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Background: No evidence based approach to reduce duration of untreated psychosis (DUP) has been effective in the UK. Existing interventions have many components and have been difficult to replicate. The majority of DUP in Birmingham, UK is accounted for by delays within mental health services (MHS) followed by help-seeking delay and, we hypothesise, these require explicit targeting. This study examined the feasibility and impact of an intervention to reduce DUP, targeting help-seeking and MHSs delays. Methods: A dual-component intervention, comprising a direct care pathway, for 16-25 year olds, and a community psychosis awareness campaign, using our youth-friendly website as the central hub, was implemented, targeting the primary sources of care pathway delays experienced by those with long DUP. Evaluation, using a quasi-experimental, design compared DUP of cases in two areas of the city receiving early detection vs detection as usual, controlling for baseline DUP in each area. Results: DUP in the intervention area was reduced from a median 71 days (mean 285) to 39 days (mean 104) following the intervention, with no change in the control area. Relative risk for the reduction in DUP was 0.74 (95 % CI 0.35 to 0.89; p = .004). Delays in MHSs and help-seeking were also reduced. Conclusions: Our targeted approach appears to be successful in reducing DUP and could provide a generalizable methodology applicable in a variety of healthcare contexts with differing sources of delay. More research is needed, however, to establish whether our approach is truly effective. [ABSTRACT FROM AUTHOR]

Background: Reducing the duration of untreated psychosis (DUP) is an aspiration of international guidelines for first episode psychosis; however, public health initiatives have met with mixed results. Systematic reviews suggest that greater focus on the sources of delay within care pathways, (which will vary between healthcare settings) is needed to achieve sustainable reductions in DUP (BJP 198: 256-263; 2011). Methods/Design: A quasi-experimental trial, comparing a targeted intervention area with a 'detection as usual' area in the same city. A proof-of-principle trial, no a priori assumptions are made regarding effect size; key outcome will be an estimate of the potential effect size for a definitive trial. DUP and number of new cases will be collected over an 18-month period in target and control areas and compared; historical data on DUP collected in both areas over the previous three years, will serve as a benchmark. The intervention will focus on reducing two significant DUP component delays within the overall care pathway: delays within the mental health service and help-seeking delay. Discussion: This pragmatic trial will be the first to target known delays within the care pathway for those with a first episode of psychosis. If successful, this will provide a generalizable methodology that can be implemented in a variety of healthcare contexts with differing sources of delay. [ABSTRACT FROM AUTHOR]

Background: Generation Scotland: the Scottish Family Health Study aims to identify genetic variants accounting for variation in levels of quantitative traits underlying the major common complex diseases (such as cardiovascular disease, cognitive decline, mental illness) in Scotland. Methods∕Design: Generation Scotland will recruit a family-based cohort of up to 50,000 individuals (comprising siblings and parent-offspring groups) across Scotland. It will be a six-year programme, beginning in Glasgow and Tayside in the first two years (Phase 1) before extending to other parts of Scotland in the remaining four years (Phase 2). In Phase 1, individuals aged between 35 and 55 years, living in the East and West of Scotland will be invited to participate, along with at least one (and preferably more) siblings and any other first degree relatives aged 18 or over. The total initial sample size will be 15,000 and it is planned that this will increase to 50,000 in Phase 2. All participants will be asked to contribute blood samples from which DNA will be extracted and stored for future investigation. The information from the DNA, along with answers to a life-style and medical history questionnaire, clinical and biochemical measurements taken at the time of donation, and subsequent health developments over the life course (traced through electronic health records) will be stored and used for research purposes. In addition, a detailed public consultation process will begin that will allow respondents' views to shape and develop the study. This is an important aspect to the research, and forms the continuation of a long-term parallel engagement process. Discussion: As well as gene identification, the family-based study design will allow measurement of the heritability and familial aggregation of relevant quantitative traits, and the study of how genetic effects may vary by parent-of-origin. Long-term potential outcomes of this research include the targeting of disease prevention and treatment, and the development of screening tools based on the new genetic information. This study approach is complementary to other population-based genetic epidemiology studies, such as UK Biobank, which are established primarily to characterise genes and genetic risk in the population. [ABSTRACT FROM AUTHOR]

The capacity to undertake systematic surveys of common variation through genome-wide association analysis has the potential to deliver substantial insights into type 2 diabetes (T2D) pathogenesis. We recently completed genotyping of 1954 T2D cases (enriched for positive family history/early onset) and 2922 population-based controls (all UK origin) on the Affymetrix 500k chip as part of the Wellcome Trust Case-Control Consortium. The preliminary analyses reported here are based on ∼309,000 SNPs with exemplary quality control and minor allele frequency (MAF)>5% [estimated to provide ∼60% coverage of CEU HapMap (MAF>5%, pairwise, r²>0.8)]. Variants within TCF7L2 emerge as the strongest cluster of susceptibility variants (12 SNPs, best = rs7901695, p=9.9x 10[sup -13]), but we find an additional 5 signals achieving nominal genome-wide significance with additive model p<6x10[sup -6] (controlling the false discovery rate at 0.05). These signals (located on chromosomes 1, 2, 6, 12 and 16) include a cluster of 5 SNPs with p< 10[sup -4] at ∼20.8Mbp on chr6, in a region including the CDK5 regulatory subunit associated protein 1-like 1 gene (CDKAL1) [for example, rs9465871, OR(95%CIs) for allele T (MAF∼80%) dominance: 0.51(0.37-0.70), exact p=1x10[sup -5]]. Extensive replication studies in 3073 T2D cases and 3879 controls (0.70(0.53-0.92), exact p=0.005) and meta-analysis across all ∼11800 subjects (0.61 (0.49-0.75), exact p=5.7x 10[sup -7]) provide supporting evidence for this finding. Haplotype-based analyses across a 2Mb region surrounding rs9465871 show no additional signal. Based on HapMap CEU data, rs9465871 is in perfect LD with several other intronic variants within CDKAL1; we have thus far covered ∼60% of common variation in the region (r²>0.8). Whilst further replication studies and fine-mapping will be required to refine the allelic architecture of this locus, these findings provide strong preliminary evidence that the CDKAL1 region harbours a novel locus affecting T2D risk. [ABSTRACT FROM AUTHOR]

Background: Although it has long been recognized that smooth muscle Na/K ATPase modulates vascular tone and blood pressure (BP), the role of its accessory protein phospholemman has not been characterized. The aim of this study was to test the hypothesis that phospholemman phosphorylation regulates vascular tone in vitro and that this mechanism plays an important role in modulation of vascular function and BP in experimental models in vivo and in humans.Methods: In mouse studies, phospholemman knock-in mice (PLM3SA; phospholemman [FXYD1] in which the 3 phosphorylation sites on serines 63, 68, and 69 are mutated to alanines), in which phospholemman is rendered unphosphorylatable, were used to assess the role of phospholemman phosphorylation in vitro in aortic and mesenteric vessels using wire myography and membrane potential measurements. In vivo BP and regional blood flow were assessed using Doppler flow and telemetry in young (14-16 weeks) and old (57-60 weeks) wild-type and transgenic mice. In human studies, we searched human genomic databases for mutations in phospholemman in the region of the phosphorylation sites and performed analyses within 2 human data cohorts (UK Biobank and GoDARTS [Genetics of Diabetes Audit and Research in Tayside]) to assess the impact of an identified single nucleotide polymorphism on BP. This single nucleotide polymorphism was expressed in human embryonic kidney cells, and its effect on phospholemman phosphorylation was determined using Western blotting.Results: Phospholemman phosphorylation at Ser63 and Ser68 limited vascular constriction in response to phenylephrine. This effect was blocked by ouabain. Prevention of phospholemman phosphorylation in the PLM3SA mouse profoundly enhanced vascular responses to phenylephrine both in vitro and in vivo. In aging wild-type mice, phospholemman was hypophosphorylated, and this correlated with the development of aging-induced essential hypertension. In humans, we identified a nonsynonymous coding variant, single nucleotide polymorphism rs61753924, which causes the substitution R70C in phospholemman. In human embryonic kidney cells, the R70C mutation prevented phospholemman phosphorylation at Ser68. This variant's rare allele is significantly associated with increased BP in middle-aged men.Conclusions: These studies demonstrate the importance of phospholemman phosphorylation in the regulation of vascular tone and BP and suggest a novel mechanism, and therapeutic target, for aging-induced essential hypertension in humans. [ABSTRACT FROM AUTHOR]

Importance: Neuropathic pain (NP) has important clinical and socioeconomic consequences for individuals and society. Increasing evidence indicates that genetic factors make a significant contribution to NP, but genome-wide association studies (GWASs) are scant in this field and could help to elucidate susceptibility to NP., Objective: To identify genetic variants associated with NP susceptibility., Design, Setting, and Participants: This genetic association study included a meta-analysis of GWASs of NP using 3 independent cohorts: ie, Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS); Generation Scotland: Scottish Family Health Study (GS:SFHS); and the United Kingdom Biobank (UKBB). Data analysis was conducted from April 2018 to December 2019., Exposures: Individuals with NP (ie, case participants; those with pain of ≥3 months' duration and a Douleur Neuropathique en 4 Questions score ≥3) and individuals with no pain (ie, control participants) with or without diabetes from GoDARTS and GS:SFHS were identified using validated self-completed questionnaires. In the UKBB, self-reported prescribed medication and hospital records were used as a proxy to identify case participants (patients recorded as receiving specific anti-NP medicines) and control participants., Main Outcomes and Measures: GWAS was performed using linear mixed modeling. GWAS summary statistics were combined using fixed-effect meta-analysis. A total of 51 variants previously shown to be associated with NP were tested for replication., Results: This study included a total of 4512 case participants (2662 [58.9%] women; mean [SD] age, 61.7 [10.8] years) and 428 489 control participants (227 817 [53.2%] women; mean [SD] age, 62.3 [11.5] years) in the meta-analysis of 3 cohorts with European descent. The study found a genome-wide significant locus at chromosome 12q23.1, which mapped to SLC25A3 (rs369920026; odds ratio [OR] for having NP, 1.68; 95% CI, 1.40-2.02; P = 1.30 × 10-8), and a suggestive variant at 13q14.2 near CAB39L (rs7992766; OR, 1.09; 95% CI, 1.05-1.14; P = 1.22 × 10-7). These mitochondrial phosphate carriers and calcium binding genes are expressed in brain and dorsal root ganglia. Colocalization analyses using expression quantitative loci data found that the suggestive variant was associated with expression of CAB39L in the brain cerebellum (P = 1.01 × 10-14). None of the previously reported variants were replicated., Conclusions and Relevance: To our knowledge, this was the largest meta-analyses of GWAS to date. It found novel genetic variants associated with NP susceptibility. These findings provide new insights into the genetic architecture of NP and important information for further studies.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10 -8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10 -8 ) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10 -3 ) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Background: Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK., Methods: A genome-wide association study was performed adjusting for age, sex, BMI and nine population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication., Results: We identified three genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10-11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10-10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10-8 for rs62053992. In the replication stage, among four significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively)., Conclusions: We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain., (© The Author(s) 2020. Published by Oxford University Press.)

Objective: Self-harm remains a serious public health concern; however, identifying adolescents at risk is challenging. While self-harm has been linked with difficulties in emotional regulation postinjury, comparatively little is known about how such difficulties may impact on the future development of self-harm behavior., Methods: A total of 318 pupils aged 14-15 years completed measures on history of direct self-injurious behavior (D-SIB), emotional regulation, depression, and anxiety at two time points across a six-month period., Results: Of 13% (42) of participants reported their first episode of D-SIB over the six-month period and reported increased difficulties with emotional regulation prior to initial D-SIB. Regression analyses found significant associations for emotional regulation and specifically lack of emotional clarity prior to first episode of D-SIB. Lack of emotional awareness and difficulties with impulse control was significantly associated in those with ongoing D-SIB., Conclusions: Prior to first episode of D-SIB, young people may experience difficulty regulating emotions, a difficulty which appears less pronounced following their engagement with D-SIB. Our findings implicate difficulties in the early evaluation and understanding of emotions which may later impair attempts at emotion modulation and increase risk of D-SIB. Such findings might help inform early identification of adolescents at risk of initial D-SIB., (© 2018 The American Association of Suicidology.)

Knee pain is one of the most common musculoskeletal complaints that brings people to medical attention. Approximately 50% of individuals over the age of 50 report an experience of knee pain within the past 12 months. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and seek supporting evidence in cohorts from 23andMe, the Osteoarthritis Initiative, and the Johnston County Osteoarthritis Project. We identified two loci that reached genome-wide significance in the UK Biobank: rs143384, located in GDF5 ( P  = 1.32 × 10 -12 ), a gene previously implicated in osteoarthritis; and rs2808772, located near COL27A1 ( P  = 1.49 × 10 -8 ). These findings were supported in cohorts with self-reported osteoarthritis/radiographic knee osteoarthritis without pain information. In this report on genome-wide association of knee pain, we identified two loci in or near GDF5 and COL27A1 that are associated with knee pain., Competing Interests: Competing interestsJ.S., A.A. and members of the 23andMe Research Team are employees of 23andMe, Inc., and hold stock or stock options in 23andMe. Other authors declare no competing interests.