Dementias Platform UK: Bringing genetics into life.

INTRODUCTION: The Dementias Platform UK (DPUK) Data Portal is a data repository bringing together a wide range of cohorts. Neurodegenerative dementias are a group of diseases with highly heterogeneous pathology and an overlapping genetic component that is poorly understood. The DPUK collection of independent cohorts can facilitate research in neurodegeneration by combining their genetic and phenotypic data. METHODS: For genetic data processing, pipelines were generated to perform quality control analysis, genetic imputation, and polygenic risk score (PRS) derivation with six genome-wide association studies of neurodegenerative diseases. Pipelines were applied to five cohorts. DISCUSSION: The data processing pipelines, research-ready imputed genetic data, and PRS scores are now available on the DPUK platform and can be accessed upon request though the DPUK application process. Harmonizing genome-wide data for multiple datasets increases scientific opportunity and allows the wider research community to access and process data at scale and pace.

Scavenger receptor class B type I genetic variants associated with disease severity in chronic hepatitis C virus infection.

Analysis of host genetic polymorphisms is an increasingly important tool for understanding and predicting pathogenesis and treatment response of viral diseases. The gene locus of scavenger receptor class B type I (SR-BI), encoding a cell entry factor and receptor for hepatitis C virus (HCV), contains several genetic polymorphisms. We applied a probe extension assay to determine the frequency of six single nucleotide polymorphisms (SNPs) within the SR-BI gene locus in 374 individuals with history of HCV infection. In addition, SR-BI messenger RNA (mRNA) levels were analyzed in liver biopsy specimens of chronically infected HCV subjects. The rs5888 variant allele T was present at a higher frequency in subjects with advanced fibrosis (χ2 , p = 0.016) and after adjusting for age, duration of infection and alcohol intake as confounding factors. Haplotype analysis of SNP frequencies showed that a haplotype consisting of rs61932577 variant allele C and rs5888 variant allele T was associated with an increased risk of advanced liver fibrosis (defined by an Ishak score 4-6) (adjusted odds ratio 2.81; 95% confidence interval 1.06-7.46. p = 0.038). Carriers of the rs5888 variant allele T displayed reduced SR-BI mRNA expression in liver biopsy specimens. In conclusion the rs5888 polymorphism variant is associated with decreased SR-BI expression and an increased risk of development of advanced fibrosis in chronic HCV infection. These findings provide further evidence for a role of SR-BI in HCV pathogenesis and provides a genetic marker for prediction of those infected individuals at greater risk of developing severe disease.

Upregulated expression of FFAR2 and SOC3 genes is associated with gout.

OBJECTIVE: To examine the expression of Free fatty acid receptor 2 (FFAR2) and Suppressor of cytokine signalling 3 (SOCS3) genes in asymptomatic hyperuricaemia (AH), AH with MSU crystal deposition, inter-critical gout and gout flare. METHODS: Study participants (n = 120) comprised 34 people with serum urate (SU) <360 µmol/l, 69 with AH ± MSU crystal deposition and 17 with a gout flare. Sixteen of the 17 patients with a gout flare attended a second visit 6-12 weeks later. Gene expression levels were assessed using RT-qPCR and results computed as fold changes (FC) after normalization to the reference gene. RESULTS: FFAR2 was significantly upregulated during gout flares (FC = 2.9) compared with normal SU, AH, and AH + MSU crystal deposition (FC = 1.1, P < 0.0001 for each comparison). FFAR2 was also significantly upregulated during inter-critical gout (FC = 1.8) compared with normal SU, AH and AH + MSU (FC = 1.1, P < 0.001 for each comparison). SOCS3 was significantly upregulated during gout flares (FC = 3.4) compared with normal SU, AH, and AH + MSU crystal deposition (FC = 1.1, 1.1 and 1.2, respectively, P < 0.0001 for each comparison). SOCS3 was also upregulated during inter-critical gout (FC = 2.1) compared with normal SU (P = 0.02) and AH (P = 0.006) (FC = 1.1 and 1.2, respectively). FFAR2 expression was upregulated during gout flare compared with inter-critical gout and SOCS3 expression showed negative correlation with flare duration (r = -0.49, P < 0.05). CONCLUSION: FFAR2 upregulation is associated with gout and may trigger gout flares. SOCS3 may have a role in amelioration of gout flares.

Parental bonding style and illness severity in a longitudinal study of individuals with first episode psychosis.

A parenting style with high amounts of control combined with low caring or nurturing behaviour has been reported in association with mental disorders including schizophrenia. However, the association of parenting style with illness severity in individuals with schizophrenia has never been evaluated retrospectively or over a longitudinal time course. In a subset (n = 84) of the participants included in the AESOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses)-10 study, we evaluated participants' perceptions of their own parents' bonding style at the time of their first episode of psychosis using the parental bonding instrument (PBI). We then examined the association between different bonding styles, illness course and severity, and global functioning over a 10-year follow-up. Participants who perceived that their fathers had a more caring and less controlling parenting style showed better functioning at follow-up. However, in contrast to previous research, participants who reported having been subject to uncaring and controlling parenting styles were not found to have a notably worse course of illness or symptom severity over the follow-up period. These results indicate that more optimal parental bonding styles may be associated with better overall functioning in individuals with psychosis but not with other measures of illness outcome.

Napping behaviour, daytime sleepiness, and arousal in high performance athletes and non-athlete controls.

Napping offers a strategy to manage sleep, aid recovery and enhance performance in elite sport. However, relatively little research attention has focussed on the natural history of athlete napping or tested the widely held assumption that athlete napping is mainly a consequence of degraded night-time sleep. Within a sample of 158 team (n = 76) and individual (n = 80) sport athletes, and 82 non-athlete controls, we analysed napping behaviour in relation to sleep quality, daytime sleepiness, and pre-sleep somatic and cognitive arousal. There was no significant association between athlete/non-athlete status and the prevalence, frequency, or duration of naps. Comparisons of athlete nappers and non-nappers found no significant differences in sleep quantity or quality. While nap propensity was significantly related to higher daytime sleepiness, this influence was moderated or augmented by levels of pre-sleep cognitive arousal. For some nappers, those with higher levels of arousal may need to be sleepier than those with lower levels of arousal in order to successfully initiate daytime sleep. Approximately 50% of athletes did not nap. If the benefits of athlete napping are to be fully exploited, the needs of this substantial group for whom napping may be problematic should be recognised and addressed.

Sleep extension and metabolic health in male overweight/obese short sleepers: A randomised controlled trial.

While limited evidence suggests that longer sleep durations can improve metabolic health in habitual short sleepers, there is no consensus on how sustained sleep extension can be achieved. A total of 18 men (mean [SD] age 41 [ 9] years), who were overweight/obese (mean [SD] body mass index 30 [3] kg/m2 ) and short sleepers at increased risk of type 2 diabetes were randomised to a 6-week sleep-extension programme based on cognitive behavioural principles (n = 10) or a control (n = 8) group. The primary outcome was 6-week change in actigraphic total sleep time (TST). Fasting plasma insulin, insulin resistance (Homeostatic Model Assessment for Insulin Resistance [HOMA-IR]), blood pressure, appetite-related hormones from a mixed-meal tolerance test, and continuous glucose levels were also measured. Baseline to 6-week change in TST was greater in the sleep-extension group, at 79 (95% confidence interval [CI] 68.90, 88.05) versus 6 (95% CI -4.43, 16.99) min. Change in the sleep-extension and control groups respectively also showed: lower fasting insulin (-11.03 [95% CI -22.70, 0.65] versus 7.07 [95% CI -4.60, 18.74] pmol/L); lower systolic (-11.09 [95% CI -17.49, -4.69] versus 0.76 [95% CI -5.64, 7.15] mmHg) and diastolic blood pressure (-12.16 [95% CI -17.74, -6.59] versus 1.38 [95% CI -4.19, 6.96] mmHg); lower mean amplitude of glucose excursions (0.34 [95% CI -0.57, -0.12] versus 0.05 [95% CI -0.20, 0.30] mmol/L); lower fasting peptide YY levels (-18.25 [95%CI -41.90, 5.41] versus 21.88 [95% CI -1.78, 45.53] pg/ml), and improved HOMA-IR (-0.51 [95% CI -0.98, -0.03] versus 0.28 [95% CI -0.20, 0.76]). Our protocol increased TST and improved markers of metabolic health in male overweight/obese short sleepers.

A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene.

Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer's disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic Alzheimer's disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer's disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer's disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer's disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells. Collectively, our data support a link between genetic risk for Alzheimer's disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer's disease and COVID-19, and development of biomarkers to track disease progression.

Are polymorphisms affecting serum urate, renal urate handling and alcohol intake associated with co-morbidities in gout cases? A case-control study using data from the UK Biobank.

To examine the association between common comorbidities, eGFR and loci involved in the hyperuricaemia-gout transition. This study was conducted in people with gout from the UK Biobank. Logistic regression was used to examine the association between self-reported physician-diagnosed hypertension, diabetes, hypercholesterolemia and ischaemic heart disease (IHD) with the following variants: rs1260326(GCKR), rs16890979(SLC2A9), rs2231142(ABCG2), rs1229984(ADH1B) and rs2078267(SLC22A11) and adjusted for age, sex and 10-principal components. Linear regression was used to examine the association with eGFR. 7,049 participants with gout were included. After adjusting for multiple testing, there was a statistically significant positive association between urate lowering allele at SLC2A9 and hypertension, and negative association between urate raising allele at ABCG2 and hypertension (OR 1.17 and OR 0.86, respectively). Number of urate lowering risk alleles associated with hypertension [OR (95%CI) 1.13 (1.06-1.21)]. High eGFR associated with urate raising allele at rs2231142 (ß = 1.38). The SNP in ADH1B that protects from alcohol excess showed a negative association with IHD (OR 0.53). Unlike in general population studies urate lowering genetic variants associate with hypertension in gout patients with dose-response. This may be due to high prevalence of other risk factors of hypertension such as obesity, poor diet etc. and needs validation in independent datasets.

Variants in urate transporters, ADH1B, GCKR and MEPE genes associate with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank.

OBJECTIVES: To perform a genome-wide association study (GWAS) of gout cases versus asymptomatic hyperuricaemia (AH) controls, and gout cases versus normouricaemia controls, and to generate a polygenic risk score (PRS) to determine gout-case versus AH-control status. METHODS: Gout cases and AH controls (serum urate (SU) ≥6.0 mg/dL) from the UK Biobank were divided into discovery (4934 cases, 56 948 controls) and replication (2115 cases, 24 406 controls) cohorts. GWAS was conducted and PRS generated using summary statistics in discovery cohort as the base dataset and the replication cohort as the target dataset. The predictive ability of the model was evaluated. GWAS were performed to identify variants associated with gout compared with normouricaemic controls using SU <6.0 mg/dL and <7.0 mg/dL thresholds, respectively. RESULTS: Thirteen independent single nucleotide polymorphisms (SNPs) in ABCG2, SLC2A9, SLC22A11, GCKR, MEPE, PPM1K-DT, LOC105377323 and ADH1B reached genome-wide significance and replicated as predictors of AH to gout transition. Twelve of 13 associations were novel for this transition, and rs1229984 (ADH1B) was identified as GWAS locus for gout for the first time. The best PRS model was generated from association data of 17 SNPs; and had predictive ability of 58.5% that increased to 69.2% on including demographic factors. Two novel SNPs rs760077(MTX1) and rs3800307(PRSS16) achieved GWAS significance for association with gout compared with normouricaemic controls using both SU thresholds. CONCLUSION: The association of urate transporters with gout supports the central role of hyperuricaemia in its pathogenesis. Larger GWAS are required to identify if variants in inflammatory pathways contribute to progression from AH to gout.

Association between serum urate, gout and comorbidities: a case-control study using data from the UK Biobank.

OBJECTIVES: To examine the association between comorbidities and serum urate (SU), gout and comorbidities, and to determine whether the association between gout and comorbidities is independent of SU. METHODS: We performed a case-control study using UK Biobank data. Two separate analyses were conducted: one excluding participants with gout to investigate the association between comorbidities and SU and the other with participants with gout as the index condition to examine the association between gout and comorbidities. SU was measured at the baseline visit. Self-reported physician-diagnosed illnesses were used to define gout and comorbidities, except for chronic kidney disease (CKD), which was defined using an estimated glomerular filtration rate cut-off. Participants prescribed urate-lowering treatment were also classified as gout. Logistic regression was used to examine associations. Odds ratios (ORs) and 95% CIs were calculated and adjusted for covariates including comorbidities and SU. RESULTS: Data for 458 781 UK Biobank participants were used to examine the association between comorbidities and SU. There was an association between hypertension, ischaemic heart disease (IHD), congestive cardiac failure (CCF), hyperlipidaemia, CKD and SU with and adjusted OR (aOR) of 1.10-3.14 for each 1 mg/dl SU increase. A total of 10 265 gout cases and 458 781 controls were included in the analysis of association between gout and comorbidities. Gout associated independently with hypertension, IHD, CCF, hyperlipidaemia and diabetes, with aORs of 1.21-4.15 after adjusting for covariates including SU. CONCLUSION: Comorbidities associate with increasing SU. The association between gout and cardiometabolic comorbidities was independent of SU, suggesting separate SU-independent mechanisms such as inflammation driven by crystal deposition, pro-inflammatory genotype or non-purine dietary factors.

A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease.

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.

Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex.

Human DNA methylation data have been used to develop biomarkers of ageing, referred to as 'epigenetic clocks', which have been widely used to identify differences between chronological age and biological age in health and disease including neurodegeneration, dementia and other brain phenotypes. Existing DNA methylation clocks have been shown to be highly accurate in blood but are less precise when used in older samples or in tissue types not included in training the model, including brain. We aimed to develop a novel epigenetic clock that performs optimally in human cortex tissue and has the potential to identify phenotypes associated with biological ageing in the brain. We generated an extensive dataset of human cortex DNA methylation data spanning the life course (n = 1397, ages = 1 to 108 years). This dataset was split into 'training' and 'testing' samples (training: n = 1047; testing: n = 350). DNA methylation age estimators were derived using a transformed version of chronological age on DNA methylation at specific sites using elastic net regression, a supervised machine learning method. The cortical clock was subsequently validated in a novel independent human cortex dataset (n = 1221, ages = 41 to 104 years) and tested for specificity in a large whole blood dataset (n = 1175, ages = 28 to 98 years). We identified a set of 347 DNA methylation sites that, in combination, optimally predict age in the human cortex. The sum of DNA methylation levels at these sites weighted by their regression coefficients provide the cortical DNA methylation clock age estimate. The novel clock dramatically outperformed previously reported clocks in additional cortical datasets. Our findings suggest that previous associations between predicted DNA methylation age and neurodegenerative phenotypes might represent false positives resulting from clocks not robustly calibrated to the tissue being tested and for phenotypes that become manifest in older ages. The age distribution and tissue type of samples included in training datasets need to be considered when building and applying epigenetic clock algorithms to human epidemiological or disease cohorts.

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease.

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case-control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer's disease in seven independent case-control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer's disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer's disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer's disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-ß precursor protein (APP) and extracellular Aß42 and Aß40 (the 42- and 40-residue isoforms of the amyloid-ß peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aß42 and Aß40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.

Psychomotor Performance Decrements following a Successful Physical Activity Intervention for Insomnia.

Objectives: Evidence supports the view that reductions in cognitive hyperarousal contribute substantially to improved sleep outcomes following cognitive and behavioral interventions for insomnia disorder. Assuming an inverted-u relationship between arousal and performance, a theoretical possibility, supported by limited empirical data, is that the same mediating processes could negatively impact aspects of psychomotor performance, reducing speed on tests of reaction time. Participants: Sedentary participants (mean age = 59.8; SD = 9.46) meeting research diagnostic criteria for insomnia were randomized to either an exercise intervention of ≥150 min of moderate-intensity activity per week (n = 20), or a wait-list control group (n = 21). Of these, n = 17 intervention and n = 18 control participants completed 6-month follow-up assessments. Methods: Digit span, and simple and complex vigilance task performance was assessed using a computerized protocol at baseline and 6-month follow-up. Dependent variables included digit span, simple reaction time (SRT), complex reaction time (CRT), false positive responses, number of lapses, and SRT/CRT ratio (indicative of the magnitude of difference between simple and complex RT performance). The primary clinical outcome was Insomnia Severity Index (ISI) score. Results: In comparisons of baseline to follow-up change, ISI scores showed clinically significant improvement in the intervention group at 6-month follow-up (F (8,26) = 5.16; P = 0.03). Baseline vigilance performance was equivalent in both groups. At 6-month follow-up, however, the intervention group showed significantly slower simple reaction time F(4,30) = 10.25, p < 0.01, and a significantly decreased SRT/CRT ratio (F(4,30) = 13.22, p < 0.01). Conclusions: Among people meeting diagnostic criteria for insomnia, beneficial sleep outcomes following successful behavioral interventions may, under some circumstances, come at the cost of slower psychomotor performance.

Urinary leak following partial nephrectomy: a contemporary review of 975 cases.

INTRODUCTION: To describe the incidence, contemporary management, risk factors and outcomes of urinary leak following open and robotic partial nephrectomy at a tertiary care, comprehensive cancer center. MATERIALS AND METHODS: We reviewed 975 patients who underwent partial nephrectomy at Moffitt Cancer Center from January 2009 to May 2017. Patient demographic, perioperative and follow up data was recorded and compared stratified for postoperative urine leak. Fisher's exact and Wilcoxon sum-rank testing were performed for categorical and continuous variables as indicated. RESULTS: Twenty-three of 975 (2.3%) patients experienced a urine leak after partial nephrectomy. Median nephrometry score for urine leak patients was 8 (SD +/- 1.3). Median postoperative days to detection was 3.5 and most leaks were discovered due to high drain output. Operative factors associated with urinary leak included open surgery, estimated blood loss, and not using a sliding-clip renorrhaphy (p < 0.05). Ten (44%) were managed conservatively, 9 (39%) patients required ureteral stent placement, 3 (13%) needed a percutaneous nephrostomy tube, one patient (4%) required percutaneous drainage for urinoma (4%). One patient ultimately failed conservative management and required nephrectomy 45 days after the original surgery. Mean time to stent and drain removal was 40 +/- 17 and 24 +/- 7 days, respectively. Five patients with symptomatic leaks were readmitted with a mean length of stay of 3.2 +/- 1.8 days. CONCLUSIONS: The overall incidence of urinary leak after partial nephrectomy remains low regardless of surgical approach. Perioperative characteristics such as tumor complexity and high blood loss, in addition to open surgery and not using a sliding-clip bolstered renorrhaphy are associated with urine leak.

Heritability and genetic variance of dementia with Lewy bodies.

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

Neuropsychological function at first episode in treatment-resistant psychosis: findings from the ÆSOP-10 study.

BACKGROUND: Neuropsychological investigations can help untangle the aetiological and phenomenological heterogeneity of schizophrenia but have scarcely been employed in the context of treatment-resistant (TR) schizophrenia. No population-based study has examined neuropsychological function in the first-episode of TR psychosis. METHODS: We report baseline neuropsychological findings from a longitudinal, population-based study of first-episode psychosis, which followed up cases from index admission to 10 years. At the 10-year follow up patients were classified as treatment responsive or TR after reconstructing their entire case histories. Of 145 cases with neuropsychological data at baseline, 113 were classified as treatment responsive, and 32 as TR at the 10-year follow-up. RESULTS: Compared with 257 community controls, both case groups showed baseline deficits in three composite neuropsychological scores, derived from principal component analysis: verbal intelligence and fluency, visuospatial ability and executive function, and verbal memory and learning (p values⩽0.001). Compared with treatment responders, TR cases showed deficits in verbal intelligence and fluency, both in the extended psychosis sample (t = -2.32; p = 0.022) and in the schizophrenia diagnostic subgroup (t = -2.49; p = 0.017). Similar relative deficits in the TR cases emerged in sub-/sensitivity analyses excluding patients with delayed-onset treatment resistance (p values<0.01-0.001) and those born outside the UK (p values<0.05). CONCLUSIONS: Verbal intelligence and fluency are impaired in patients with TR psychosis compared with those who respond to treatment. This differential is already detectable - at a group level - at the first illness episode, supporting the conceptualisation of TR psychosis as a severe, pathogenically distinct variant, embedded in aberrant neurodevelopmental processes.

Regular physical activity and insomnia: An international perspective.

Both very low and very high levels of regular physical activity have been associated with degraded sleep quality. Cross-national variations in habitual physical activity levels, therefore, may contribute to cross-national differences in insomnia prevalence. The present study assesses and compares the extent to which weekly durations of moderate-intensity physical activity contribute to insomnia risk. Demographic, sleep, physical activity and general health profiles were obtained from a convenience sample of 9,238 adults drawn from five countries (South Africa, Australia, China, South Korea and the UK) using social media. Insomnia prevalence, using DSM-5 criteria, ranged from 4.1% (China) to 14.8% (UK). Evaluating risk using logistic regression adjusted only for age and gender, the lowest level of activity (<10 continuous min per week) was associated with significant insomnia risk (odds ratio = 1.37; 95% confidence interval = 1.05-1.79; p < 0.05). However, when adjusted for all covariates except country, only the highest level of physical activity (>300 min per week) was associated with significantly increased insomnia risk (odds ratio = 1.30; 95% confidence interval = 1.03-2.51; p < 0.05). Risk associated with high activity remained after the addition of "country" to the model (odds ratio = 1.31; 95% confidence interval = 1.02-1.69; p < 0.05). Across all models, female gender, low-rated health, low education and older age consistently increased insomnia risk. These cross-national data indicate that extremes of inactivity/activity can significantly influence insomnia risk independent of country. Insomnia risk associated with very low levels of activity may be mediated by poorer health and disadvantageous social status. However, while very high levels of activity increase insomnia risk independent of health and demographic factors, they may also confound with personally and occupationally demanding lifestyles.

Complement receptor 1 gene (CR1) intragenic duplication and risk of Alzheimer's disease.

Single nucleotide variants (SNVs) within and surrounding the complement receptor 1 (CR1) gene show some of the strongest genome-wide association signals with late-onset Alzheimer's disease. Some studies have suggested that this association signal is due to a duplication allele (CR1-B) of a low copy repeat (LCR) within the CR1 gene, which increases the number of complement C3b/C4b-binding sites in the mature receptor. In this study, we develop a triplex paralogue ratio test assay for CR1 LCR copy number allowing large numbers of samples to be typed with a limited amount of DNA. We also develop a CR1-B allele-specific PCR based on the junction generated by an historical non-allelic homologous recombination event between CR1 LCRs. We use these methods to genotype CR1 and measure CR1-B allele frequency in both late-onset and early-onset cases and unaffected controls from the United Kingdom. Our data support an association of late-onset Alzheimer's disease with the CR1-B allele, and confirm that this allele occurs most frequently on the risk haplotype defined by SNV alleles. Furthermore, regression models incorporating CR1-B genotype provide a better fit to our data compared to incorporating the SNV-defined risk haplotype, supporting the CR1-B allele as the variant underlying the increased risk of late-onset Alzheimer's disease.