Iron-rich air pollution nanoparticles: An unrecognised environmental risk factor for myocardial mitochondrial dysfunction and cardiac oxidative stress.

Exposure to particulate air pollution is a major environmental risk factor for cardiovascular mortality and morbidity, on a global scale. Both acute and chronic cardiovascular impacts have so far been attributed to particulate-mediated oxidative stress in the lung and/or via 'secondary' pathways, including endothelial dysfunction, and inflammation. However, increasing evidence indicates the translocation of inhaled nanoparticles to major organs via the circulation. It is essential to identify the composition and intracellular targets of such particles, since these are likely to determine their toxicity and consequent health impacts. Of potential major concern is the abundant presence of iron-rich air pollution nanoparticles, emitted from a range of industry and traffic-related sources. Bioreactive iron can catalyse formation of damaging reactive oxygen species, leading to oxidative stress and cell damage or death. Here, we identify for the first time, in situ, that exogenous nanoparticles (~15-40 nm diameter) within myocardial mitochondria of young, highly-exposed subjects are dominantly iron-rich, and co-associated with other reactive metals including aluminium and titanium. These rounded, electrodense nanoparticles (up to ~ 10 x more abundant than in lower-pollution controls) are located within abnormal myocardial mitochondria (e.g. deformed cristae; ruptured membranes). Measurements of an oxidative stress marker, PrPC and an endoplasmic reticulum stress marker, GRP78, identify significant ventricular up-regulation in the highly-exposed vs lower-pollution controls. In shape/size/composition, the within-mitochondrial particles are indistinguishable from the iron-rich, combustion- and friction-derived nanoparticles prolific in roadside/urban environments, emitted from traffic/industrial sources. Incursion of myocardial mitochondria by inhaled iron-rich air pollution nanoparticles thus appears associated with mitochondrial dysfunction, and excess formation of reactive oxygen species through the iron-catalyzed Fenton reaction. Ventricular oxidative stress, as indicated by PrPC and GRP78 up-regulation, is evident even in children/young adults with minimal risk factors and no co-morbidities. These new findings indicate that myocardial iron overload resulting from inhalation of airborne, metal-rich nanoparticles is a plausible and modifiable environmental risk factor for cardiac oxidative stress and cardiovascular disease, on an international scale.

The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner.

Disruption of the laminar and columnar organization of the brain is implicated in several psychiatric disorders. Here, we show in utero gain-of-function of the psychiatric risk gene transcription factor 4 (TCF4) severely disrupts the columnar organization of medial prefrontal cortex (mPFC) in a transcription- and activity-dependent manner. This morphological phenotype was rescued by co-expression of TCF4 plus calmodulin in a calcium-dependent manner and by dampening neuronal excitability through co-expression of an inwardly rectifying potassium channel (Kir2.1). For we believe the first time, we show that N-methyl-d-aspartate (NMDA) receptor-dependent Ca2+ transients are instructive to minicolumn organization because Crispr/Cas9-mediated mutation of NMDA receptors rescued TCF4-dependent morphological phenotypes. Furthermore, we demonstrate that the transcriptional regulation by the psychiatric risk gene TCF4 enhances NMDA receptor-dependent early network oscillations. Our novel findings indicate that TCF4-dependent transcription directs the proper formation of prefrontal cortical minicolumns by regulating the expression of genes involved in early spontaneous neuronal activity, and thus our results provides insights into potential pathophysiological mechanisms of TCF4-associated psychiatric disorders.

Survey of Irish general practitioners' preferences for continuing professional development.

BACKGROUND: Doctors' continuing professional development (CPD) training needs are known to be strongly influenced by national and local contextual characteristics. Given the changing national demographic profile and government-mandated changes to primary care health care provision, this study aimed to investigate Irish General Practitioners' (GPs) perceptions of, and preferences for, current and future CPD programmes. METHODS: A cross-sectional questionnaire, using closed- and open-ended questions, was administered to Irish GPs, focusing on training needs analysis; CPD course content; preferred format and the learning environment. RESULTS: The response rate was 719/1000 (71.9%). GPs identified doctor-patient communication as the most important and best-performed GP skill. Discrepancies between perceived importance (high) and current performance (low) emerged for time/workload management, practice finance and business skills. GPs identified clinically-relevant primary care topics and non-clinical topics (stress management, business skills, practice management) as preferences for future CPD. Flexible methods for CPD delivery were important. Gender and practice location (urban or rural) significantly influenced CPD participation and future course preference. CONCLUSION: The increasing diversity of services offered in the Irish primary care setting, in both clinical and non-clinical areas, should be tailored based to include GP practice location and structure.

Early postnatal GABAA receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1.

Exploring drug targets based on disease-associated molecular mechanisms during development is crucial for the generation of novel prevention and treatment strategies for neurodevelopmental psychiatric conditions. We report that prefrontal cortex (PFC)-specific postnatal knockdown of DISC1 via in utero electroporation combined with an inducible knockdown expression system drives deficits in synaptic GABAA function and dendritic development in pyramidal neurons, as well as abnormalities in sensorimotor gating, albeit without profound memory deficits. We show for the first time that DISC1 is specifically involved in regulating cell surface expression of α2 subunit-containing GABAA receptors in immature developing neurons, but not after full maturation. Notably, pharmacological intervention with α2/3 subtype-selective GABAA receptor positive allosteric modulators during the early postnatal period ameliorates dendritic deficits and behavioral abnormalities induced by knockdown of DISC1. These findings highlight a critical role of DISC1-mediated disruption of postnatal GABA signaling in aberrant PFC maturation and function.

Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

Meta-analysis of genome-wide association studies of anxiety disorders.

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.

The management of colorectal liver metastases.

Colorectal cancer remains a leading cause of cancer-related death in Europe. Approximately one-quarter of patients have synchronous hepatic metastases and metachronous liver metastases occur in a further 30%. The scope of surgery in management of colorectal metastases has evolved to include selected patients with extra-hepatic disease for whom R0 resection is considered feasible; however, locoregional treatments are increasingly recognised as viable management options in those patients deemed unsuitable for surgery and there is an expanding body of evidence regarding their ability to achieve local control and increase progression-free survival in the liver. Locoregional therapies increasingly practised in the management of unresectable liver metastatic colorectal cancer (mCRC) include percutaneous ablation, primarily in the form of radiofrequency ablation or microwave ablation, although there remains a lack of data regarding long-term outcome. Radio-embolisation (RE) is the most comprehensively studied embolisation technique in the context of colorectal liver metastases, predominantly using yttrium 90 (90Y). The data published to date suggests that 90Y represents a safe and effective cytoreductive modality. The optimal dose and timing of therapies remains uncertain and further studies are required to determine its relationship with systemic treatment. Irinotecan-loaded drug-eluting beads (DEBIRI) transcatheter arterial chemo-embolisation (TACE) represents a further therapy with considerable potential. There is evidence of improved overall survival in the salvage setting. As with the other therapies discussed, further research is required to elucidate the optimal role and timing of these treatments within the increasingly crowded space of therapies for mCRC.

Comparison of outcomes for cancer patients discussed and not discussed at a multidisciplinary meeting.

OBJECTIVES: Comparison of outcomes for cancer patients discussed and not discussed at a multidisciplinary meeting (MDM). STUDY DESIGN: Retrospective analysis of the association of MDM discussion with survival. METHODS: All newly diagnosed cancer patients from 2009 to 2012, presenting to a large regional cancer service in South West Victoria, Australia (620 colorectal, 657 breast, 593 lung and 511 haematological) were recorded and followed up to 5 years after diagnosis. Treatment patterns and survival of patients whose treatment was discussed at an MDM compared to those who were not, were explored. RESULTS: The proportion of patients presented to an MDM within 60 days after diagnosis was 56% (n = 366) for breast cancer, 59% (n = 363) for colorectal cancer, 27% (n = 137) for haematological malignancies and 60% (n = 355) for lung cancer. Seventy-three percent (n = 886) of patients discussed at an MDM had their tumour stage recorded in their medical records while only 52% (n = 604) of patients not discussed had their tumour stage recorded (P < 0.01). We found for haematological and lung cancer patients that those presented to an MDM prior to treatment had a significant reduction in mortality (lung cancer hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50-0.76, P < 0.01) (haematological cancer HR 0.58, 95% CI 0.35-0.96, P = 0.03) compared to patients whose cases were not discussed at an MDM after adjusting for the potential cofounders of age, stage, comorbidities and treatment. This was not the case for colorectal and breast cancer patients where there was no significant difference. CONCLUSION: MDM discussion has been recommended as best practice in the management of cancer patients, however, from a public health perspective this creates potential issues around access and resources. It is likely that MDM presentation patterns and outcomes across tumour streams are linked in complex ways. We believe that our data would demonstrate that these patterns differ across tumour streams and that more detailed work is required to better allocate relatively scarce and potentially costly MDM resources to tumour streams and patient groups that may get the most benefit.

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples.

Knockdown of the dyslexia-associated gene Kiaa0319 impairs temporal responses to speech stimuli in rat primary auditory cortex.

One in 15 school age children have dyslexia, which is characterized by phoneme-processing problems and difficulty learning to read. Dyslexia is associated with mutations in the gene KIAA0319. It is not known whether reduced expression of KIAA0319 can degrade the brain's ability to process phonemes. In the current study, we used RNA interference (RNAi) to reduce expression of Kiaa0319 (the rat homolog of the human gene KIAA0319) and evaluate the effect in a rat model of phoneme discrimination. Speech discrimination thresholds in normal rats are nearly identical to human thresholds. We recorded multiunit neural responses to isolated speech sounds in primary auditory cortex (A1) of rats that received in utero RNAi of Kiaa0319. Reduced expression of Kiaa0319 increased the trial-by-trial variability of speech responses and reduced the neural discrimination ability of speech sounds. Intracellular recordings from affected neurons revealed that reduced expression of Kiaa0319 increased neural excitability and input resistance. These results provide the first evidence that decreased expression of the dyslexia-associated gene Kiaa0319 can alter cortical responses and impair phoneme processing in auditory cortex.

Strategy to control type I error increases power to identify genetic variation using the full biological trajectory.

Genome-wide association studies have been successful in identifying loci that underlie continuous traits measured at a single time point. To additionally consider continuous traits longitudinally, it is desirable to look at SNP effects at baseline and over time using linear-mixed effects models. Estimation and interpretation of two coefficients in the same model raises concern regarding the optimal control of type I error. To investigate this issue, we calculate type I error and power under an alternative for joint tests, including the two degree of freedom likelihood ratio test, and compare this to single degree of freedom tests for each effect separately at varying alpha levels. We show which joint tests are the optimal way to control the type I error and also illustrate that information can be gained by joint testing in situations where either or both SNP effects are underpowered. We also show that closed form power calculations can approximate simulated power for the case of balanced data, provide reasonable approximations for imbalanced data, but overestimate power for complicated residual error structures. We conclude that a two degree of freedom test is an attractive strategy in a hypothesis-free genome-wide setting and recommend its use for genome-wide studies employing linear-mixed effects models.

The at-risk medical student--what more can we do?

Securing a place in medical school is extremely difficult-students who are successful all have similar high levels of academic achievement. So why do some students, and not others, have difficulty with the course, and in some cases, leave the programme? Studies on medical school attrition offer valuable insight into why medical students under-perform. Identification of the 'at-risk' student can trigger additional support and early remediation, helping some students remain in their chosen profession.

The contribution of EUS to the management of endoscopic and surgical complications.

Endoscopic Ultrasound (EUS) stands as a remarkable innovation in the realm of gastroenterology and its allied disciplines. EUS has evolved to such an extent that it now assumes a pivotal role in both diagnosis and therapeutics. In addition, it has developed as a tool which is also capable of addressing complications arising from endoscopic and surgical procedures. This minimally invasive technique combines endoscopy with high-frequency ultrasound, facilitating, high-resolution images of the gastrointestinal tract and adjacent structures. Complications within the gastrointestinal tract, whether stemming from endoscopic or surgical procedures, frequently arise due to disruption in the integrity of the gastrointestinal tract wall. While these complications are usually promptly detected, there are instances where their onset is delayed. EUS plays a dual role in the management of these complications. Firstly, in its ability to assess and increasingly to definitively manage complications through drainage procedures. It is increasingly employed to manage post-surgical collections, abscesses biliary strictures and bleeding. Its high-resolution imaging capability allows precise real-time visualisation of these complications.

Intravenous alteplase in minor nondisabling ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: Minor ischemic stroke, defined as National Institute of Health Stroke Scale score of 0-5 on admission, represents half of all acute ischemic strokes. The role of intravenous alteplase (IVA) among patients with minor stroke is inconclusive; therefore, we evaluated clinical outcomes of these patients treated with or without IVA. MATERIALS AND METHODS: We searched Medline, Embase, Scopus, and the Cochrane library until August 1, 2023. Inclusion was restricted to the English literature of studies that reported on minor nondisabling stroke patients treated with or without IVA. Odds ratios (ORs) with their corresponding 95% CIs were utilized using a random-effects model. Efficacy outcomes included rates of excellent (modified Rankin scale [mRS] of 0-1) and good (mRS of 0-2) functional outcome at 90 days. The main safety outcome was symptomatic intracerebral hemorrhage (sICH). RESULTS: Five eligible studies, two RCTs and three observational studies, comprising 2764 patients (31.8% female) met inclusion criteria. IVA was administered to 1559 (56.4%) patients. Pooled analysis of the two RCTs revealed no difference between the two groups in terms of 90-days excellent functional outcomes (OR 0.76 [95% CI, 0.51-1.13]; I2 = 0%) and sICH rates (OR 3.76 [95% CI, 0.61-23.20]). No significant differences were observed between the groups in terms of good functional outcomes, 90-day mortality, and 90-day stroke recurrence. CONCLUSION: This meta-analysis of minor nondisabling stroke suggests that IVA did not prove more beneficial compared to no-IVA.

BDNF and TNF-α polymorphisms in memory.

Here, we investigate the genetic basis of human memory in healthy individuals and the potential role of two polymorphisms, previously implicated in memory function. We have explored aspects of retrospective and prospective memory including semantic, short term, working and long-term memory in conjunction with brain derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-α). The memory scores for healthy individuals in the population were obtained for each memory type and the population was genotyped via restriction fragment length polymorphism for the BDNF rs6265 (Val66Met) SNP and via pyrosequencing for the TNF-α rs113325588 SNP. Using univariate ANOVA, a significant association of the BDNF polymorphism with visual and spatial memory retention and a significant association of the TNF-α polymorphism was observed with spatial memory retention. In addition, a significant interactive effect between BDNF and TNF-α polymorphisms was observed in spatial memory retention. In practice visual memory involves spatial information and the two memory systems work together, however our data demonstrate that individuals with the Val/Val BDNF genotype have poorer visual memory but higher spatial memory retention, indicating a level of interaction between TNF-α and BDNF in spatial memory retention. This is the first study to use genetic analysis to determine the interaction between BDNF and TNF-α in relation to memory in normal adults and provides important information regarding the effect of genetic determinants and gene interactions on human memory.

Efficacy of green infrastructure in reducing exposure to local, traffic-related sources of airborne particulate matter (PM).

One aim of roadside green infrastructure (GI) is to mitigate exposure to local, traffic-generated pollutants. Here, we determine the efficacy of roadside GI in improving local air quality through the deposition and/or dispersion of airborne particulate matter (PM). PM was collected on both pumped air filters and on the leaves of a recently installed 'tredge' (trees managed as a head-high hedge) at an open road environment next to a primary school in Manchester, U.K. The magnetic properties of PM deposited on leaves and filters (size fractions PM10 and PM2.5) were deduced from hysteresis loops, first-order reversal curves (FORCs), and low-temperature remanence measurements. These were complemented with electron microscopy to identify changes in magnetic PM concentration downwind of the tredge/GI. We show that the tredge is permeable to airflow using a simple CO2 tracer experiment; hence, it allows interception and subsequent deposition of PM on its leaves. Magnetic loadings per m3 of air from filters (PM10 saturation magnetisation, Ms, at 5 K) were reduced by 40 % behind the tredge and a further 63 % in the playground; a total reduction of 78 % compared to roadside air. For the PM2.5 fraction, the reduction in magnetic loading behind the tredge was remarkable (82 %), reflecting efficient diffusional capture of sub-5 nm Fe-oxide particles by the tredge. Some direct mixing of roadside and playground air occurs at the back of the playground, caused by air flow over, and/or through gaps in, the slowly-permeable tredge. The magnetic loading on tredge leaves increased over successive days, capturing ~23 % of local, traffic-derived PM10. Using a heuristic two-dimensional turbulent mixing model, we assess the limited dispersion of PM < 22.5 µm induced by eddies in the tredge wake. This study demonstrates that PM deposition on leaves reduces exposure significantly in this school playground setting; hence, providing a cost-effective mitigation strategy.

Influenza vaccine effect on risk of stroke occurrence: a systematic review and meta-analysis.

Background: Stroke is a significant global cause of mortality and long-term disability, potentially influenced by infections that heighten systemic inflammation and thrombotic events. The full impact of influenza vaccination on stroke remains uncertain. This systematic review and meta-analysis aimed to investigate the association between influenza immunization and stroke incidence. Methods: We searched for randomized controlled trials (RCTs), case-control, and cohort studies published in PubMed/Medline, Cochrane-Central-Register-of-Controlled-Trials (CENTRAL), and Embase until 5 December 2022, and identified articles investigating the effect of influenza vaccine on stroke occurrence. All articles were screened by two independent reviewers. We performed a meta-analysis to investigate the risk of stroke occurrence in vaccinated vs. unvaccinated individuals. The random-effects model was used in all statistical analyses. Results: Among the 26 articles meeting our criteria, 10 were retrospective cohort studies, 9 were case-control studies, 3 were prospective cohort studies, 3 were RCTs and 1 case-series. Overall, the studies showed a significant decrease in the risk of stroke incidence/hospitalization among vaccinated patients (OR = 0.81, 95% CI [0.77-0.86], p = 0.00001). Furthermore, studies showed flu vaccine decreases the occurrence of mortality among stroke patients (OR = 0.50, 95% CI [0.37-0.68], p = 0.00001). Sub-group analysis revealed significant protective effect for patients with specific comorbidities including atrial fibrillation (OR = 0.68, 95% CI [0.57-0.81], p = 0.0001), diabetes (OR = 0.76, 95% CI [0.66-0.87], p = 0.0001), Chronic obstructive pulmonary disease (OR = 0.70, 95% CI [0.61-0.81], p = 0.00001), and hypertension (OR = 0.76, 95% CI [0.70-83], p = 0.00001). Conclusion: The current meta-analysis further supports prior findings that influenza vaccination reduces stroke risk, particularly in patients with comorbidities. Guidelines should promote vaccination for at-risk individuals.

Confirmation that Xq27 and Xq28 are susceptibility loci for migraine in independent pedigrees and a case-control cohort.

Investigations into migraine genetics have suggested that susceptibility loci exist on the X chromosome. These reports are supported by evidence that demonstrates male probands as having a higher proportion of affected first-degree relatives as well as the female preponderance of 3:1 that the disorder displays. We have previously implicated the Xq24-28 locus in migraine using two independent multigenerational Australian pedigrees that demonstrated excess allele sharing at the Xq24, Xq27 and Xq28 loci. Here, we expand this work to investigate a further six independent migraine pedigrees using 11 microsatellite markers spanning the Xq27­28 region. Furthermore, 11 candidate genes are investigated in an Australian case-control cohort consisting of 500 cases and 500 controls. Microsatellite analysis showed evidence of excess allele sharing to the Xq27 marker DXS8043 (LOD* 1.38 P00.005) in MF879 whilst a second independent pedigree showed excess allele sharing to DXS8061 at Xq28 (LOD* 1.5 P00.004). Furthermore, analysis of these key markers in a case control cohort showed significant association to migraine in females at the DXS8043 marker (T1 P00.009) and association with MO at DXS8061 (T1 P00.05). Further analysis of 11 key genes across these regions showed significant association of a three-marker risk haplotype in the NSDHL gene at Xq28 (P00.0082). The results of this study add further support to the presence of migraine susceptibility loci on chromosome Xq27 and Xq28 as well as point to potential candidate genes in the regions that warrant further investigation.

Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder.

A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 × 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 × 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N=18 945, schizophrenia plus bipolar disorder N=21 274 and controls N=38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 × 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 × 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.

GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia.

We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.