GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Pine Sawyers (Coleoptera: Cerambycidae) Attracted to α-Pinene, Monochamol, and Ipsenol in North America.

Detection tools are needed for Monochamus species (Coleoptera: Cerambycidae) because they are known to introduce pine wilt disease by vectoring nematodes in Asia, Europe, and North America. In 2012-2014, we examined the effects of the semiochemicals monochamol and ipsenol on the flight responses of the sawyer beetles Monochamus carolinensis (Olivier), Monochamus clamator (LeConte), Monochamus mutator LeConte, Monochamus notatus (Drury), Monochamus obtusus Casey, Monochamus scutellatus (Say), and Monochamus titillator (F.) complex (Coleoptera: Cerambycidae) to traps baited with α-pinene. Experiments were set in pine forests in New Brunswick and Ontario (Canada), and Arizona, Georgia, Michigan, Montana, Oregon, South Carolina, Utah, and Washington (United States). In brief, 40 traps were placed in 10 blocks of 4 traps per block per location. Traps were baited with: 1) α-pinene; 2) α-pinene + monochamol; 3) α-pinene + ipsenol; and 4) α-pinene + monochamol + ipsenol. Monochamol increased catches of six species and one species complex of Monochamus with an additive effect of ipsenol for five species and one species complex. There was no evidence of synergy between monochamol and ipsenol on beetle catches. Monochamol had no effect on catches of other Cerambycidae or on any associated species of bark beetles, weevils, or bark beetle predators. We present a robust data set suggesting that the combination of α-pinene, ipsenol, and monochamol may be a useful lure for detecting Monochamus species.

Variation in the Williams syndrome GTF2I gene and anxiety proneness interactively affect prefrontal cortical response to aversive stimuli.

Characterizing the molecular mechanisms underlying the heritability of complex behavioral traits such as human anxiety remains a challenging endeavor for behavioral neuroscience. Copy-number variation (CNV) in the general transcription factor gene, GTF2I, located in the 7q11.23 chromosomal region that is hemideleted in Williams syndrome and duplicated in the 7q11.23 duplication syndrome (Dup7), is associated with gene-dose-dependent anxiety in mouse models and in both Williams syndrome and Dup7. Because of this recent preclinical and clinical identification of a genetic influence on anxiety, we examined whether sequence variation in GTF2I, specifically the single-nucleotide polymorphism rs2527367, interacts with trait and state anxiety to collectively impact neural response to anxiety-laden social stimuli. Two hundred and sixty healthy adults completed the Tridimensional Personality Questionnaire Harm Avoidance (HA) subscale, a trait measure of anxiety proneness, and underwent functional magnetic resonance imaging (fMRI) while matching aversive (fearful or angry) facial identity. We found an interaction between GTF2I allelic variations and HA that affects brain response: in individuals homozygous for the major allele, there was no correlation between HA and whole-brain response to aversive cues, whereas in heterozygotes and individuals homozygous for the minor allele, there was a positive correlation between HA sub-scores and a selective dorsolateral prefrontal cortex (DLPFC) responsivity during the processing of aversive stimuli. These results demonstrate that sequence variation in the GTF2I gene influences the relationship between trait anxiety and brain response to aversive social cues in healthy individuals, supporting a role for this neurogenetic mechanism in anxiety.

Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression.

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32 or PPP1R1B) has been of interest in schizophrenia owing to its critical function in integrating dopaminergic and glutaminergic signaling. In a previous study, we identified single-nucleotide polymorphisms (SNPs) and a frequent haplotype associated with cognitive and imaging phenotypes that have been linked with schizophrenia, as well as with expression of prefrontal cortical DARPP-32 messenger RNA (mRNA) in a relatively small sample of postmortem brains. In this study, we examined the association of expression of two major DARPP-32 transcripts, full-length (FL-DARPP-32) and truncated (t-DARPP-32), with genetic variants of DARPP-32 in three brain regions receiving dopaminergic input and implicated in schizophrenia (the dorsolateral prefrontal cortex (DLPFC), hippocampus and caudate) in a much larger set of postmortem samples from patients with schizophrenia, bipolar disorder, major depression and normal controls (>700 subjects). We found that the expression of t-DARPP-32 was increased in the DLPFC of patients with schizophrenia and bipolar disorder, and was strongly associated with genotypes at SNPs (rs879606, rs90974 and rs3764352), as well as the previously identified 7-SNP haplotype related to cognitive functioning. The genetic variants that predicted worse cognitive performance were associated with higher t-DARPP-32 expression. Our results suggest that variation in PPP1R1B affects the abundance of the splice variant t-DARPP-32 mRNA and may reflect potential molecular mechanisms implicated in schizophrenia and affective disorders.

Kinetic instabilities that limit ß in the edge of a tokamak plasma: a picture of an H-mode pedestal.

Plasma equilibria reconstructed from the Mega-Amp Spherical Tokamak have sufficient resolution to capture plasma evolution during the short period between edge-localized modes (ELMs). Immediately after the ELM, steep gradients in pressure, P, and density, n(e), form pedestals close to the separatrix, and they then expand into the core. Local gyrokinetic analysis over the ELM cycle reveals the dominant microinstabilities at perpendicular wavelengths of the order of the ion Larmor radius. These are kinetic ballooning modes in the pedestal and microtearing modes in the core close to the pedestal top. The evolving growth rate spectra, supported by gyrokinetic analysis using artificial local equilibrium scans, suggest a new physical picture for the formation and arrest of this pedestal.

Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia.

Although the developers of the Positive and Negative Syndrome Scale (PANSS) grouped items into three subscales, factor analyses indicate that a five-factor model better characterizes PANSS data. However, lack of consensus on which model to use limits the comparability of PANSS variables across studies. We counted "votes" from published factor analyses to derive consensus models. One of these combined superior fit in our Caucasian sample (n=458, CFI=.970), and in distinct Japanese sample (n=164, CFI=.964), relative to the original three-subscale model, with a sorting of items into factors that was highly consistent across the studies reviewed.

Tuberculosis in HIV programmes in lower-income countries: practices and risk factors.

BACKGROUND: Tuberculosis (TB) is a common diagnosis in human immunodeficiency virus (HIV) infected patients on antiretroviral treatment (ART). OBJECTIVE: To describe TB-related practices in ART programmes in lower-income countries and identify risk factors for TB in the first year of ART. METHODS: Programme characteristics were assessed using standardised electronic questionnaire. Patient data from 2003 to 2008 were analysed and incidence rate ratios (IRRs) calculated using Poisson regression models. RESULTS: Fifteen ART programmes in 12 countries in Africa, South America and Asia were included. Chest X-ray, sputum microscopy and culture were available free of charge in respectively 13 (86.7%), 14 (93.3%) and eight (53.3%) programmes. Eight sites (53.3%) used directly observed treatment and five (33.3%) routinely administered isoniazid preventive treatment (IPT). A total of 19 413 patients aged ≥ 16 years contributed 13,227 person-years of follow-up; 1081 new TB events were diagnosed. Risk factors included CD4 cell count (>350 cells/µl vs. <25 cells/µl, adjusted IRR 0.46, 95%CI 0.33-0.64, P < 0.0001), sex (women vs. men, adjusted IRR 0.77, 95%CI 0.68-0.88, P = 0.0001) and use of IPT (IRR 0.24, 95%CI 0.19-0.31, P < 0.0001). CONCLUSIONS: Diagnostic capacity and practices vary widely across ART programmes. IPT prevented TB, but was used in few programmes. More efforts are needed to reduce the burden of TB in HIV co-infected patients in lower income countries.

Prioritising prevention strategies for patients in antiretroviral treatment programmes in resource-limited settings.

Expanded access to antiretroviral therapy (ART) offers opportunities to strengthen HIV prevention in resource-limited settings. We invited 27 ART programmes from urban settings in Africa, Asia and South America to participate in a survey, with the aim to examine what preventive services had been integrated in ART programmes. Twenty-two programmes participated; eight (36%) from South Africa, two from Brazil, two from Zambia and one each from Argentina, India, Thailand, Botswana, Ivory Coast, Malawi, Morocco, Uganda and Zimbabwe and one occupational programme of a brewery company included five countries (Nigeria, Republic of Congo, Democratic Republic of Congo, Rwanda and Burundi). Twenty-one sites (96%) provided health education and social support, and 18 (82%) provided HIV testing and counselling. All sites encouraged disclosure of HIV infection to spouses and partners, but only 11 (50%) had a protocol for partner notification. Twenty-one sites (96%) supplied male condoms, seven (32%) female condoms and 20 (91%) provided prophylactic ART for the prevention of mother-to child transmission. Seven sites (33%) regularly screened for sexually transmitted infections (STI). Twelve sites (55%) were involved in activities aimed at women or adolescents, and 10 sites (46%) in activities aimed at serodiscordant couples. Stigma and discrimination, gender roles and funding constraints were perceived as the main obstacles to effective prevention in ART programmes. We conclude that preventive services in ART programmes in lower income countries focus on health education and the provision of social support and male condoms. Strategies that might be equally or more important in this setting, including partner notification, prompt diagnosis and treatment of STI and reduction of stigma in the community, have not been implemented widely.

Genes, cognition and brain through a COMT lens.

Various genes are known to modulate the delicate balance of dopamine in prefrontal cortex and influence cortical information processing. Catechol-O-methyltransferase (COMT) on chromosome 22q11 is the most widely studied of these genes. Val158Met, a common, functional variant in the coding sequence that increases or decreases the enzymatic activity of the gene has been shown to impact the efficiency of prefrontally-mediated cognition, specifically executive functioning, working memory, fluid intelligence and attentional control. We review the rapidly evolving literature exploring the association between COMT genotype and cognitive performance, and illustrate how this polymorphism has served a pivotal role in characterizing various interacting dimensions of complexity in the relationship between genes and cognition. We review how Val158Met has been used to help develop and validate behavioral and neurophysiological phenotypes, as a critical tool in dissecting overlapping neural functional systems and exploring interactions within and between genes, and in exploring how gene effects on cognition are modulated by environmental, demographic and developmental factors. Despite the impressive range of findings, the COMT story is also a bracing reminder of how much work remains to translate this knowledge into practical clinical applications.

SRTR program-specific reports on outcomes: a guide for the new reader.

Differences in outcomes indeed exist among transplant programs and organ procurement organizations (OPO). A growing set of tools are available from the Scientific Registry of Transplant Recipients (SRTR) to measure and assess these outcomes in the different phases of the transplant process. These tools are not intended to compare two individual programs, rather to help identify programs whose practices may need further scrutiny, to be either avoided, corrected or emulated. To understand which differences in outcomes might be due to underlying differences in populations served and which might be due to differences in treatment, it is important to compare outcomes to 'risk-adjusted' expected values. Further, it is important to recognize and assess the role that random chance may play in these outcomes by considering the p-value or confidence interval of each estimate. We present the reader with a basic explanation of these tools and their interpretation in the context of reading the SRTR Program-Specific Reports. We describe the intended audience of these reports, including patients, monitoring and process improvement bodies, payers and others such as the media. Use of these statistics in a way that reflects a basic understanding of these concepts and their limitations is beneficial for all audiences.

Traditional Healers; HIV/AIDS and Company Programmes in South Africa

This paper explores the organisational structures of traditional healers; outlines their explanations of HIV/AIDS; and discusses how they can be integrated with company programmes. The South African Traditional Health Practitioners Act seeks to register; regulate and promote traditional healers; but its ability to do this depends on strong; formalised associations of traditional healers. The different forms of traditional healer groupings in South Africa are described along with the implications that their organisational structure has for knowledge; competition and service standards. Traditional healers' diverse and fluid beliefs about HIV and AIDS are explained together with ways in which cooperation between companies; allopathic medicine and African traditional healing practices could be promoted in workplace responses to HIV/AIDS. It is suggested that such collaboration should focus on 'windows of compatibility' rather than on overall agreement. Moreover; it is argued that any response to HIV/AIDS must be embedded within a wider set of agreements; the most critical being a genuine process of referral between the traditional and allopathic healthcare systems. Companies are in a strong position to initiate such reforms; and this would support the professionalisation of traditional healers as well as help coordinate a wider and more effective response to the HIV epidemic in South Africa

Workplace Peer Educators and Stress

Peer educators form an important component of company responses to HIV and AIDS. Based on interviews with peer educators working in and around a mining company in South Africa's North-West Province; the study examines the relationship between involvement in peer education and stress. The paper discusses how becoming a peer educator can be a response to the often personal stress brought about by the HIV epidemic. In addition; structural difficulties; skills deficiencies and other obstacles to effective communication with their peers can create stress. The stress that active peer education brings to individuals is discussed; particularly in regard to the embeddedness of peer educators within their communities. The need for confidentiality also magnifies stress in the case of individuals who disregard peer educators' advice. Peer educators face many stresses in managing and supporting their own lives; thus their (voluntary) work as peer educators should not be taken out of context. Using this approach; we discuss how the role of peer educator should be conceptualised and how they can be organised and supported in order that their stress be minimised and effective engagement maximised

Use and Neglect of Best-Practice HIV/AIDS Programme Guides by South African Companies

Numerous guidelines set out best-practice policies for HIV/AIDS interventions in the workplace. This study analysed 14 recognised codes and guidelines to gain an understanding of the theoretical consensus regarding the key components of best-practice workplace HIV/AIDS interventions. Nine key components of best practice were drawn from the analysis; interviews aimed to verify these components by determining the extent to which HIV/AIDS practitioners in South Africa share a similar understanding of best practice. Participants in a research questionnaire and semi-structured interviews included managers responsible for company HIV/AIDS programmes; HIV/AIDS experts; consultants; and disease management service providers. There was a high level of agreement between the practitioners who were interviewed and the codes and guidelines that were analysed concerning what best practice entails. However; reported usage of the recognised codes and guidelines to inform workplace HIV/AIDS interventions was low. Although large companies in South Africa may recognise certain interventions as examples of best practice; it appears that these are not being readily implemented. This appears to be partly because the cost-benefit of a recommended intervention is not immediately apparent or conclusive; and also because the concept of best practice with respect to workplace HIV/AIDS interventions is not yet fully accepted

A systematic review of quantitative and qualitative research on the role and effectiveness of written information available to patients about individual medicines.

OBJECTIVES: To establish the role and value of written information available to patients about individual medicines from the perspective of patients, carers and professionals. To determine how effective this information is in improving patients' knowledge and understanding of treatment and health outcomes. DATA SOURCES: Electronic databases searched to late 2004, experts in information design, and stakeholder workshops (including patients and patient organisations). REVIEW METHODS: Data from selected studies were tabulated and the results were qualitatively synthesised along with findings from the information design and stakeholder workshop strands. RESULTS: Most people do not value the written information they receive. They had concerns about the use of complex language and poor visual presentation and in most cases the research showed that the information did not increase knowledge. The research showed that patients valued written information that was tailored to their individual circumstances and illness, and that contained a balance of harm and benefit information. Most patients wanted to know about any adverse effects that could arise. Patients require information to help decision-making about whether to take a medicine or not and (once taking a medicine) with ongoing decisions about the management of the medicine and interpreting symptoms. Patients did not want written information to be a substitute for spoken information from their prescriber. While not everyone wanted written information, those who did wanted sufficient detail to meet their need. Some health professionals thought that written information for patients should be brief and simple, with concerns about providing side-effect information. They saw increasing compliance as a prime function, in contrast to patients who saw an informed decision not to take a medicine as an acceptable outcome. CONCLUSIONS: The combination of a quantitative and qualitative review, an exploration of best practice in information design, plus the input of patients at stakeholder workshops, allowed this review to look at all perspectives. There is a gap between currently provided leaflets and information which patients would value and find more useful. The challenge is to develop methods of provision flexible enough to allow uptake of varying amounts and types of information, depending on needs at different times in an illness. This review has identified a number of areas where future research could be improved in terms of the robustness of its design and conduct, and the use of patient-focused outcomes. The scope for this research includes determining the content, delivery and layout of statutory leaflets that best meet patients' needs, and providing individualised information, which includes both benefit and harm information. In particular, studies of the effectiveness and role and value of Internet-based medicines information are needed.

Effects of HIV-related stigma among an early sample of patients receiving antiretroviral therapy in Botswana.

Botswana, with its estimated HIV prevalence of 37%, instituted a policy of universal access to antiretroviral therapy (ART) in 2002. Initial enrolment lagged behind expectations, with a shortfall in voluntary testing that observers have attributed to HIV-related stigma - although there are no published data on stigma among HIV-positive individuals in Botswana. We interviewed 112 patients receiving ART in 2000, finding evidence of pervasive stigma in patterns of disclosure, social sequelae, and delays in HIV testing. Ninety-four percent of patients reported keeping their HIV status secret from their community, while 69% withheld this information even from their family. Twenty-seven percent of patients said that they feared loss of employment as a result of their HIV status. Forty percent of patients reported that they delayed getting tested for HIV; of these, 51% cited fear of a positive test result as the primary reason for delay in seeking treatment, which was often due to HIV-related stigma. These findings suggest that success of large-scale national ART programmes will require initiatives targeting stigma and its social, economic and political correlates.

SRTR center-specific reporting tools: Posttransplant outcomes.

Measuring and monitoring performance--be it waiting list and posttransplant outcomes by a transplant center, or organ donation success by an organ procurement organization and its partnering hospitals--is an important component of ensuring good care for people with end-stage organ failure. Many parties have an interest in examining these outcomes, from patients and their families to payers such as insurance companies or the Centers for Medicare and Medicaid Services; from primary caregivers providing patient counseling to government agencies charged with protecting patients. The Scientific Registry of Transplant Recipients produces regular, public reports on the performance of transplant centers and organ procurement organizations. This article explains the statistical tools used to prepare these reports, with a focus on graft survival and patient survival rates of transplant centers--especially the methods used to fairly and usefully compare outcomes of centers that serve different populations. The article concludes with a practical application of these statistics--their use in screening transplant center performance to identify centers that may need remedial action by the OPTN/UNOS Membership and Professional Standards Committee.

Analytical methods and database design: implications for transplant researchers, 2005.

Understanding how transplant data are collected is crucial to understanding how the data can be used. The collection and use of Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR) data continues to evolve, leading to improvements in data quality, timeliness and scope while reducing the data collection burden. Additional ascertainment of outcomes completes and validates existing data, although caveats remain for researchers. We also consider analytical issues related to cohort choice, timing of data submission, and transplant center variations in follow-up data. All of these points should be carefully considered when choosing cohorts and data sources for analysis. The second part of the article describes some of the statistical methods for outcome analysis employed by the SRTR. Issues of cohort and follow-up period selection lead into a discussion of outcome definitions, event ascertainment, censoring and covariate adjustment. We describe methods for computing unadjusted mortality rates and survival probabilities, and estimating covariate effects through regression modeling. The article concludes with a description of simulated allocation modeling, developed by the SRTR for comparing outcomes of proposed changes to national organ allocation policies.

Cell signalling by oxidized lipids and the role of reactive oxygen species in the endothelium.

The controlled formation of ROS (reactive oxygen species) and RNS (reactive nitrogen species) is now known to be critical in cellular redox signalling. As with the more familiar phosphorylation-dependent signal transduction pathways, control of protein function is mediated by the post-translational modification at specific amino acid residues, notably thiols. Two important classes of oxidant-derived signalling molecules are the lipid oxidation products, including those with electrophilic reactive centres, and decomposition products such as lysoPC (lysophosphatidylcholine). The mechanisms can be direct in the case of electrophiles, as they can modify signalling proteins by post-translational modification of thiols. In the case of lysoPC, it appears that secondary generation of ROS/RNS, dependent on intracellular calcium fluxes, can cause the secondary induction of H2O2 in the cell. In either case, the intracellular source of ROS/RNS has not been defined. In this respect, the mitochondrion is particularly interesting since it is now becoming apparent that the formation of superoxide from the respiratory chain can play an important role in cell signalling, and oxidized lipids can stimulate ROS formation from an undefined source. In this short overview, we describe recent experiments that suggest that the cell signalling mediated by lipid oxidation products involves their interaction with mitochondria. The implications of these results for our understanding of adaptation and the response to stress in cardiovascular disease are discussed.