Publications by authors named "Kevin Morgan"

267 Publications

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

Brain 2021 Oct 7. Epub 2021 Oct 7.

UK Dementia Research Institute at UCL, Gower Street, London WC1E 6BT, UK.

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.
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http://dx.doi.org/10.1093/brain/awab337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500089PMC
October 2021

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

J Sleep Res 2021 Aug 29:e13469. Epub 2021 Aug 29.

School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.

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/m ) 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.
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http://dx.doi.org/10.1111/jsr.13469DOI Listing
August 2021

Genome-wide association findings from the brains for dementia research cohort.

Neurobiol Aging 2021 Jun 25. Epub 2021 Jun 25.

Biosciences, School of Science & Technology, Nottingham Trent University, Nottingham, UK. Electronic address:

The Brains for Dementia Research (BDR) cohort (~3200) is a longitudinal clinicopathological programme, complimented with genetic analysis for the purposes of aetiological investigation into dementia. Here the data from genetic association analyses are presented from the initial collection of DNA from the BDR cohort. The aim of this study was to investigate the preliminary association signals for pathologically confirmed Alzheimer's disease samples compared to controls with no other pathology (n = 520). Genome-wide genotyping was carried out using the NeuroChip platform. Analysis utilised the standard PLINK software for association studies. Genome-wide Bonferroni significant association were observed on chr19 around the APOE/TOMM40 locus across 2 distinct linkage disequilibrium blocks. Eleven of the top 35 association signals have been identified in previous studies, in addition to an intriguing SNP association within the FPR1 gene locus. This study suggests the BDR is genetically comparable to other Alzheimer's disease cohorts and offers an independent resource to verify findings, and additional genetic data for meta-analyses.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.05.014DOI Listing
June 2021

A meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex.

Nat Commun 2021 06 10;12(1):3517. Epub 2021 Jun 10.

University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.

Epigenome-wide association studies of Alzheimer's disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer's disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource ( www.epigenomicslab.com/ad-meta-analysis/ ).
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http://dx.doi.org/10.1038/s41467-021-23243-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192929PMC
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

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.

Ann Rheum Dis 2021 09 8;80(9):1220-1226. Epub 2021 Apr 8.

Academic Rheumatology, University of Nottingham, Nottingham, UK.

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.
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http://dx.doi.org/10.1136/annrheumdis-2020-219796DOI Listing
September 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Psychological and pharmacological treatments for insomnia: Blending for patient benefit.

Authors:
Kevin Morgan

Sleep Med Rev 2021 Apr 12;56:101415. Epub 2021 Jan 12.

School of Sport, Exercise and Health Sciences, Loughborough University LE11 3TU, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.smrv.2020.101415DOI Listing
April 2021

Genetic risk for Alzheimer's disease influences neuropathology via multiple biological pathways.

Brain Commun 2020 12;2(2):fcaa167. Epub 2020 Oct 12.

College of Medicine and Health, University of Exeter, Exeter, Devon, EX2 5DW, UK.

Alzheimer's disease is a highly heritable, common neurodegenerative disease characterized neuropathologically by the accumulation of β-amyloid plaques and tau-containing neurofibrillary tangles. In addition to the well-established risk associated with the locus, there has been considerable success in identifying additional genetic variants associated with Alzheimer's disease. Major challenges in understanding how genetic risk influences the development of Alzheimer's disease are clinical and neuropathological heterogeneity, and the high level of accompanying comorbidities. We report a multimodal analysis integrating longitudinal clinical and cognitive assessment with neuropathological data collected as part of the Brains for Dementia Research study to understand how genetic risk factors for Alzheimer's disease influence the development of neuropathology and clinical performance. Six hundred and ninety-three donors in the Brains for Dementia Research cohort with genetic data, semi-quantitative neuropathology measurements, cognitive assessments and established diagnostic criteria were included in this study. We tested the association of genotype and Alzheimer's disease polygenic risk score-a quantitative measure of genetic burden-with survival, four common neuropathological features in Alzheimer's disease brains (neurofibrillary tangles, β-amyloid plaques, Lewy bodies and transactive response DNA-binding protein 43 proteinopathy), clinical status (clinical dementia rating) and cognitive performance (Mini-Mental State Exam, Montreal Cognitive Assessment). The ε4 allele was significantly associated with younger age of death in the Brains for Dementia Research cohort. Our analyses of neuropathology highlighted two independent pathways from ε4, one where β-amyloid accumulation co-occurs with the development of tauopathy, and a second characterized by direct effects on tauopathy independent of β-amyloidosis. Although we also detected association between ε4 and dementia status and cognitive performance, these were all mediated by tauopathy, highlighting that they are a consequence of the neuropathological changes. Analyses of polygenic risk score identified associations with tauopathy and β-amyloidosis, which appeared to have both shared and unique contributions, suggesting that different genetic variants associated with Alzheimer's disease affect different features of neuropathology to different degrees. Taken together, our results provide insight into how genetic risk for Alzheimer's disease influences both the clinical and pathological features of dementia, increasing our understanding about the interplay between genotype and other genetic risk factors.
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http://dx.doi.org/10.1093/braincomms/fcaa167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750986PMC
October 2020

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

Rheumatology (Oxford) 2021 07;60(7):3243-3251

Academic Rheumatology, University of Nottingham, Nottingham, UK.

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.
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http://dx.doi.org/10.1093/rheumatology/keaa773DOI Listing
July 2021

Genetic variants in glutamate-, Aβ-, and tau-related pathways determine polygenic risk for Alzheimer's disease.

Neurobiol Aging 2021 05 12;101:299.e13-299.e21. Epub 2020 Nov 12.

Human Genetics Group, School of Life Sciences, University of Nottingham, Nottingham, UK. Electronic address:

Synapse loss is an early event in late-onset Alzheimer's disease (LOAD). In this study, we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOAD. We used summary statistics from the International Genetics of Alzheimer's Project genome-wide association meta-analysis of 74,046 patients for model construction and tested the "synaptic PRS" in 2 independent data sets of controls and pathologically confirmed LOAD. The mean synaptic PRS was 2.3-fold higher in LOAD than that in controls (p < 0.0001) with a predictive accuracy of 72% in the target data set (n = 439) and 73% in the validation data set (n = 136), a 5%-6% improvement compared with the APOE locus (p < 0.00001). The model comprises 8 variants from 4 previously identified (BIN1, PTK2B, PICALM, APOE) and 2 novel (DLG2, MINK1) LOAD loci involved in glutamate signaling (p = 0.01) or APP catabolism or tau binding (p = 0.005). As the simplest PRS model with good predictive accuracy to predict LOAD, we conclude that synapse-encoding genes are enriched for LOAD risk-modifying loci. The synaptic PRS could be used to identify individuals at risk of LOAD before symptom onset.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.11.009DOI Listing
May 2021

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

Brain 2020 12;143(12):3763-3775

University of Exeter Medical School, University of Exeter, Exeter, UK.

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.
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http://dx.doi.org/10.1093/brain/awaa334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805794PMC
December 2020

Napping in high-performance athletes: Sleepiness or sleepability?

Eur J Sport Sci 2021 Mar 26;21(3):321-330. Epub 2020 Mar 26.

Gilchrist Performance, Reading, UK.

Daytime napping is a common practice in high-performance athletes, and is widely assumed to reflect sleepiness arising from sports-related sleep debt. The possibility that athlete naps may also be indicative of 'sleepability', a capacity to nap on demand that is only weakly related to homeostatic sleep pressure, has not previously been tested. The present study compared daytime sleep latencies in high-performance athletes and non-athlete controls using a single nap opportunity model. Elite ( = 10), and sub-elite ( = 10) athletes, and non-athlete controls ( = 10) attended the laboratory for a first adaption trial, and a subsequent experimental trial. Subjective sleepiness was assessed using the Karolinska Sleepiness Scale (KSS) at 14:00, 14:30 and immediately prior to a 20-minute nap opportunity at 15:00. Sleep latencies were measured using polysomnography, and defined as the time from lights out to the first epoch of any stage of sleep (N1, N2, N3, REM). In unadjusted comparisons with non-athlete controls, elite athletes showed significantly shorter sleep latencies in both the adaptation ( < 0.05) and experimental trials ( < 0.05). These significant differences were maintained in models controlling for pre-trial KSS scores and pre-trial total sleep time (all  < 0.05). Sleep latency scores for sub-elite athletes showed similar trends, but were more labile. These results are consistent with a conclusion that, among elite athletes, napping behaviour can reflect sleepability and may not necessarily result from nocturnal sleep disruption and daytime sleepiness.
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http://dx.doi.org/10.1080/17461391.2020.1743765DOI Listing
March 2021

Psychological stress, cognitive decline and the development of dementia in amnestic mild cognitive impairment.

Sci Rep 2020 02 27;10(1):3618. Epub 2020 Feb 27.

Faculty of Medicine, Clinical Experimental Sciences, University of Southampton, Southampton, UK.

To determine the relationship between psychological stress with cognitive outcomes in a multi-centre longitudinal study of people with amnestic mild cognitive impairment (aMCI) we assessed three parameters of psychological stress (Recent Life Changes Questionnaire (RLCQ); the Perceived Stress Scale (PSS) and salivary cortisol) and their relationship with rates of cognitive decline over an 18 month follow up period and conversion to dementia over a 5.5 year period. In 133 aMCI and 68 cognitively intact participants the PSS score was higher in the aMCI compared with control group but neither the RLCQ scores nor salivary cortisol measures were different between groups. In the aMCI group the RLCQ and the PSS showed no significant association with cognitive function at baseline, cognitive decline or with conversion rates to dementia but high salivary cortisol levels were associated with RLCQ scores and poorer cognitive function at baseline and lower rates of cognitive decline. No relationship was found between salivary cortisol levels and conversion rate to dementia. We conclude that psychological stress as measured by the RLCQ or PSS was not associated with adverse cognitive outcomes in an aMCI population and hypothesise that this may reflect diminished cortisol production to psychological stress as the disease progresses.
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http://dx.doi.org/10.1038/s41598-020-60607-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046646PMC
February 2020

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

Can J Urol 2020 02;27(1):10118-10124

Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, Florida, USA.

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.
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February 2020

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies.

Acta Neuropathol Commun 2020 01 29;8(1). Epub 2020 Jan 29.

Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
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http://dx.doi.org/10.1186/s40478-020-0879-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990558PMC
January 2020

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease.

PLoS One 2019 8;14(7):e0218111. Epub 2019 Jul 8.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218111PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613773PMC
February 2020

Cognitive Change in Schizophrenia and Other Psychoses in the Decade Following the First Episode.

Am J Psychiatry 2019 10 1;176(10):811-819. Epub 2019 Jul 1.

The Department of Psychosis Studies (Zanelli, Dazzan, Pilecka, Reis Marques, David, Murray, Reichenberg) and the Department of Psychology (Pilecka), Institute of Psychiatry, Psychology, and Neuroscience, King's College London; the Department of Psychiatry, Harvard Medical School, Boston (Mollon); the Department of Psychiatry (Sandin, Reichenberg), the Department of Environmental Medicine and Public Health, and the Friedman Brain Institute (Reichenberg), Icahn School of Medicine at Mount Sinai, New York; the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm (Sandin); the Centre for Public Mental Health, Health Service and Population Research Department, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (C. Morgan); the Department of Psychology, University of Westminster, London (K. Morgan); the Department of Psychiatry, Trinity College, Dublin (Fearon); the Division of Psychiatry and Applied Psychology, University of Nottingham, Nottingham, U.K. (Doody); and the Department of Psychiatry, University of Cambridge, Cambridge, U.K., and the Institute of Mental Health, University College London (Jones).

Objective: Schizophrenia is associated with a marked cognitive impairment that is widely believed to remain stable after illness onset. Yet, to date, 10-year prospective studies of cognitive functioning following the first episode with good methodology are rare. The authors examined whether schizophrenia patients experience cognitive decline after the first episode, whether this decline is generalized or confined to individual neuropsychological functions, and whether decline is specific to schizophrenia.

Methods: Participants were from a population-based case-control study of patients with first-episode psychosis who were followed prospectively up to 10 years after first admission. A neuropsychological battery was administered at index presentation and at follow-up to patients with a diagnosis of schizophrenia (N=65) or other psychoses (N=41) as well as to healthy comparison subjects (N=103).

Results: The schizophrenia group exhibited declines in IQ and in measures of verbal knowledge and of memory, but not processing speed or executive functions. Processing speed and executive function impairments were already present at the first episode and remained stable thereafter. The magnitude of declines ranged between 0.28 and 0.66 standard deviations. Decline in measures of memory was not specific to schizophrenia and was also apparent in the group of patients with other psychoses. Healthy individuals with low IQ showed no evidence of decline, suggesting that a decline is specific to psychosis.

Conclusions: Patients with schizophrenia and other psychoses experience cognitive decline after illness onset, but the magnitude of decline varies across cognitive functions. Distinct mechanisms consequent to the illness and/or psychosocial factors may underlie impairments across different cognitive functions.
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http://dx.doi.org/10.1176/appi.ajp.2019.18091088DOI Listing
October 2019

Correction: Alzheimer's disease polygenic risk score as a predictor of conversion from mild-cognitive impairment.

Transl Psychiatry 2019 Jun 11;9(1):167. Epub 2019 Jun 11.

Human Genetics Group, University of Nottingham, Nottingham, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41398-019-0503-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559959PMC
June 2019

Alzheimer's disease polygenic risk score as a predictor of conversion from mild-cognitive impairment.

Transl Psychiatry 2019 05 24;9(1):154. Epub 2019 May 24.

Institute of Neuroscience Biomedical Research Building Campus for Ageing and Vitality Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.

Mild-cognitive impairment (MCI) occurs in up to one-fifth of individuals over the age of 65, with approximately a third of MCI individuals converting to dementia in later life. There is a growing necessity for early identification for those at risk of dementia as pathological processes begin decades before onset of symptoms. A cohort of 122 individuals diagnosed with MCI and followed up for a 36-month period for conversion to late-onset Alzheimer's disease (LOAD) were genotyped on the NeuroChip array along with pathologically confirmed cases of LOAD and cognitively normal controls. Polygenic risk scores (PRS) for each individual were generated using PRSice-2, derived from summary statistics produced from the International Genomics of Alzheimer's Disease Project (IGAP) genome-wide association study. Predictability models for LOAD were developed incorporating the PRS with APOE SNPs (rs7412 and rs429358), age and gender. This model was subsequently applied to the MCI cohort to determine whether it could be used to predict conversion from MCI to LOAD. The PRS model for LOAD using area under the precision-recall curve (AUPRC) calculated a predictability for LOAD of 82.5%. When applied to the MCI cohort predictability for conversion from MCI to LOAD was 61.0%. Increases in average PRS scores across diagnosis group were observed with one-way ANOVA suggesting significant differences in PRS between the groups (p < 0.0001). This analysis suggests that the PRS model for LOAD can be used to identify individuals with MCI at risk of conversion to LOAD.
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http://dx.doi.org/10.1038/s41398-019-0485-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534556PMC
May 2019

Heritability and genetic variance of dementia with Lewy bodies.

Neurobiol Dis 2019 07 3;127:492-501. Epub 2019 Apr 3.

Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Sweden.

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.
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http://dx.doi.org/10.1016/j.nbd.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588425PMC
July 2019

Assessment of the energy recovery potential of waste Photovoltaic (PV) modules.

Sci Rep 2019 03 27;9(1):5267. Epub 2019 Mar 27.

Department of Thermal Power Engineering, Southeast University, 2 Sipailou, Xuanwu Qu, Nanjing Shi, 210018, Jiangsu Sheng, China.

Global exponential increase in levels of Photovoltaic (PV) module waste is an increasing concern. The purpose of this study is to investigate if there is energy value in the polymers contained within first-generation crystalline silicon (c-Si) PV modules to help contribute positively to recycling rates and the circular economy. One such thermochemical conversion method that appeals to this application is pyrolysis. As c-Si PV modules are made up of glass, metal, semiconductor and polymer layers; pyrolysis has potential not to promote chemical oxidation of any of these layers to help aid delamination and subsequently, recovery. Herein, we analysed both used polymers taken from a deconstructed used PV module and virgin-grade polymers prior to manufacture to determine if any properties or thermal behaviours had changed. The calorific values of the used and virgin-grade Ethylene vinyl acetate (EVA) encapsulant were found to be high, unchanged and comparable to that of biodiesel at 39.51 and 39.87 MJ.Kg, respectively. This result signifies that there is energy value within used modules. As such, this study has assessed the pyrolysis behaviour of PV cells and has indicated the energy recovery potential within the used polymers found in c-Si PV modules.
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http://dx.doi.org/10.1038/s41598-019-41762-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437152PMC
March 2019

The Epistasis Project: A Multi-Cohort Study of the Effects of BDNF, DBH, and SORT1 Epistasis on Alzheimer's Disease Risk.

J Alzheimers Dis 2019 ;68(4):1535-1547

Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, Oxford, UK.

Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer's disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF, DBH, and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1-1.2, p = 0.005-0.3), an effect size that was consistent in the Northern European (OR = 1.1-1.2, p = 0.002-0.8) but not the smaller Spanish (OR = 0.8-1.6, p = 0.4-1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3-1.5 p = 0.002-0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2-1.3, p = 0.007-0.00008) than men (OR = 0.9-1.0, p = 0.3-0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p = 0.04) the synergistic interaction (SF = 2.2, p = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p = 0.04) than men (SF = 2.0, p = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women.
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http://dx.doi.org/10.3233/JAD-181116DOI Listing
August 2020

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

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

Behav Sleep Med 2020 May-Jun;18(3):298-308. Epub 2019 Feb 17.

School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.

: 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. : 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. : 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. : 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). : 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.
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http://dx.doi.org/10.1080/15402002.2019.1578774DOI Listing
June 2020

Genetic variability in response to amyloid beta deposition influences Alzheimer's disease risk.

Brain Commun 2019 10;1(1):fcz022. Epub 2019 Oct 10.

UK Dementia Research Institute at UCL, Gower Street, London WC1E 6BT, UK.

Genome-wide association studies of late-onset Alzheimer's disease risk have previously identified genes primarily expressed in microglia that form a transcriptional network. Using transgenic mouse models of amyloid deposition, we previously showed that many of the mouse orthologues of these risk genes are co-expressed and associated with amyloid pathology. In this new study, we generate an improved RNA-seq-derived network that is expressed in amyloid-responsive mouse microglia and we statistically compare this with gene-level variation in previous human Alzheimer's disease genome-wide association studies to predict at least four new risk genes for the disease (, , CD11b and ). Of the mouse orthologues of these genes is likely to respond directly to amyloid at the transcriptional level, similarly to established risk gene , because the increase in and transcripts in response to amyloid deposition in transgenic mice is significantly higher than both the increase of the average microglial transcript and the increase in microglial number. In contrast, the mouse orthologues of , /CD11b and (, /CD11b and ) show increased transcripts in the presence of amyloid plaques similar in magnitude to the increase of the average microglial transcript and the increase in microglia number, except that and transcripts increase significantly quicker than the average microglial transcript as the plaque load becomes dense. This work suggests that genetic variability in the microglial response to amyloid deposition is a major determinant for Alzheimer's disease risk, and identification of these genes may help to predict the risk of developing Alzheimer's disease. These findings also provide further insights into the mechanisms underlying Alzheimer's disease for potential drug discovery.
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http://dx.doi.org/10.1093/braincomms/fcz022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145452PMC
October 2019

Sleep duration and all-cause mortality: links to physical activity and prefrailty in a 27-year follow up of older adults in the UK.

Sleep Med 2019 02 24;54:231-237. Epub 2018 Nov 24.

Clinical Sleep Research Unit, School of Sport, Exercise and Health Sciences, Loughborough University, Leicestershire, LE11 3TU, UK. Electronic address:

Objectives: To assess sleep duration-mortality relationships across a 27-year follow-up period in a well characterized random sample of older people, and to test the hypothesis that mortality risks associated with long sleep duration confound with, and can be explained by, low levels of functional capacity indicative of frailty.

Methods: Face-to-face interviews conducted among 1002 randomly sampled older (65+) people in 1985 provided baseline profiles of health, functional capacity, physical activity, and sleep quality and duration. Health and functional status in each of 6 sleep duration categories (≤4, 5, 6, 7, 8, ≥9 h) was examined. At censorship in 2012, 927 deaths were recorded. Relationships between sleep duration and 27-year all-cause mortality were then examined in a series of incrementally adjusted Cox regression models.

Results: Associations between sleep duration and measures of sleep quality were predominantly linear, with longer sleep times indicating superior sleep quality. Relationships between sleep duration and functional capacity, on the other hand, were predominantly quadratic, with most approximating a U-shaped function. Adjusted for age, gender, social class, insomnia symptoms, physical health, depression, BMI and smoking status, long sleep duration and continuous hypnotic drug use at baseline were significantly and independently associated with elevated mortality risk (HR: 1.37; 95% CI: 1.05-1.78; HR: 1.24; 95% CI: 1.01-1.51). When indices of frailty were added to the model, hazard ratios for long sleep duration and hypnotic drug became non-significant, while the lowest physical activity quintile and very slow walking speed significantly increased mortality risk (HR: 1.79; 95% CI: 1.40-2.30; HR: 1.41; 95% CI: 1.15-1.73 respectively).

Conclusions: In analyses of sleep-related mortality outcomes long sleep durations confound with, and may be indicative of, incipient frailty among older participants.
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http://dx.doi.org/10.1016/j.sleep.2018.11.008DOI Listing
February 2019

A comprehensive screening of copy number variability in dementia with Lewy bodies.

Neurobiol Aging 2019 03 24;75:223.e1-223.e10. Epub 2018 Oct 24.

Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK.

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541211PMC
March 2019
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