Francis O’Neill

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Background The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients. Methods The association of DTNBP1 in the Irish Study of High Density Schizophrenia Families (ISHDSF) prompted our investigation of AKT1 for association with disease in this sample. Eight single nucleotide polymorphisms spanning AKT1 were analyzed for association with schizophrenia across four definitions of affection and according to Operational Criteria Checklist of Psychotic Illness (OPCRIT) symptom scales. We examined expression of AKT1 messenger RNA from postmortem brain tissue of schizophrenic, bipolar, and control individuals. Results No single marker showed significant association, but the risk haplotype previously found over-transmitted to Caucasian schizophrenic patients was significantly under-transmitted in the ISHDSF (.01 < p < .05), across all OPCRIT symptom dimensions. Exploratory haplotype analysis confirmed association with schizophrenia toward the 5’ end of AKT1 (.008 < p < .049, uncorrected). We found significantly decreased RNA levels in prefrontal cortex of schizophrenic individuals, consistent with reduced AKT1 protein levels reported in schizophrenic brain. Conclusions The replication of association of AKT1 gene variants in a further Caucasian family sample adds support for involvement of AKT signaling in schizophrenia, perhaps encompassing a broader clinical phenotype that includes mood dysregulation. We show that AKT signaling might be compromised in schizophrenic and bipolar patients via reduced RNA expression of specific AKT isoforms. The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients. The association of DTNBP1 in the Irish Study of High Density Schizophrenia Families (ISHDSF) prompted our investigation of AKT1 for association with disease in this sample. Eight single nucleotide polymorphisms spanning AKT1 were analyzed for association with schizophrenia across four definitions of affection and according to Operational Criteria Checklist of Psychotic Illness (OPCRIT) symptom scales. We examined expression of AKT1 messenger RNA from postmortem brain tissue of schizophrenic, bipolar, and control individuals. No single marker showed significant association, but the risk haplotype previously found over-transmitted to Caucasian schizophrenic patients was significantly under-transmitted in the ISHDSF (.01 < p < .05), across all OPCRIT symptom dimensions. Exploratory haplotype analysis confirmed association with schizophrenia toward the 5’ end of AKT1 (.008 < p < .049, uncorrected). We found significantly decreased RNA levels in prefrontal cortex of schizophrenic individuals, consistent with reduced AKT1 protein levels reported in schizophrenic brain. The replication of association of AKT1 gene variants in a further Caucasian family sample adds support for involvement of AKT signaling in schizophrenia, perhaps encompassing a broader clinical phenotype that includes mood dysregulation. We show that AKT signaling might be compromised in schizophrenic and bipolar patients via reduced RNA expression of specific AKT isoforms.

Objectives To evaluate the clinical effectiveness of group art therapy for people with schizophrenia and to test whether any benefits exceed those of an active control treatment.Design Three arm, rater blinded, pragmatic, randomised controlled trial.Setting Secondary care services across 15 sites in the United Kingdom.Participants 417 people aged 18 or over, who had a diagnosis of schizophrenia and provided written informed consent to take part in the study.Interventions Participants, stratified by site, were randomised to 12 months of weekly group art therapy plus standard care, 12 months of weekly activity groups plus standard care, or standard care alone.Art therapy and activity groups had up to eight members and lasted for 90 minutes.In art therapy, members were given access to a range of art materials and encouraged to use these to express themselves freely.Members of activity groups were offered various activities that did not involve use of art or craft materials and were encouraged to collectively select those they wanted to pursue. Main outcome measuresThe primary outcomes were global functioning, measured using the global assessment of functioning scale, and mental health symptoms, measured using the positive and negative syndrome scale, 24 months after randomisation.Main secondary outcomes were levels of group attendance, social functioning, and satisfaction with care at 12 and 24 months.Results 417 participants were assigned to either art therapy (n=140), activity groups (n=140), or standard care alone (n=137).Primary outcomes between the three study arms did not differ.The adjusted mean difference between art therapy and standard care at 24 months on the global assessment of functioning scale was -0.9 (95% confidence interval -3.8 to 2.1), and on the positive and negative syndrome scale was 0.7 (-3.1 to 4.6).Secondary outcomes did not differ between those referred to art therapy or those referred to standard care at 12 or 24 months. ConclusionsReferring people with established schizophrenia to group art therapy as delivered in this trial did not improve global functioning, mental health, or other health related outcomes.

The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent.None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

It is not only unclear why hallucinations in schizophrenia occur with different prevalence by modality, but also to what extent they do. Reliable prevalence estimates of hallucinations by modality in schizophrenia are currently lacking, particularly for non-auditory hallucinations. Studies have also tended to report lifetime, not point prevalence by modality. This study assessed the prevalence and co-occurrence of hallucinations, for both lifetime and point prevalence, across the auditory, visual, olfactory, and tactile modalities, in people diagnosed with chronic schizophrenia-spectrum disorders in Ireland (N=693) and Australia (N=218). Lifetime prevalence was 64–80% auditory, 23–31% visual, 9–19% tactile, and 6–10% olfactory. Past month prevalence was 23–27% auditory, 5–8% visual, 4–7% tactile, and 2% olfactory. The majority of participants had only hallucinated in one modality, with this nearly always being the auditory. Approximately one-third had hallucinated in two modalities, most commonly the auditory and visual. Most currently hallucinating patients also hallucinated in a single modality, again, nearly always the auditory. Whereas 30–37% of patients with lifetime auditory hallucinations had experienced visual hallucinations, 83–97% of patients with experience of visual hallucinations had experienced auditory hallucinations. These findings help delineate the modality distribution of hallucinations in schizophrenia, and provide an explanatory target for theoretical models.

Endothelial dysfunction begins in early CKD and contributes to cardiovascular mortality. HDL is considered antiatherogenic, but may have adverse vascular effects in cardiovascular disease, diabetes, and inflammatory conditions. The effect of renal failure on HDL properties is unknown. We studied the endothelial effects of HDL isolated from 82 children with CKD stages 2-5 (HDL(CKD)), who were free of underlying inflammatory diseases, diabetes, or active infections. Compared with HDL from healthy children, HDL(CKD) strongly inhibited nitric oxide production, promoted superoxide production, and increased vascular cell adhesion molecule-1 expression in human aortic endothelial cells, and reduced cholesterol efflux from macrophages. The effects on endothelial cells correlated with CKD grade, with the most profound changes induced by HDL from patients on dialysis, and partial recovery observed with HDL isolated after kidney transplantation. Furthermore, the in vitro effects on endothelial cells associated with increased aortic pulse wave velocity, carotid intima-media thickness, and circulating markers of endothelial dysfunction in patients. Symmetric dimethylarginine levels were increased in serum and fractions of HDL from children with CKD. In a longitudinal follow-up of eight children undergoing kidney transplantation, HDL-induced production of endothelial nitric oxide, superoxide, and vascular cell adhesion molecule-1 in vitro improved significantly at 3 months after transplantation, but did not reach normal levels. These results suggest that in children with CKD without concomitant disease affecting HDL function, HDL dysfunction begins in early CKD, progressing as renal function declines, and is partially reversed after kidney transplantation.

This study was an attempt to replicate evidence for a vulnerability locus for schizophrenia and associated disorders in the 8p22-21 region reported by Pulver and colleagues.The linkage sample of the Irish Study of High-Density Schizophrenia Families consists of 265 multiplex families containing 1,408 individuals. Fifteen markers covering 30 centimorgans on chromosome 8p were tested. Three statistical methods were used: two-point and multipoint heterogeneity lod scores and a multipoint nonparametric test.According to two-point heterogeneity lod scores, the strongest evidence for linkage was found for markers D8S1731 (maximum lod score = 2.00), D8S1715 (maximum lod score = 2.52), and D8S133 (maximum lod score = 2.08) by assuming a phenotypic definition of all psychiatric illness and a range of genetic models. According to multipoint heterogeneity lod scores, the strongest evidence for linkage (maximum lod score = 2.34), found by using a dominant genetic model and a broad definition of the schizophrenia spectrum, extended over a 10-cM region between markers D8S1715 and D8S1739. Multipoint nonparametric linkage found the strongest evidence (maximum z = 2.51) over a broader region when either a diagnosis of core schizophrenia or a narrow definition of the schizophrenia spectrum was used. This putative vulnerability locus was segregating in 10%-25% of the families studied.This study supports the existence of a vulnerability locus for schizophrenia on chromosome 8p. In this sample, this locus appears to influence the risk of illness in only a modest proportion of families and predisposes to a range of schizophrenia spectrum and possibly nonspectrum disorders.

Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analyzed 6882 cases and 11 255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in additional 14 568 cases and 15 274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P < 0.05); however, none would survive correction for multiple testing. These loci include recurrent deletions at 16p12.1, a locus previously associated with neurodevelopmental disorders (P = 0.0084 in the discovery sample and P = 0.023 in the replication sample). Other plausible candidates include non-recurrent deletions at the glutamate transporter gene SLC1A1, a CNV locus recently suggested to be involved in schizophrenia through linkage analysis, and duplications at 1p36.33 and CGNL1. A burden analysis of large (>500 kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.

The Schizophrenia Psychiatric Genome-wide Association (GWAS) Consortium recently reported on five novel schizophrenia susceptibility loci. The most significant finding mapped to a micro-RNA, MIR-137, which may be involved in regulating the function of other schizophrenia and bipolar disorder susceptibility genes. We genotyped 821 patients with confirmed DSM-IV diagnoses of schizophrenia, bipolar affective disorder I and schizoaffective disorder for the risk SNP (rs1625579) and investigated the clinical profiles of risk allele carriers using a within-case design. We also assessed neurocognitive performance in a subset of cases (n = 399) and controls (n = 171). Carriers of the risk allele had lower scores for an OPCRIT-derived positive symptom factor (p = 0.04) and lower scores on a lifetime measure of psychosis incongruity (p = 0.017). Risk allele carriers also had more cognitive deficits involving episodic memory and attentional control. This is the first evidence that the MIR-137 risk variant may be associated with a specific subgroup of psychosis patients. Although the effect of this single SNP was not clinically relevant, investigation of the impact of carrying multiple risk SNPs in the MIR-137 regulatory network on diagnosis and illness profile may be warranted.

Abstract The regulator of the G‐protein signaling 4 ( RGS4 ) gene was shown to have a different expression pattern in schizophrenia patients in a microarray study. A family‐based study subsequently implicated the association of this gene with schizophrenia. We replicated the study with our sample from the Irish Study of High Density Schizophrenia Families (ISHDSF). Single marker transmission disequilibrium tests (TDT) for the four core SNPs showed modest association for SNP 18 (using a narrow diagnostic approach with FBAT P = 0.044; with PDT P = 0.0073) and a trend for SNP 4 (with FBAT P = 0.1098; with PDT P = 0.0249). For SNP 1 and 7, alleles overtransmitted to affected subjects were the same as previously reported. Haplotype analyses suggested that haplotype G‐G‐G for SNP1–4–18, which is the most abundant haplotype (42.3%) in the Irish families, was associated with the disease (narrow diagnosis, FBAT P = 0.0061, PDT P = 0.0498). This was the same haplotype implicated in the original study. While P values were not corrected for multiple testing because of the clear prior hypothesis, these results could be interpreted as supporting evidence for the association between RGS4 and schizophrenia. © 2004 Wiley‐Liss, Inc.

Reports of substantial evidence for genetic linkage of schizophrenia to chromosome 1q were evaluated by genotyping 16 DNA markers across 107 centimorgans of this chromosome in a multicenter sample of 779 informative schizophrenia pedigrees. No significant evidence was observed for such linkage, nor for heterogeneity in allele sharing among the eight individual samples. Separate analyses of European-origin families, recessive models of inheritance, and families with larger numbers of affected cases also failed to produce significant evidence for linkage. If schizophrenia susceptibility genes are present on chromosome 1q, their population-wide genetic effects are likely to be small.

Early descriptive work and controlled family and adoption studies support the hypothesis that a range of personality and nonschizophrenic psychotic disorders aggregate in families of schizophrenic probands. Can we validate, using molecular polygene scores from genome-wide association studies (GWAS), this schizophrenia spectrum?The predictive value of polygenic findings reported by the Psychiatric GWAS Consortium (PGC) was applied to 4 groups of relatives from the Irish Study of High-Density Schizophrenia Families (ISHDSF; N = 836) differing on their assignment within the schizophrenia spectrum. Genome-wide single nucleotide polymorphism data for affected and unaffected relatives were used to construct per-individual polygene risk scores based on the PGC stage-I results. We compared mean polygene scores in the ISHDSF with mean scores in ethnically matched population controls (N = 929).The schizophrenia polygene score differed significantly across diagnostic categories and was highest in those with narrow schizophrenia spectrum, lowest in those with no psychiatric illness, and in-between in those classified in the intermediate, broad, and very broad schizophrenia spectrum. Relatives of all of these groups of affected subjects, including those with no diagnosis, had schizophrenia polygene scores significantly higher than the control sample.In the relatives of high-density families, the observed pattern of enrichment of molecular indices of schizophrenia risk suggests an underlying, continuous liability distribution and validates, using aggregate common risk alleles, a genetic basis for the schizophrenia spectrum disorders. In addition, as predicted by genetic theory, nonpsychotic members of multiply-affected schizophrenia families are significantly enriched for replicated, polygenic risk variants compared with the general population.

Evidence suggests that genetic factors may influence both schizophrenia (Scz) and its clinical presentation. In recent years, genome-wide association studies (GWAS) have demonstrated considerable success in identifying risk loci. Detection of "modifier loci" has the potential to further elucidate underlying disease processes.We performed GWAS of empirically derived positive and negative symptom scales in Irish cases from multiply affected pedigrees and a larger, independent case-control sample, subsequently combining these into a large Irish meta-analysis. In addition to single-SNP associations, we considered gene-based and pathway analyses to better capture convergent genetic effects, and to facilitate biological interpretation of these findings. Replication and testing of aggregate genetic effects was conducted using an independent European-American sample.Though no single marker met the genome-wide significance threshold, genes and ontologies/pathways were significantly associated with negative and positive symptoms; notably, NKAIN2 and NRG1, respectively. We observed limited overlap in ontologies/pathways associated with different symptom profiles, with immune-related categories over-represented for negative symptoms, and addiction-related categories for positive symptoms. Replication analyses suggested that genes associated with clinical presentation are generalizable to non-Irish samples.These findings strongly support the hypothesis that modifier loci contribute to the etiology of distinct Scz symptom profiles. The finding that previously implicated "risk loci" actually influence particular symptom dimensions has the potential to better delineate the roles of these genes in Scz etiology. Furthermore, the over-representation of distinct gene ontologies/pathways across symptom profiles suggests that the clinical heterogeneity of Scz is due in part to complex and diverse genetic factors.

HDL functionality has been shown to be impaired in inflammatory conditions, including coronary artery disease. The present study aims to determine the impact of low grade and acute inflammation on HDL function and structure.i) The endothelial protective effects of HDL were compared between 26 periodontal patients and 26 age and sex matched controls by measuring paraoxonase activity in serum and nitric oxide bioavailability and superoxide production in endothelial cells. Paraoxonase activity and nitric oxide bioavailability were reduced, while superoxide production was increased (p<0.01) in periodontal patients compared to controls. ii) HDL function, including cholesterol efflux and vascular cell adhesion molecule-1 expression, was subsequently measured in the periodontal patients following an inflammatory stimulus. There was an acute deterioration in HDL's endothelial protective function, without change in cholesterol efflux, after 24h (p<0.01 for all). These functional changes tracked increases of inflammatory markers and altered HDL composition. Finally, HDL function returned to baseline levels after resolution of inflammation.This study demonstrates that even minor alterations in systemic inflammation can impair the endothelial protective effects of HDL. These functional changes were independent of cholesterol efflux and were associated with remodeling of the HDL proteome. All measures of HDL's endothelial protective functions recovered with resolution of inflammation. These findings suggest that HDL dysfunction may represent a novel mechanism linking inflammation with progression of atheroma.

Patients with rheumatoid arthritis (RA) are at increased cardiovascular risk. Recent studies suggest that high-density lipoprotein (HDL) may lose its protective vascular phenotype in inflammatory conditions. However, the effects of common anti-inflammatory treatments on HDL function are not yet known.We compared the function of HDL in 18 patients with RA and 18 matched healthy controls. Subsequently, patients were randomised to (methotrexate+infliximab (M+I) (5 mg/kg)) or methotrexate+placebo (M+P) infusions for 54 weeks. At week 54 and thereafter, all patients received infliximab therapy until completion of the trial (110 weeks), enabling assessment of the impact of 1 year of infliximab therapy in all patients. HDL functional properties were assessed at baseline, 54 weeks and 110 weeks by measuring the impact on endothelial nitric oxide (NO) bioavailability and superoxide production (SO), paraoxonase activity (PON-1) and cholesterol efflux.All HDL vascular assays were impaired in patients compared with controls. After 54 weeks, NO in response to HDL was significantly greater in patients who received M+I compared with those who received M+P. Endothelial SO in response to HDL was reduced in both groups, but PON-1 and cholesterol efflux remained unchanged. All vascular measures improved compared with baseline after ≥1 infliximab therapy in the analysis at 110 weeks. No significant trend was noted for cholesterol efflux.HDL function can be improved with anti-inflammatory treatment in patients with RA. The M+I combination was superior to the M+P alone, suggesting that the tumour necrosis factor-α pathway may have a role in HDL vascular properties.

Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR.We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.d. = 3.20) for secondary data analysis. We identified a list of potential predictors from clinical and demographic data recorded at first-episode. These potential predictors were entered in two models: a multivariable logistic regression to identify which were independently associated with TR and a penalised logistic regression, which performed variable selection, to produce a parsimonious prediction model. This model was internally validated using a 5-fold, 50-repeat cross-validation optimism-correction.Our sample consisted of N = 2216 participants of which 385 (17 %) developed TR. Younger age of psychosis onset and fewer years in education were independently associated with increased odds of developing TR. The prediction model selected 7 out of 17 variables that, when combined, could quantify the risk of being TR better than chance. These included age of onset, years in education, gender, BMI, relationship status, alcohol use, and positive symptoms. The optimism-corrected area under the curve was 0.59 (accuracy = 64 %, sensitivity = 48 %, and specificity = 76 %).Our findings show that treatment resistance can be predicted, at first-episode of psychosis. Pending a model update and external validation, we demonstrate the potential value of prediction models for TR.

Runs of homozygosity (ROH), regions of the genome containing many consecutive homozygous SNPs, may represent two copies of a haplotype inherited from a common ancestor. A rare variant on this haplotype could thus be present in a homozygous and potentially recessive state. To detect rare risk variants for schizophrenia, we performed an ROH analysis in a homogeneous Irish genome wide association study (GWAS) dataset consisting of 1606 cases and 1794 controls. There was no genome-wide excess of ROH in cases compared to controls (p=0.7986). No consensus ROH at individual loci showed association with schizophrenia after genome-wide correction.

Multiplex families have higher recurrence risk of schizophrenia compared to the families of sporadic cases, but the source of this increased recurrence risk is unknown. We used schizophrenia genome-wide association study data (N = 156,509) to construct polygenic risk scores (PRS) in 1005 individuals from 257 multiplex schizophrenia families, 2114 ancestry-matched sporadic cases, and 2205 population controls, to evaluate whether increased PRS can explain the higher recurrence risk of schizophrenia in multiplex families compared to ancestry-matched sporadic cases. Using mixed-effects logistic regression with family structure modeled as a random effect, we show that SCZ PRS in familial cases does not differ significantly from sporadic cases either with, or without family history (FH) of psychotic disorders (All sporadic cases p = 0.90, FH+ cases p = 0.88, FH- cases p = 0.82). These results indicate that increased burden of common schizophrenia risk variation as indexed by current SCZ PRS, is unlikely to account for the higher recurrence risk of schizophrenia in multiplex families. In the absence of elevated PRS, segregation of rare risk variation or environmental influences unique to the families may explain the increased familial recurrence risk. These findings also further validate a genetically influenced psychosis spectrum, as shown by a continuous increase of common SCZ risk variation burden from unaffected relatives to schizophrenia cases in multiplex families. Finally, these results suggest that common risk variation loading are unlikely to be predictive of schizophrenia recurrence risk in the families of index probands, and additional components of genetic risk must be identified and included in order to improve recurrence risk prediction.

The synapsin III gene, SYN3, which belongs to the family of synaptic vesicle-associated proteins, has been implicated in the modulation of neurotransmitter release and in synaptogenesis, suggesting a potential role in several neuropsychiatric diseases. The human SYN3 gene is located on chromosome 22q12-13, a candidate region implicated in previous linkage studies of schizophrenia. However, association studies of SYN3 and schizophrenia have produced inconsistent results. In this study, four SYN3 SNPs (rs133945 (-631 C>G), rs133946 (-196 G>A), rs9862 and rs1056484) were tested in three sets of totally 3759 samples that comprise 655 affected subjects and 626 controls in the Irish Case-Control Study of Schizophrenia (ICCSS), 1350 samples incorporating 273 pedigrees in the Irish Study of High Density Schizophrenia Families (ISHDSF), and 564 unrelated schizophrenia patients and 564 healthy individuals in a Chinese case-control sample. The expression levels of SYN3 in schizophrenic patients and unaffected controls were compared using postmortem brain cDNAs provided by the Stanley Medical Research Institute (SMRI). There was no significant association in either the Irish or Chinese case-control samples, nor in the combined samples. Consistent with this finding, we did not find any significant difference in allele or haplotype frequencies when we used the pedigree disequilibrium test to analyze the Irish family sample. In the expression studies, no significant difference (p=0.507) was observed between patients and controls. Both the association studies and expression studies didn't support a major role for SYN3 in the susceptibility of schizophrenia in Irish and Chinese populations.

The 5q21-31 region has been implicated as harboring risk genes for schizophrenia in many linkage studies. In our previous report of stepwise fine mapping of this region, the MEGF10 gene was one of the genes showing consistent associations in our screening subsample. In this study, we carried out independent replication and expression studies of the MEGF10 gene.Association studies with 8 SNPs in the MEGF10 gene were performed in the Irish case-control study of schizophrenia (ICCSS) sample (652 case and 617 control subjects). The expression of MEGF10 was also compared between healthy control subjects and schizophrenia patients using postmortem brain cDNA libraries.In the ICCSS sample, associations with the disease were found in the same risk alleles and haplotypes as that observed in our fine-mapping studies. The major allele (A) of rs27388 was overrepresented in affected individuals (p = .0169), which remained significant after correction for multiple testing. In expression studies, MEGF10 had higher expression levels in the affected than the unaffected (p = .015). Schizophrenia patients with a 1/1 genotype at rs27388 had higher expressions than those patients with 1/2 and 2/2 genotypes (p = .0008).Evidence from both association and expression studies suggests that MEGF10 is likely associated with schizophrenia. The major allele and 1/1 genotype at rs27388 impose higher risks for the disease.

To assess the utility of corneal confocal microscopy in identifying small fiber damage in patients with burning mouth syndrome (BMS).A prospective cross-sectional cohort study was conducted at two United Kingdom dental hospitals between 2014 and 2017. A total of 17 consecutive patients with idiopathic BMS aged between 18 and 85 years and 14 healthy age-matched control subjects were enrolled in this study. Corneal subbasal nerve plexus measures were quantified in images acquired using a laser-scanning in vivo corneal confocal microscope. The main outcome measures were corneal nerve fiber density, nerve branch density, nerve fiber length, and Langerhans cell density.Of the 17 patients with BMS, 15 (88%) were women, and the mean (standard deviation) age of the sample was 61.7 (6.5) years. Of the healthy controls, 7 (50%) were women, and the mean (standard deviation) age was 59.3 (8.68) years. Corneal nerve fiber density (no./mm2) (BMS: 29.27 ± 6.22 vs controls: 36.19 ± 5.9; median difference = 6.71; 95% CI: 1.56 to 11.56; P = .007) and corneal nerve fiber length (mm/mm2) (BMS: 21.06 ± 4.77 vs controls: 25.39 ± 3.91; median difference = 4.5; 95% CI: 1.22 to 6.81; P = .007) were significantly lower in BMS patients compared to controls, and Langerhans cell density (no./mm2) (BMS: 74.04 ± 83.37 vs controls: 29.17 ± 45.14; median difference = -21.27; 95% CI: -65.35 to -2.91; P = .02) was significantly higher.Using a rapid noninvasive ophthalmic imaging technique, this study provides further evidence for small fiber damage in BMS and has potential utility for monitoring disease progression and/or response. Furthermore, this technique shows a hitherto undocumented increased density of immune cells in this group of patients.

A major problem with longitudinal studies is the bias generated due to attrition, particularly apparent amongst patients suffering from psychotic disorders. Factors associated with study-participation were investigated as part of a larger research collaboration (STRATA). Out of 479 eligible participants, only 50 (10,4%) were successfully followed up. The present study investigated whether study participation differed depending on baseline characteristics. Results indicated that individuals who did not participate were more likely to report an alcohol use disorder while those who did respond were more likely to have been in full-time education for longer and be of white ethnicity. Participation did not differ depending on diagnosis, symptoms, GAF, age of onset or depression.

Recent failures of clinical trials promoting HDL-elevating therapies have prompted research groups to focus on its functional activity in disease. Endothelial effects of HDL can be measured with in vitro cell assays. The reproducibility and biological relevance of these assays have not been explored both in healthy individuals and those at increased cardiovascular (CV) risk.HDL dependent nitric oxide (NO) bioavailability, superoxide (SO) production and serum paraoxonase-1 (PON-1) activity were measured in 35 healthy adults (34.37 24-49) and 8 patients (43.56 37-49) suffering from a chronic inflammatory condition (periodontitis-PD). Assay reproducibility was assessed by independent technicians on consecutive days to determine inter and intra analyser variability for each assay. The 35 healthy individuals were further divided into young (n = 16) and middle aged (n = 19) groups and compared with regards to HDL functions. Within-subject biological variation of HDL function was determined in a sub-group of 25 healthy volunteers at intervals of one day and 1 month, and in 8 patients at intervals of one day and 1 week. Power curves were also generated to estimate the number of patients that would be required for HDL functional assays in a cross-over and parallel study design.NO bioavailability was the most reproducible assay in healthy adults (coefficient of variation = 1.72%, 1.92 - intra and inter respectively) and PD patients (CV = 4.4% and 5.5%). All measures demonstrated no statistical difference between young and healthy middle aged population. No single assay demonstrated significant variations over time, indicating that within patient variations are negligible. Our power curves for NO bioavailability and PON-1 activity suggest that low number of patients will be required to detect significant differences in HDL function in a cross over and parallel study design.This study suggests that in vitro HDL functional assays are reliable and can be used to assess HDL functionality in healthy and diseased populations. NO bioavailability was the most reproducible assay, but PON-1 activity remains the most practical for application in clinical trials due to its capacity for scale.

Research question The purpose of this scoping review is to explore the extant literature devoted to elite athlete activism, advocacy, and protest. Three research questions guided the study: (1) How has sports activism, advocacy and protest been covered in the literature? (2) What themes and topics are covered in the elite sport activism/advocacy/protest literature? (3) What are the research gaps in the athlete activism/advocacy/protest literature that could be organised in a future research agenda?

Abstract FBXL21 gene encodes an F‐box containing protein functioning in the SCF ubiquitin ligase complex. The role of the F‐box protein is to recruit proteins designated for degradation to the ligase complex so they would be ubiquitinated. Using both family and case–control samples, we found consistent associations in and around FBXL21 gene. In the family sample (Irish study of high density schizophrenia families, ISHDSF, 1,350 subjects from 273 families), a minimal PDT P ‐value of 0.0011 was observed at rs31555. In the case–control sample (Irish case–control study of schizophrenia, ICCSS, 814 cases and 625 controls), significant associations were observed at two markers (rs1859427 P = 0.0197, and rs6861170 P = 0.0197). In haplotype analyses, haplotype 1‐1 (C‐T) of rs1859427–rs6861170 was overtransmitted in the ISHDSF ( P = 0.0437) and was overrepresented in the ICCSS ( P = 0.0177). For both samples, the associated alleles and haplotypes were identical. These data suggested that FBXL21 may be associated with schizophrenia in the Irish samples. © 2008 Wiley‐Liss, Inc.

Background Interpersonal dependence is thought to be important in a number of physical and psychological disorders. There are several developmental theories that suggest environmental influences in childhood are important. Method A twin study methodology was used to look at the genetic and environmental influences on interpersonal dependence as measured by a sub-scale of the Interpersonal Dependency Inventory with a population-based sample of 2230 twins. Results Psychometric analysis revealed that this was a stable measure and that there was a substantial degree of construct validity Both univariate and longitudinal twin analysis suggested that there was a modest genetic influence and a large, specific environment influence on interpersonal dependency as measured by this scale. The longitudinal analysis revealed that the genetic influence was stable over the time-scale sampled and the environmental influence was moderately stable. Conclusions This finding is at odds with theories that suggest shared environment is important in the aetiology of interpersonal dependency.

Summary A 63‐year‐old female developed respiratory failure and was admitted to the Intensive Care Unit for non‐invasive ventilation, inotropic support and antibiotic therapy. The patient was initially stable but then suddenly deteriorated with acute pulmonary oedema requiring mechanical ventilation. An electrocardiogram showed an acute ST elevation myocardial infarction and the patient subsequently had an urgent coronary angiogram which revealed normal coronary arteries but apical ballooning characteristic of Takotsubo cardiomyopathy. A short review is provided of this relatively newly described heart syndrome which has the potential to present in numbers of intensive care patients. This case emphasises the importance of being aware of uncommon causes of acute ECG changes in the critically ill.

The long preclinical phase of atherosclerosis involves the interaction of genetic and environmental factors that modulate the progression of disease from early life. A variety of noninvasive tests have been used to study the arterial phenotype of childhood, allowing identification of arterial alterations long before clinical symptoms of cardiovascular (CV) disease become apparent. These techniques have improved our understanding of the evolution of atherosclerosis, indentifying three major developmental factors which influence the future risk of CV disease in childhood: prenatal growth, early postnatal growth and childhood obesity. Specific changes in arterial properties and increased values of blood pressure are detectable in children with low birth weight, suggesting that intrauterine growth retardation could programme the future risk of CV disease. However, an accelerated growth rate in infancy and early childhood is often associated with low birth weight and with specific vascular alterations, making it difficult to distinguish the contribution of prenatal and postnatal growth patterns to later cardiovascular disease risk. Relationships between growth patterns and CV disease risk are further complicated by the link between rapid postnatal growth and later development of childhood overweight and obesity, conditions associated with early changes in vascular physiology and that potentially affect future CV outcome. This article aims to provide an overview of evidence in support of fetal programming and growth acceleration hypotheses for adult CV disease. Specific attention is given to obesity-related vascular alterations and their effects on future CV disease risk. We also summarise current non-invasive approaches to investigate the precursors and early development of CV disease, emphasising their potential applications in childhood.

The aim of the present study was to contribute to the inconsistent literature on the comorbid relationship of alcohol problems and depressive symptoms from late adolescent to emerging adulthood by accounting for their trajectories and their conjoint relationship while controlling for the influence of externalising symptoms.We utilised data, from a longitudinal school cohort from Northern Ireland (Belfast Youth Developmental Study), over three time points where the participants were 16, 17 and 21 years of age. A total of 3118 participants were included, 1713 females and 1405 males. Second-order latent growth models were applied to examine growth trajectories. Parallel process growth models were used to assess whether growth trajectories of the symptoms were associated. Externalising symptoms were subsequently added as a covariate.Alcohol problems among males significantly increased over time but decreased in females. Depressive symptoms initially increased then decreased in both genders. Results indicated associations of the alcohol problems and depression, both initially and with time. Accounting for externalising symptoms only somewhat diminished this effect in males but not in females. An increase of initial levels of depression was associated with a decrease in alcohol problems over time. This association was only true among females. After controlling for externalising symptoms, the relationship was no longer observed.The present study provides further evidence of a significant relationship of alcohol problems and depression in adolescents and further supports a small literature indicating that depression may have protective effects of alcohol problems. Finally, the study shows the importance of accounting for externalising symptoms.

Background Public support for the implementation of personalised medicine policies (PMPs) within routine care is important owing to the high financial costs involved and the potential for redirection of resources from other services. Aims We aimed to determine the attributes of a PMP most likely to elicit public support for implementation. We also aimed to determine whether such support differed between a depression PMP and one for cystic fibrosis. Method In a discrete-choice experiment, paired vignettes illustrating both the current model of care (CMoC) and a hypothetical PMP for either depression or cystic fibrosis were presented to a representative sample of the UK public ( n = 2804). Each vignette integrated varying attributes, including anticipated therapeutic benefit over CMoC, and the annual cost to the taxpayer. Respondents were invited to express their preference for either the PMP or CMoC within each pair. Results The financial cost was the most important attribute influencing public support for PMPs. Respondents favoured PMP implementation where it benefited a higher proportion of patients or was anticipated to be more effective than CMoC. A reduction in services for non-eligible patients reduced the likelihood of support for PMPs. Respondents were more willing to fund PMPs for cystic fibrosis than for depression. Conclusions Cost is a significant factor in the public's support for PMPs, but essential caveats, such as protection for services available to PMP-ineligible patients, may also apply. Further research should explore the factors contributing to condition-specific nuances in public support for PMPs.

Symptom report scales are used in clinical practice to monitor patient outcomes. Using them permits the definition of a minimum clinically important difference (MCID) beyond which a patient may be judged as having responded to treatment. Despite recommendations that clinicians routinely use MCIDs in clinical practice, statisticians disagree about how MCIDs should be used to evaluate individual patient outcomes and responses to treatment. To address this issue, we asked how clinicians actually use MCIDs to evaluate patient outcomes in response to treatment. Sixty-eight psychiatrists made judgments about whether hypothetical patients had responded to treatment based on their pre- and posttreatment change scores on the widely used Positive and Negative Syndrome Scale. Psychiatrists were provided with the scale's MCID on which to base their judgments. Our secondary objective was to assess whether knowledge of the patient's genotype influenced psychiatrists' responder judgments. Thus, psychiatrists were also informed of whether patients possessed a genotype indicating hyperresponsiveness to treatment. While many psychiatrists appropriately used the MCID, others accepted a far lower posttreatment change as indicative of a response to treatment. When psychiatrists accepted a lower posttreatment change than the MCID, they were less confident in such judgments compared to when a patient's posttreatment change exceeded the scale's MCID. Psychiatrists were also less likely to identify patients as responders to treatment if they possessed a hyperresponsiveness genotype. Clinicians should recognize that when judging patient responses to treatment, they often tolerate lower response thresholds than warranted. At least some conflate their judgments with information, such as the patient's genotype, that is irrelevant to a post hoc response-to-treatment assessment. Consequently, clinicians may be at risk of persisting with treatments that have failed to demonstrate patient benefits.

Clozapine, whilst associated commonly with a transient and benign increase in liver enzymes, has also been associated with varying presentations of hepatitis in existing case reports. This report describes what we believe to be the first documented case of acute liver injury and pleural effusion associated with clozapine, resolving after cessation of the agent. The case supports existing literature in advocating a high index of suspicion, particularly in the 4-5 weeks following clozapine initiation, when considering nonspecific clinical symptoms and signs.

Clozapine, whilst associated commonly with a transient and benign increase in liver enzymes, has also been associated with varying presentations of hepatitis in existing case reports. This report describes what we believe to be the first documented case of acute liver injury and pleural effusion associated with clozapine, resolving after cessation of the agent. The case supports existing literature in advocating a high index of suspicion, particularly in the 4-5 weeks following clozapine initiation, when considering nonspecific clinical symptoms and signs.

Abstract Patients with pulmonary fibrosis (PF) are recommended pulmonary rehabilitation which improves health outcomes. Such physical activity (PA) programmes are meant to promote sustainable behavioural change as exercise activities are valued, enjoyed and considered meaningful. Dance is one exercise form, but COVID-19 may have negatively impacted participation and quality of life of vulnerable populations due to lockdown and consequent isolation. This qualitative study aimed to investigate the perspectives of adults living with PF who had participated in a dance intervention. In partnership with the Irish Lung Fibrosis Association (ILFA), A group of 16 patients with PF, members of ILFA, participated in 75 minutes online dance intervention for eight weeks delivered by an experienced choreographer. An exploratory qualitative study using thematic analysis of semi structured interviews was carried out to understand feasibility as well as health and wellbeing impacts of dancing among the participants. Eight participants (6 Female, 2 male; mean age 72.3 years) completed one to one semi-structured qualitative interviews. Four key themes emerged: 1) Dance is fun - we're not exercising 2) Improved sense of wellbeing 3) Positive impact of own online social space 4) Connecting dance impacts to clinical health. Overall, participants mentioned that our virtual dance intervention was acceptable, enjoyable, preferable, and feasible. They strongly perceived health benefits especially breathing efficiency and mental health improvements for managing their day-to-day struggles with PF. Emerging themes could influence the development and evaluation of dance as an alternate form of PA for patients with PF, exploring its benefits and sustainability. As dance is a low-cost activity that can be done at home, dance interventions may be used as an exercise pathway for patients with pulmonary diseases. More organised and continuous events in future may reveal cost-benefit ratio and impact on health outcomes. Key messages • Dance – More favourable, higher adherence rate, better health and wellbeing outcomes and achieve higher targets of recommended PA levels in the community. • Social prescribing – Creating and promoting alternative exercise forms which patient’s can and should enjoy an activity of their choice and have a choice.

Background: Longitudinal studies are essential for understanding the trajectory and prognosis of patients diagnosed with schizophrenia, in particular those who are treatment resistant as this outcome is difficult to predict. However, follow-up is challenging within this patient population due to high relapse rates, difficulties recontacting participants due to regular change of address, and patients’ symptoms leading to their refusal to take part. Methods: We describe one of the work packages of STRATA (Schizophrenia: Treatment Resistance and Therapeutic Advances) as an example of the challenges facing follow-up studies in schizophrenia research. The main aim of STRATA is to identify differences between treatment-resistant and treatment-responsive patients with schizophrenia and create a method for early identification of treatment resistant patients; thereby allowing earlier transition to more suitable treatments such as clozapine. Cohorts of patients from pre-existing studies of first-episode psychosis are presently being recontacted. Three studies across the UK (“AESOP,” Nottingham and London samples; “RPGI” and “NIFEPS,” Belfast samples) were included in STRATA. In total, 484 participants were eligible for recontact; 157 participants from AESOP, 85 from the RPGI; and 242 from the NIFEPS study. Participants were contacted via their clinical team, letter, or phone. Participants were invited to take part in a 40-minute interview in which demographic, substance use, medication history, and symptomatology (PANSS) data was collected. Participants were also asked to provide a blood and urine sample. Ethical permission was obtained to contact participants using information collected at previous visits and to obtain up to date contact addresses. Results: Out of the 484 participants who were recontacted, 13 were deceased, 9 were excluded, 23 requested information after the first contact but then ceased to respond, 47 declined to participate, and addresses were not identified for 63 participants. Thirty-four consented and completed all the assessments. The remaining 295 participants have yet to respond. Clozapine had been prescribed to 8.82% of completed participants and 47.06% have been prescribed 3 or more antipsychotics. Conclusion: The present study confirms the difficulties in longitudinal studies of patients diagnosed with schizophrenia. More research is needed in order to identify the attitudes and practices, which keep patients from participating in research. Additionally, in the general population, it is estimated that about two-third of individuals diagnosed with schizophrenia are treatment resistant. We can therefore conclude that treatment resistance is somewhat over-represented in the present sample. STRATA is supported by grant MR/L011794/1 from the Medical Research Council (MRC).

Experimental research has shown that poor sleep triggers psychotic experiences, even in healthy participants. This warrants an in-depth investigation of this mechanism in a naturalistic environment, an exploration of which particular aspects of poor sleep trigger psychotic symptoms, and a test for reverse effects of symptoms on sleep. For this purpose, we conducted a 14-day ambulatory assessment study with 82 young adults (age: M = 21.24 years, SD = 1.54; 64.6% female), half of which were characterized by elevated psychosis proneness. Objective sleep parameters (actigraphically-measured sleep time, wake after sleep onset, sleep efficiency), self-reported sleep parameters (feeling rested, dream recall, dream valence), and psychotic symptoms (paranoid symptoms, hallucinatory experiences) were assessed once per day. Using multilevel regressions (928 data points), we found that shorter sleep time and negative dream valence predicted paranoid symptoms, whereas feeling less rested and dream recall predicted hallucinatory experiences. In participants with elevated psychosis proneness, associations with the aforementioned sleep parameters were increased for hallucinatory experiences but not for paranoid symptoms. Finally, we found bidirectional associations between poor sleep and paranoid symptoms but only unidirectional associations between poor sleep and hallucinatory experiences. The findings corroborate the relevance of sleep disturbance as a predictor of psychotic experiences. Future studies should further investigate the potential of sleep interventions to prevent psychotic symptoms and disorders.

Background: HDL elevating therapies have thus far failed to improve CV outcome and the loss of anti-atherosclerotic properties of HDL has recently been reported in CAD. This suggests specific biological activities of HDL, rather than its cholesterol content, may be crucial in mediating the anti-atherogenic effects of HDL. Aim: To determine the impact of acute systemic inflammation on various measures of HDL function. Methods: 50 subjects with periodontitis (PD) (Age 49.8 [6.5]) underwent dental treatment. In vivo changes in endothelial function were determined using Flow Mediated Dilatation (FMD). HDL function was assayed at baseline, at the peak of the inflammatory response (24 hours after PD treatment) and following resolution (6 months post PD treatment). HDL-mediated cholesterol efflux was measured in J774 macrophage cells, pre-treated with cAMP. Impact of HDL on cultured endothelial aortic cells was assayed by measuring HDL-dependent Nitric Oxide bioavailibility (NO) and superoxide (SO) production using ESR Spectroscopy. HDL-associated Paraoxonasae-1 (PON1) activity was measured by spectrophotometry. Results and Discussion: 24 hours after dental treatment HDL became dysfunctional, as shown by reduced NO and increased SO production by cultured endothelial cells (P&lt;0.01 for both). In addition, PON1 activity was reduced (P=&lt;0.05), but no difference was found in cholesterol efflux capacity. At 6 months, these changes in HDL function returned to baseline levels, whereas cholesterol efflux capacity remained unchanged. Endothelial effects of HDL tracked with changes in inflammatory markers and FMD. Conclusion: HDL becomes dysfunctional during acute inflammation resulting in abnormal endothelial responses, in the absence of any change in efflux capacity. Furthermore, the acute impairment of HDL function is reversible upon resolution of inflammation and tracks changes in FMD. These results suggest HDL function may contribute to the vascular alterations observed during an inflammatory response and may represent a novel mechanism whereby inflammation may promote atherosclerosis, i.e. by altering the endothelial effects of HDL.

Poster Presentations / Osteoarthritis and Cartilage 18, Supplement 2 (2010) S45-S256 a meta-analysis of GWAS with > 2,500,000 imputed SNPs in Caucasian women from four population-based cohorts: three cohorts from the Rotterdam Study (RS-I, RS-II, and RS-III) and the Erasmus Rucphen Family (ERF) Study.Controls using analgesics were excluded.In total approximately 680 cases and 4180 controls were included in the meta-analysis.The program METAL was used to perform the meta-analysis using an additive model.The genomic control method was used to correct for any residual population stratification or relatedness not accounted for by the four most important PCs (all lambda's < 1.1). Results:The average prevalence of CWP in the four studies was 15%.The most significant signal of the meta-analysis was at 4p15.3, in intron 1 of Prominin 1 (PROM1), which reached borderline genome wide significance (p=5.5×10 - ).The effect allele T (minor allele frequency = 6%) of the most significant SNP gives a consistent higher risk for CWP in all four cohorts examined (meta-analysis OR per T-allele: 1.74, 95% CI: 1.43-2.14,p=5.5×10 -8 ).As observed from RS-I data, the effect allele also gives a higher risk for joint specific pain in hip (p = 0.024, OR: 1.34, 95% CI: 1.03-1.71),hand (p=0.021,OR: 1.31, 95% CI: 1.04-1.65),and low back and neck (p=0.001,OR: 1.43, 95% CI: 1.16-1.76).The PROM1 gene encodes a pentaspan transmembrane glycoprotein, for which no link with CWP has been established yet.Conclusions: This large GWAS meta-analysis on CWP shows a strongly suggestive association for CWP in women at chr4p15.3, just escaping genome-wide significance.Therefore, replication in other cohorts is needed, which might unveil further loci for CWP.

Psychotic symptoms, such as delusions and hallucinations, are among the most common and distressing neuropsychiatric symptoms in Alzheimer's disease (AD). AD with psychosis has been proposed as a distinct endophenotype, associated with more severe cognitive deficits and faster cognitive decline. The aetiology of these symptoms is unclear but they may be attributed to genetic risk factors revealed during neurodegeneration. CHRNA7, the gene for the alpha 7 nicotinic acetylcholine receptor, has been associated with schizophrenia in linkage and association studies. Objective: To investigate genetic variation in CHRNA7 in relation to AD with psychosis. The study group consisted of 409 Northern Irish patients with a diagnosis of probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA). Patients were assessed for the presence of psychotic symptoms using the Neuropsychiatric Inventory (NPI). Fourteen highly polymorphic intronic single nucleotide polymorphisms (SNPs) across CHRNA7 were selected and genotyped using Taqman technology and PCR-RFLP. Haploview was used to define linkage disequilibrium. Genotype and haplotype frequencies were compared using chi-squared analysis. Following correction for multiple testing, a significant association between delusions and the T allele of rs6494223 (p = 0.014, OR = 1.63, CI = 1.22–2.17) was found. Haplotype analysis revealed four blocks of high linkage disequilibrium across CHRNA7 but there were no associations between haplotypes and AD with psychosis. This novel finding suggests that the alpha 7 nicotinic acetylcholine receptor may be a suitable target in the treatment of AD with psychosis but further work in this area is required.

Back to table of contents Previous article Next article Letters to the EditorFull AccessDr. Fanous and Colleagues ReplyAYMAN H. FANOUS M.D.,EDWIN J. van den OORD Ph.D.BRIEN P. RILEY Ph.D.STEVEN H. AGGEN Ph.D.MICHAEL C. NEALE Ph.D.KENNETH S. KENDLER M.D.,F. ANTHONY O’NEILL M.D.,DERMOT WALSH M.B., F.R.C.P.I.,AYMAN H. FANOUS M.D.Search for more papers by this author,EDWIN J. van den OORD Ph.D.Search for more papers by this authorBRIEN P. RILEY Ph.D.Search for more papers by this authorSTEVEN H. AGGEN Ph.D.Search for more papers by this authorMICHAEL C. NEALE Ph.D.Search for more papers by this authorKENNETH S. KENDLER M.D.Search for more papers by this author,F. ANTHONY O’NEILL M.D.Search for more papers by this author,DERMOT WALSH M.B., F.R.C.P.I.Search for more papers by this author,Published Online:1 May 2006https://doi.org/10.1176/ajp.2006.163.5.941AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To The Editor: We read with interest the letter submitted by Drs. Doi and Usui regarding our article. Several points are made in their letter. First of all, the authors state that our main finding, that subjects inheriting the high-risk haplotype in DTNBP1 had higher levels of negative symptoms than expected by chance, “was derived from the observation that the high-risk haplotype frequency was higher in the subjects in the upper 40th percentile for the negative symptom factor.” Actually, our results were not derived from analyses of the frequency of the high-risk haplotype in the various clinical subgroups, although frequencies were provided in our table. Rather, we employed the Transmission-Disequilibrium Test (1) . This is a popular family-based association method that tests for excess transmission of alleles (or haplotypes) from heterozygotic parents to affected offspring. This transmission information, moreover, is not present in allele frequencies, which are derived from examining the entire group as a whole. In our experience, employing case-control methods, which are based on allele frequencies, in our group of 270 high-density schizophrenia families is less powerful than family-based tests such as the Transmission-Disequilibrium Test. Second, they state that the “frequency of the high-risk haplotype was higher in the upper 20%–40% subgroup for the negative symptom factor than in the upper 0%–20% subgroup.” Actually, the two groups that we tested were 1) the upper 0%–20% subgroup and 2) the 0%–40% subgroup. Therefore, the former was a subset of the latter group, comprising approximately half of it. Although we saw no preferential transmission to the 0%–20% group, we interpreted this as being due to insufficient power to detect association, which was recovered when we broadened our definition of affection to additionally include subjects in the upper 21%–40%. We believe that the interpretation of Drs. Doi and Usui, i.e., that these results suggest a protective effect of the DTNBP1 high-risk haplotype, would therefore not follow. As an additional check, we went back to analyze the 21%–40% group. We found that the ratio of observed-to-expected transmissions was basically the same as that in the 0%–20% group. Our interpretation of the results is that the DTNBP1 high-risk haplotype preferentially increases risk for a more or less specific clinical form of illness, namely, one that is associated with higher levels of negative symptoms. It is not clear to us that this has implications for a protective effect of the DTNBP1 genotype on the illness. A protective effect requires that one or more haplotypes be less likely to be transmitted to affected offspring than would be expected by chance. In the case of DTNBP1 , if the high-risk haplotype were truly protective against negative symptoms, then it should be transmitted to all groups defined by high levels of negative symptoms (i.e., 0%–20%, 0%–40%, and 21%–40%) less— not more—as we observed, than would be expected by chance. In furthering their argument, Drs. Doi and Usui adduce results indicating that the neuregulin 1 high-risk haplotype was associated with nondeficit (not deficit) schizophrenia (Bakker et al. in previous letter). We believe that these data can just as well be interpreted in a similar way as our data and that these haplotypes increase the risk of a more or less specific form of illness. We have previously called genes containing such haplotypes “modifier-susceptibility genes” (2) . Finally, we would like to thank Drs. Doi and Usui for their interest in our article and hope that we have provided some clarity on the topic. Washington, D.C.Richmond, Va.Belfast, U.K.Dublin, IrelandReprints are not available; however, Letters to the Editor can be downloaded at http://ajp.psychiatryonline.org.References1. Spielman RS, McGinnis RE, Ewens WJ: Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52:506–516Google Scholar2. Fanous AH, Kendler KS: Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework. Mol Psychiatry 2005; 10:6–13Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 163Issue 5 May, 2006Pages 941-942THE AMERICAN JOURNAL OF PSYCHIATRY May 2006 Volume 163 Number 5 Metrics PDF download History Published online 1 May 2006 Published in print 1 May 2006

Abstract Less common, less recognized, and often misdiagnosed cranial neuralgias and neuropathies include occipital neuralgia, auriculotemporal neuralgia, great auricular neuralgia, and superior laryngeal neuralgia. Pain is due to compression by muscles, fascia, arteries, bony abnormalities, or tumours at one of multiple potential sites during the course of the nerve involved. The exact pathophysiological mechanisms remain unknown but nothing suggests they are substantially different from those of other peripheral neuralgias. Diagnosis is clinical, based on the quality and location of pain, pain provocation, and effect of nerve blocks. The main differential diagnosis is with major cranial neuralgias while non-neuropathic pain conditions, such as temporomandibular disorder and referred pain from cervical structures, must also be considered. Nerve blocks are useful for precise diagnosis and—as a series of injections—for therapy. Neuroablative and decompressive procedures are reserved for refractory cases.

S: 1996 World Congress on Psychiatric Genetics: IV. (B). GENETICS OF NON-PSYCHOTIC PSYCHIATRIC DISORDERS: PDF Only