Apolipoprotein H (ApoH) is a multi-functional plasma glycoprotein that has been associated with negative health outcomes. ApoH levels have high heritability. We undertook a genome-wide association study of ApoH levels using the largest sample to date and replicated the results in an independent cohort (total N = 1,255). In the discovery phase, a meta-analysis of two cohorts, the Sydney Memory and Ageing Study (Sydney MAS) and the Older Australian Twins Study (OATS) (n = 942) revealed genome-wide significant results in or near the APOH gene on chromosome 17 (top SNP, rs7211380, p = 1 × 10−11). The results were replicated in an independent cohort, the Hunter Community Study (p < 0.002) (n = 313). Conditional and joint analysis (COJO) confirmed the association of the chromosomal 17 region with ApoH levels. The set of independent SNPs identified by COJO explained 23% of the variance. The relationships between the top SNPs and cardiovascular/lipid/cognition measures and diabetes were assessed in Sydney MAS, with suggestive results observed for diabetes and cognitive performance. However, replication of these results in the smaller OATS cohort was not found. This work provides impetus for future research to better understand the contribution of genetics to ApoH levels and its possible impacts on health.
The burden of morbidity represented by patients with long term conditions (LTCs) varies substantially between general practices. This study aimed to determine the characteristics of general practices with high morbidity burden.
Retrospective cross-sectional study; general practices in England, 2014/15. Three composite morbidity measures (MMs) were constructed to quantify LTC morbidity at practice level: a count of LTCs derived from the 20 LTCs included in the UK Quality and Outcomes Framework (QOF) disease registers, expressed as ‘number of QOF LTCs per 100 registered patients’; the % of patients with one or more QOF LTCs; the % of patients with one or more of 15 broadly defined LTCs included in the GP Patient Survey (GPPS). Determinants of MM scores were analysed using multi-level regression models. Analysis was based on a national dataset of English general practices (n = 7779 practices); GPPS responses (n = 903,357); general practice characteristics (e.g. list size, list size per full time GP); patient demographic characteristics (age, deprivation status); secondary care utilisation (out-patient, emergency department, emergency admission rates).
Mean MM scores (95% CIs) were: 57.7 (±22.3) QOF LTCs per 100 registered patients; 22.8% (±8.2) patients with a QOF LTC; 63.5% (±11.7) patients with a GPPS LTC. The proportion of elderly patients and social deprivation scores were the strongest predictors of each MM score; scores were largely independent of practice characteristics. MM scores were positive predictors of secondary care utilization and negative predictors’ access, continuity of care and overall satisfaction.
Wide variation in LTC morbidity burden was observed across English general practice. Variation was determined by demographic factors rather than practice characteristics. Higher rates of secondary care utilisation in practices with higher morbidity burden have implications for resource allocation and commissioning budgets; lower reported satisfaction in these practices suggests that practices may struggle with increased workload. There is a need for a readily available metric to define the burden of morbidity and multimorbidity in general practice.
Primary care; Long term conditions; Multimorbidity; Patient experience; Secondary care utilisation
Variations of the cholesteryl ester transfer protein polymorphism (CETP I405V/rs5882) have been associated with an increased risk for neurodegeneration, particularly when examined in conjunction with the epsilon 4 isoform of apolipoprotein E (ApoE4). Despite these identified relationships, the impact of I405V on gray matter microstructure remains unknown. The present study examined the impact of the CETP I405V polymorphism on gray matter integrity among 52 healthy adults between ages 51–85. Gray matter was measured bilaterally using diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Participants were grouped according to a dominant statistical model (II genotype vs. IV/VV genotypes) and secondary analyses were completed to examine the interactive effects of CETP and ApoE4 on DTI metrics. Compared to individuals with the IV/VV genotypes, II homozygotes demonstrated significantly higher MD in bilateral temporal, parietal, and occipital gray matter. Secondary analyses revealed higher FA and AD in the left temporal lobe of IV/VV genotypes with an ApoE4 allele. Our results provide preliminary evidence that CETP II homozygosity is a predisposing risk factor for gray matter abnormalities in posterior brain regions in healthy older adults, independent of an ApoE4 allele.
CETP; APOE; Gray Matter; DTI
The favorable biophysical attributes of non-antibody scaffolds make them attractive alternatives to monoclonal antibodies. However, due to the well-known stability-function trade-off, these gains tend to be marginal after functional selection. A notable example is the fibronectin Type III (FN3) domain, FNfn10, which has been previously evolved to bind lysozyme with 1 pM affinity (FNfn10-α-lys), but suffers from poor thermodynamic and kinetic stability. To explore this stability-function compromise further, we grafted the lysozyme-binding loops from FNfn10-α-lys onto our previously engineered, ultra-stable FN3 scaffold, FN3con. The resulting variant (FN3con-α-lys) bound lysozyme with a markedly reduced affinity, but retained high levels of thermal stability. The crystal structure of FNfn10-α-lys in complex with lysozyme revealed unanticipated interactions at the protein–protein interface involving framework residues of FNfn10-α-lys, thus explaining the failure to transfer binding via loop grafting. Utilizing this structural information, we redesigned FN3con-α-lys and restored picomolar binding affinity to lysozyme, while maintaining thermodynamic stability (with a thermal melting temperature 2-fold higher than that of FNfn10-α-lys). FN3con therefore provides an exceptional window of stability to tolerate deleterious mutations, resulting in a substantial advantage for functional design. This study emphasizes the utility of consensus design for the generation of highly stable scaffolds for downstream protein engineering studies.
consensus design, loop grafting, protein engineering, stability-function trade-off, X-ray crystallography
Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European‐ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12–30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty‐two disease‐associated SNPs from the PGC‐BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10−5, AUC = 0.60). In families with a high‐polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at‐risk youth, regardless of affected status, compared to unrelated controls (GEE‐χ2 = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease‐associated variants than unrelated controls and first‐degree relatives, and illustrate the potential utility of PRS assessment in a family context. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
bipolar disorder; polygenic risk; prospective; family; AUC analysis
Demand for England’s accident and emergency (A&E) services is increasing and is particularly concentrated in areas of high deprivation. The extent to which primary care services, relative to population characteristics, can impact on A&E is not fully understood.
To conduct a detailed analysis to identify population and primary care characteristics associated with A&E attendance rates, particularly those that may be amenable to change by primary care services.
Design and setting
This study used a cross-sectional population-based design. The setting was general practices in England, in the year 2011–2012.
Multivariate linear regression analysis was used to create a model to explain the variability in practice A&E attendance rates. Predictor variables included population demographics, practice characteristics, and measures of patient experiences of primary care.
The strongest predictor of general practice A&E attendance rates was social deprivation: the Index of Multiple Deprivation (IMD-2010) (β = 0.3. B = 1.4 [95% CI =1.3 to 1.6]), followed by population morbidity (GPPS responders reporting a long-standing health condition) (β = 0.2, B = 231.5 [95% CI = 202.1 to 260.8]), and knowledge of how to contact an out-of-hours GP (GPPS question 36) (β = −0.2, B = −128.7 [95% CI =149.3 to −108.2]). Other significant predictors included the practice list size (β = −0.1, B = −0.002 [95% CI = −0.003 to −0.002]) and the proportion of patients aged 0–4 years (β = 0.1, B = 547.3 [95% CI = 418.6 to 676.0]). The final model explained 34.4% of the variation in A&E attendance rates, mostly due to factors that could not be modified by primary care services.
Demographic characteristics were the strongest predictors of A&E attendance rates. Primary care variables that may be amenable to change only made a small contribution to higher A&E attendance rates.
accident and emergency department; general practice; primary health care; socioeconomic factors
To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD).
Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years ± 0.92, range 0.89–4.19) after controlling for estimated years from expected symptom onset, APOE ε4 allelic status, and education.
In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination.
Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials.
Persistent motor impairment is common but highly heterogeneous poststroke. Genetic polymorphisms, including those identified on the brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) genes, may contribute to this variability by limiting the capacity for use-dependent neuroplasticity, and hence rehabilitation responsiveness.
To determine whether BDNF and APOE genotypes influence motor improvement facilitated by poststroke upper-limb rehabilitation.
BDNF-Val66Met and APOE isoform genotypes were determined using leukocyte DNA for 55 community-dwelling patients 2–123 months poststroke. All patients completed a dose-matched upper-limb rehabilitation program of either Wii-based Movement Therapy or Constraint-induced Movement Therapy. Upper-limb motor function was assessed pre- and post-therapy using a suite of functional measures.
Motor function improved for all patients post-therapy, with no difference between therapy groups. In the pooled data, there was no significant effect of BDNF or APOE genotype on motor function at baseline, or following the intervention. However, a significant interaction between the level of residual motor function and BDNF genotype was identified (p = 0.029), whereby post-therapy improvement was significantly less for Met allele carriers with moderate and high, but not low motor function. There was no significant association between APOE genotype and therapy outcomes.
This study identified a novel interaction between the BDNF-Val66Met polymorphism, motor-function status, and the magnitude of improvement with rehabilitation in chronic stroke. This polymorphism does not preclude, but may reduce, the magnitude of motor improvement with therapy, particularly for patients with higher, but not lower residual motor function. BDNF genotype should be considered in the design and interpretation of clinical trials.
motor rehabilitation; upper limb; stroke genetics; apolipoprotein E; brain-derived neurotrophic factor
Suboptimal treatment of cardiovascular diseases (CVD) among patients with severe mental illness (SMI) may contribute to physical health disparities.
To identify SMI characteristics associated with meeting CVD treatment and prevention guidelines.
Design and setting
Population-based electronic health record database linkage between primary care and the sole provider of secondary mental health care services in south east London, UK.
Cardiovascular disease prevalence, risk factor recording, and Quality and Outcomes Framework (QOF) clinical target achievement were compared among 4056 primary care patients with SMI whose records were linked to secondary healthcare records and 270 669 patients without SMI who were not known to secondary care psychiatric services, using multivariate logistic regression modelling. Data available from secondary care records were then used to identify SMI characteristics associated with QOF clinical target achievement.
Patients with SMI and with coronary heart disease and heart failure experienced reduced prescribing of beta blockers and angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (ACEI/ARB). A diagnosis of schizophrenia, being identified with any indicator of risk or illness severity, and being prescribed with depot injectable antipsychotic medication was associated with the lowest likelihood of prescribing.
Linking primary and secondary care data allows the identification of patients with SMI most at risk of undertreatment for physical health problems.
cardiovascular diseases; data linkage; health inequalities; primary health care; psychoses
Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia-and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10−6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10−10) and replication cohorts (p = 5.65 × 10−8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10−8, and rs6813517 [SPOCK3], p = 2.58 × 10−8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
This largest study to date exploring the genetics of memory function in ~ 40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory
Ringman et al. characterize behavioural changes in individuals with preclinical and early familial Alzheimer's disease. Significant behavioural changes do not occur prior to cognitive decline but, in common with late-onset Alzheimer’s disease, increased rates of depression, anxiety, apathy and other behavioural changes are seen early in manifest familial disease.
Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer’s disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer’s disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer’s disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer’s disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer’s disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26–0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer’s disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer’s disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers.
behaviour; depression; Alzheimer; prodromal; familial
Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer’s Network (DIAN), an autosomal dominant Alzheimer’s disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer’s disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted.
Amyloid imaging is a valuable tool for research and diagnosis in dementing
disorders. As positron emission tomography (PET) scanners have limited spatial resolution,
measured signals are distorted by partial volume effects. Various techniques have been
proposed for correcting partial volume effects, but there is no consensus as to whether
these techniques are necessary in amyloid imaging, and, if so, how they should be
implemented. We evaluated a two-component partial volume correction technique and a
regional spread function technique using both simulated and human Pittsburgh compound B
(PiB) PET imaging data. Both correction techniques compensated for partial volume effects
and yielded improved detection of subtle changes in PiB retention. However, the regional
spread function technique was more accurate in application to simulated data. Because PiB
retention estimates depend on the correction technique, standardization is necessary to
compare results across groups. Partial volume correction has sometimes been avoided
because it increases the sensitivity to inaccuracy in image registration and segmentation.
However, our results indicate that appropriate PVC may enhance our ability to detect
changes in amyloid deposition.
PET; partial volume correction; PiB; amyloid imaging
Hand grip strength (GS) is a predictor of mortality in older adults and is moderately to highly heritable, but no genetic variants have been consistently identified. We aimed to identify single nucleotide polymorphisms (SNPs) associated with GS in middle-aged to older adults using a genome-wide association study (GWAS). GS was measured using handheld dynamometry in community-dwelling men and women aged 55–85 from the Hunter Community Study (HCS, N = 2088) and the Sydney Memory and Ageing Study (Sydney MAS, N = 541). Genotyping was undertaken using Affymetrix microarrays with imputation to HapMap2. Analyses were performed using linear regression. No genome-wide significant results were observed in HCS nor were any of the top signals replicated in Sydney MAS. Gene-based analyses in HCS identified two significant genes (ZNF295, C2CD2), but these results were not replicated in Sydney MAS. One out of eight SNPs previously associated with GS, rs550942, located near the CNTF gene, was significantly associated with GS (p = 0.005) in the HCS cohort only. Study differences may explain the lack of consistent results between the studies, including the smaller sample size of the Sydney MAS cohort. Our modest sample size also had limited power to identify variants of small effect. Our results suggest that similar to various other complex traits, many genetic variants of small effect size may influence GS. Future GWAS using larger samples and consistent measures may prove more fruitful at identifying genetic contributors for GS in middle-aged to older adults.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-015-9745-5) contains supplementary material, which is available to authorized users.
Hand grip strength; Genetics; GWAS; Ageing
Concerns have been raised about a possible link between bisphosphonate use, and in particular alendronate, and upper gastrointestinal (UGI) cancer. A number of epidemiological studies have been published with conflicting results. We conducted a systematic review and meta-analysis of observational studies, to determine the risk of esophageal and gastric cancer in users of bisphosphonates compared with non-users.
We searched PubMed, MEDLINE, EMBASE, Web of Knowledge and Cochrane Database of Systematic Reviews for studies investigating bisphosphonates and esophageal or gastric cancer. We calculated pooled ORs and 95% CIs for the risk of esophageal or gastric cancer in bisphosphonate users compared with non-users. We performed a sensitivity analysis of alendronate as this was the most common single drug studied and is also the most widely used in clinical practice.
11 studies (from 10 papers) examining bisphosphonate exposure and UGI cancer (gastric and esophageal), met our inclusion criteria. All studies were retrospective, 6/11 (55%) case–control and 5/11(45%) cohort, and carried out using data from 5 longitudinal clinical databases. Combining 5 studies (1 from each database), we found no increased risk, OR 1.11 (95% CI 0.97 to 1.27) of esophageal cancer in bisphosphonate users compared with non-users and no increased risk of gastric cancer in bisphosphonate users, OR 0.96 (95% CI 0.82 to 1.12).
This is the fourth and most detailed meta-analysis on this topic. We have not identified any compelling evidence for a significantly raised risk of esophageal cancer or gastric cancer in male and female patients prescribed bisphosphonates.
Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology. Genetic variation in the oxytocin receptor gene (OXTR) has been implicated in anxiety, depression and related stress phenotypes. It is not yet known whether OXTR interacts with other risk factors such as early life trauma to heighten the severity of experienced anxiety and depression.
In this study, we examined genotypes in 653 individuals and tested whether SNP variation in OXTR correlates with severity of features of self-reported experience on the Depression Anxiety and Stress Scale (DASS), and whether this correlation is enhanced when early life trauma is taken into account. We also assessed the effects of OXTR SNPs on RNA expression levels in two separate brain tissue cohorts totaling 365 samples.
A significant effect of OXTR genotype on DASS anxiety, stress and depression scores was found and ELS events, in combination with several different OXTR SNPs, were significantly associated with differences in DASS scores with one SNP (rs139832701) showing significant association or a trend towards association for all three measures. Several OXTR SNPs were correlated with alterations in OXTR RNA expression and rs3831817 replicated across both sets of tissues.
These results support the hypothesis that the oxytocin system plays a role in the pathophysiology of mood and anxiety disorders.
Depression; anxiety; stress; oxytocin; DASS scale; SNP; RNA expression
The presenilin 1 (PSEN1) L271V mutation causes early-onset familial Alzheimer’s disease by disrupting the alternative splicing of the PSEN1 gene, producing some transcripts harboring the L271V point mutation and other transcripts lacking exon 8 (PS1∆exon8). We previously reported that PS1 L271V increased amyloid beta (Aβ) 42/40 ratios, while PS1∆exon8 reduced Aβ42/40 ratios, indicating that the former and not the exon 8 deletion transcript is amyloidogenic. Also, PS1∆exon8 did not rescue Aβ generation in PS1/2 double knockout cells indicating its identity as a severe loss-of-function splice form. PS1∆exon8 is generated physiologically raising the possibility that we had identified the first physiological inactive PS1 isoform. We studied PS1∆exon8
in vivo by crossing PS1∆exon8 transgenics with either PS1-null or Dutch APPE693Q mice. As a control, we crossed APPE693Q with mice expressing a deletion in an adjacent exon (PS1∆exon9). PS1∆exon8 did not rescue embryonic lethality or Notch-deficient phenotypes of PS1-null mice displaying severe loss of function in vivo. We also demonstrate that this splice form can interact with wildtype PS1 using cultured cells and co-immunoprecipitation (co-IP)/bimolecular fluorescence complementation. Further co-IP demonstrates that PS1∆exon8 interacts with nicastrin, participating in the γ–secretase complex formation. These data support that catalytically inactive PS1∆exon8 is generated physiologically and participates in protein-protein interactions.
This study explores the relationship between alcohol consumption, health, ethnicity and socioeconomic deprivation.
27 991 people aged 65 and over from an inner-city population, using a primary care database.
Primary and Secondary Outcome Measures
Primary outcome measures were alcohol use and misuse (>21 units per week for men and >14 for units per week women).
Older people of black and minority ethnic (BME) origin from four distinct ethnic groups comprised 29% of the sample. A total of 9248 older drinkers were identified, of whom 1980 (21.4%) drank above safe limits. Compared with older drinkers, older unsafe drinkers contained a higher proportion of males, white and Irish ethnic groups and a lower proportion of Caribbean, African and Asian groups. For older drinkers, the strongest independent predictors of higher alcohol consumption were younger age, male gender and Irish ethnicity. Independent predictors of lower alcohol consumption were Asian, black Caribbean and black African ethnicity. Socioeconomic deprivation and comorbidity were not significant predictors of alcohol consumption in older drinkers. For older unsafe drinkers, the strongest predictor variables were younger age, male gender and Irish ethnicity; comorbidity was not a significant predictor. Lower socioeconomic deprivation was a significant predictor of unsafe consumption whereas African, Caribbean and Asian ethnicity were not.
Although under-reporting in high-alcohol consumption groups and poor health in older people who have stopped or controlled their drinking may have limited the interpretation of our results, we suggest that closer attention is paid to ‘young older’ male drinkers, as well as to older drinkers born outside the UK and those with lower levels of socioeconomic deprivation who are drinking above safe limits.
MENTAL HEALTH; PUBLIC HEALTH; PRIMARY CARE
Hypertension is the most prevalent cardiovascular long-term condition in the UK and is associated with a high rate of multimorbidity (MM). Multimorbidity increases with age, ethnicity and social deprivation. Previous studies have yielded conflicting findings about the relationship between MM and blood pressure (BP) control. Our aim was to investigate the relationship between multimorbidity and systolic blood pressure (SBP) in patients with hypertension.
A cross-sectional analysis of anonymised primary care data was performed for a total of 299,180 adult patients of whom 31,676 (10.6 %) had a diagnosis of hypertension. We compared mean SBP in patients with hypertension alone and those with one or more co-morbidities and analysed the effect of type of comorbidity on SBP. We constructed a regression model to identify the determinants of SBP control.
The strongest predictor of mean SBP was the number of comorbidities, β −0.13 (p < 0.05). Other predictors included Afro-Caribbean ethnicity, β 0.05 (p < 0.05), South Asian ethnicity, β −0.03 (p < 0.05), age, β 0.05 (p < 0.05), male gender, β 0.05 (p < 0.05) and number of hypotensive drugs β 0.06 (p < 0.05). SBP was lower by a mean of 2.03 mmHg (−2.22, −1.85) for each additional comorbidity and was lower in MM regardless of the type of morbidity.
Hypertensive patients with MM had lower SBP than those with hypertension alone; the greater the number of MM, the lower the SBP. We found no evidence that BP control was related to BP targets, medication category or specific co-morbidity. Further research is needed to determine whether consultation rate, “white-coat hypertension” or medication adherence influence BP control in MM.
Vascular aging consists of complex and multifaceted processes that may be influenced by genetic polymorphisms of the renin-angiotensin system. A polymorphism in the angiotensin II type 1 receptor gene (AGTR1/rs5186) has been associated with an increased risk for arterial stiffness, hypertension, and ischemic stroke. Despite these identified relationships, the impact of AGTR1 A1166C on white matter integrity and cognition is less clear in a healthy aging population. The present study utilized indices of neuroimaging and neuropsychological assessment to examine the impact of the A1166C polymorphism on subcortical hyperintensities (SH) and cognition in 49 healthy adults between ages 51–85. Using a dominant statistical model (CC + CA (risk) vs. AA), results revealed significantly larger SH volume for individuals with the C1166 variant (p < 0.05, partial eta2 = 0.117) compared with those with the AA genotype. Post hoc analyses indicated that increased SH volume in C allele carriers could not be explained by vascular factors such as pulse pressure or body mass index. In addition, cognitive performance did not differ significantly between groups and was not significantly associated with SH in this cohort. Results suggest that presence of the C1166 variant may serve as a biomarker of risk for suboptimal brain integrity in otherwise healthy older adults prior to changes in cognition.
AGTR1; A1166C; Cerebrovascular aging; Subcortical hyperintensities; Cognition
Traumatic brain injury (TBI) may be a risk factor for criminal behaviour however multiple factors potentially confound the association.
Record linkage and Cox proportional hazards regression analyses were used to examine the association between hospital-recorded TBI (n = 7,694) and subsequent first criminal conviction in a retrospective cohort matched 1:3 with 22,905 unaffected community controls and full-sibling controls (n = 2,397). Aboriginality, substance abuse, social disadvantage, and mental illness were included in analyses as potential confounders
In multivariable models, relative to general population controls, TBI was associated with any conviction (males: Hazard Ratio (HR) = 1·58 (95% CI 1·46 to 1·72); females: HR = 1·52 (95% CI 1·28 to 1·81)); and similar Hazard Ratios were obtained for the sibling analyses in males (HR = 1.68 (95% CI 1.31-2.18)) and females (HR 1.27 (95% CI 0.71-2.29)). TBI was also associated with violent convictions relative to the general population, (males: HR = 1.65 (95% CI 1.42 to 1.92); females HR = 1.73 (95% CI 1.21 to 2.47)), and in analyses with sibling controls in men (HR = 1.89 (95% CI 1.20-3.00)), but not in women (HR 0.73, 95% CI 0.29-1.81)).
The results support a modest causal link between TBI and criminality after comprehensive adjustment for confounding. Reducing the rate of TBI, a major public health imperative, might have benefits in terms of crime reduction.
Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. All participants had European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) and suggestive single-nucleotide polymorphisms.
We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8) that encompassed the HLA locus at 6p21.3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC, for the behavioural FTD subtype. Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation incis.
Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and possibly to shed light on the pathomechanisms contributing to FTD.
The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/ MRC Centre on Parkinson’s disease, Alzheimer’s Research UK, and Texas Tech University Health Sciences Center.
Patients with coronary heart disease (CHD) who are depressed have an increased risk of further cardiac events and higher mortality.
To use a patient generated instrument (PSYCHLOPS) to define categories of concerns in patients with CHD. To define the psychometric characteristics of patients in each category.
Design and setting
Cross-sectional study set in general practices in south London.
Of 3325 patients on the CHD registers in 15 general practices, 655 completed six baseline psychometric and functional instruments: PSYCHLOPS, HADS-Depression, HADS-Anxiety, Clinical Interview Schedule – Revised, SF12-Mental and SF12-Physical. Content analysis was used to categorise patients based on their main problem, as elicited by PSYCHLOPS. Mean psychometric scores were adjusted for confounding by age, sex, deprivation and ethnicity and calculated for each response category.
Response categories were: physical problems, both non-cardiac (23.2%) and cardiac (6.0%); social problems: relationship/family (18.2%), money (7.5%), work (3.1%); functional (9.8%); psychological (6.9%); miscellaneous (7.3%); ‘no problem’ (18.2%). The highest psychological distress scores were found in ‘physical, cardiac’ and ‘psychological’ categories. The ‘no problem’ category had significantly lower psychological distress and higher functional capacity than other categories.
PSYCHLOPS enabled the identification of subtypes of CHD patients, based on a classification of self-reported problems. A high proportion of CHD patients report social problems. Psychological distress was highest in those reporting cardiac or psychological symptoms. Services should be aligned to the reported needs of patients.
primary care; coronary heart disease; functional capacity measures; mental health outcome measures; patient-generated outcome measures
The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.