-N/NOx-N = 0.36 ± 0.27) was observed while AOB activity was greater than NOB activity (AOB: 391 ± 124 mgN/L/d, NOB: 233 ± 151 mgN/L/d, p < 0.001) during the entire study. The reactor demonstrated total inorganic nitrogen (TIN) removal rate of 151 ± 74 mgN/L/d at an influent COD/ Formula: see text -N ratio of 10.4 ± 1.9 at 25 °C. The TIN removal efficiency was 57 ± 25% within the hydraulic retention time (HRT) of 3 h and within an SRT of 4-8 days. Therefore, this pilot-scale study demonstrates that application of the proposed online aeration control is able to out-select NOB in mainstream conditions providing relatively high nitrogen removal without supplemental carbon and alkalinity at a low HRT.
•This paper reviews the pharmacogenetics of the serotonin reuptake inhibitors currently endorsed for the treatment of PTSD.•The focus is on genes implicated both in PTSD and the pharmacokinetics or ...pharmacodynamics of these medications.•It concludes with overview of emerging commercial platforms and directions for future pharmacogenetic research on PTSD.
Progress in PTSD pharmacotherapy has lagged far behind that of other major mental illnesses. Unfortunately, due to the enormous costs and lengthy process involved in bringing drugs to market, delivering new treatments to patients with PTSD in the near future will remain a challenge. However, by capitalizing on recent advances in the pharmacogenetics of antidepressants, precision psychiatry approaches can be leveraged to optimize the delivery of currently-available medications in a fraction of the time and cost required to develop novel therapeutics. This paper provides a review of the pharmacogenetics of the four serotonin reuptake inhibitors (SRIs) that are currently endorsed for the treatment of PTSD (paroxetine, sertraline, fluoxetine and venlafaxine). It focuses on genes involved in SRI pharmacokinetics (including the liver enzyme genes CYP2D6 and CYP2C19 and blood-brain barrier-relevant gene ABCB1) as well as those implicated in both SRI pharmacodynamics and the pathophysiology of PTSD and related conditions (e.g., BDNF, FKBP5, HTR1A, HTR2A, TPH2). The review concludes with an overview of emerging commercial platforms for pharmacogenetic-guided prescription and a discussion of challenges and directions for future pharmacogenetic research on PTSD.
Differentially methylated regions (DMRs) are genomic regions with methylation patterns across multiple CpG sites that are associated with a phenotype. In this study, we proposed a Principal Component ...(PC) based DMR analysis method for use with data generated using the Illumina Infinium MethylationEPIC BeadChip (EPIC) array. We obtained methylation residuals by regressing the M-values of CpGs within a region on covariates, extracted PCs of the residuals, and then combined association information across PCs to obtain regional significance. Simulation-based genome-wide false positive (GFP) rates and true positive rates were estimated under a variety of conditions before determining the final version of our method, which we have named DMR
PC
. Then, DMR
PC
and another DMR method, coMethDMR, were used to perform epigenome-wide analyses of several phenotypes known to have multiple associated methylation loci (age, sex, and smoking) in a discovery and a replication cohort. Among regions that were analysed by both methods, DMR
PC
identified 50% more genome-wide significant age-associated DMRs than coMethDMR. The replication rate for the loci that were identified by only DMR
PC
was higher than the rate for those that were identified by only coMethDMR (90% for DMRPC vs. 76% for coMethDMR). Furthermore, DMR
PC
identified replicable associations in regions of moderate between-CpG correlation which are typically not analysed by coMethDMR. For the analyses of sex and smoking, the advantage of DMR
PC
was less clear. In conclusion, DMR
PC
is a new powerful DMR discovery tool that retains power in genomic regions with moderate correlation across CpGs.
The neurotransmitter gamma-aminobutyric acid (GABA) is widely distributed in the mammalian central nervous system, where it acts as a major mediator of synaptic inhibition. GABA also serves as a ...neurotransmitter in a range of invertebrate phyla, including arthropods, echinoderms, annelids, nematodes, and platyhelminthes. This article reviews evidence supporting the neurotransmitter role of GABA in gastropod molluscs, with an emphasis on its presence in identified neurons and well-characterized neural circuits. The collective findings indicate that GABAergic signaling participates in the selection and specification of motor programs, as well as the bilateral coordination of motor circuits. While relatively few in number, GABAergic neurons can influence neural circuits via inhibitory, excitatory, and modulatory synaptic actions. GABA's colocalization with peptidergic and classical neurotransmitters can broaden its integrative capacity. The functional properties of GABAergic neurons in simpler gastropod systems may provide insight into the role of this neurotransmitter phenotype in more complex brains.
Wild pigs (Sus scrofa), also known as wild swine, feral pigs, or feral hogs, are one of the most widespread and successful invasive species around the world. Wild pigs have been linked to extensive ...and costly agricultural damage and present a serious threat to plant and animal communities due to their rooting behavior and omnivorous diet. We modeled the current distribution of wild pigs in the United States to better understand the physiological and ecological factors that may determine their invasive potential and to guide future study and eradication efforts. Using national-scale wild pig occurrence data reported between 1982 and 2012 by wildlife management professionals, we estimated the probability of wild pig occurrence across the United States using a logistic discrimination function and environmental covariates hypothesized to influence the distribution of the species. Our results suggest the distribution of wild pigs in the U.S. was most strongly limited by cold temperatures and availability of water, and that they were most likely to occur where potential home ranges had higher habitat heterogeneity, providing access to multiple key resources including water, forage, and cover. High probability of occurrence was also associated with frequent high temperatures, up to a high threshold. However, this pattern is driven by pigs' historic distribution in warm climates of the southern U.S. Further study of pigs' ability to persist in cold northern climates is needed to better understand whether low temperatures actually limit their distribution. Our model highlights areas at risk of invasion as those with habitat conditions similar to those found in pigs' current range that are also near current populations. This study provides a macro-scale approach to generalist species distribution modeling that is applicable to other generalist and invasive species.
Differentially methylated regions (DMRs) are genomic regions with specific methylation patterns across multiple loci that are associated with a phenotype. We examined the genome-wide false positive ...(GFP) rates of five widely used DMR methods: comb-p, Bumphunter, DMRcate, mCSEA and coMethDMR using both Illumina HumanMethylation450 (450 K) and MethylationEPIC (EPIC) data and simulated continuous and dichotomous null phenotypes (i.e., generated independently of methylation data). coMethDMR provided well-controlled GFP rates (~5%) except when analysing skewed continuous phenotypes. DMRcate generally had well-controlled GFP rates when applied to 450 K data except for the skewed continuous phenotype and EPIC data only for the normally distributed continuous phenotype. GFP rates for mCSEA were at least 0.096 and comb-p yielded GFP rates above 0.34. Bumphunter had high GFP rates of at least 0.35 across conditions, reaching as high as 0.95. Analysis of the performance of these methods in specific regions of the genome found that regions with higher correlation across loci had higher regional false positive rates on average across methods. Based on the false positive rates, coMethDMR is the most recommended analysis method, and DMRcate had acceptable performance when analysing 450 K data. However, as both could display higher levels of FPs for skewed continuous distributions, a normalizing transformation of skewed continuous phenotypes is suggested. This study highlights the importance of genome-wide simulations when evaluating the performance of DMR-analysis methods.
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