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Educational attainment is associated with a range of positive outcomes, yet its impact on wellbeing is unclear, and complicated by high correlations with intelligence. We use genetic and observational data to investigate for the first time, whether educational attainment and intelligence are causally and independently related to wellbeing. Results from our multivariable Mendelian randomisation demonstrated a positive causal impact of a genetic predisposition to higher educational attainment on wellbeing that remained after accounting for intelligence, and a negative impact of intelligence that was independent of educational attainment. Observational analyses suggested that these associations may be subject to sex differences, with benefits to wellbeing greater for females who attend higher education compared to males. For intelligence, males scoring more highly on measures related to happiness were those with lower intelligence. Our findings demonstrate a unique benefit for wellbeing of staying in school, over and above improving cognitive abilities, with benefits likely to be greater for females compared to males.

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The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural-geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.

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The aim of the study was to evaluate the impact of manual cleaning and manual cleaning followed by Ultraviolet-C disinfection on the colony forming units of bacteria retrievable from equipment and surfaces within clinic rooms following a CF outpatient encounter. While UV disinfection has proven to be effective within general healthcare settings, it has not been evaluated in a CF centre. Microbiological sampling was performed following outpatient encounters involving 11 adult patients with CF and chronic infection with P.aeruginosa, MRSA or E. coli ESBL. The results of this study suggest that manual cleaning followed by UV-C disinfection is more effective than manual cleaning alone at reducing environmental contamination within a CF clinic and that UV-C isinfection is likely to reduce the risk of fomite transmission in the CF outpatient setting.

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Peer behaviour plays an important role in the development of social adjustment, though little is known about its genetic architecture. We conducted a twin study combined with a genome-wide complex trait analysis (GCTA) and a genome-wide screen to characterise genetic influences on problematic peer behaviour during childhood and adolescence. This included a series of longitudinal measures (parent-reported Strengths-and-Difficulties Questionnaire) from a UK population-based birth-cohort (ALSPAC, 4-17 years), and a UK twin sample (TEDS, 4-11 years). Longitudinal twin analysis (TEDS; N ≤ 7,366 twin pairs) showed that peer problems in childhood are heritable (4-11 years, 0.60 < twin-h(2) ≤ 0.71) but genetically heterogeneous from age to age (4-11 years, twin-r(g) = 0.30). GCTA (ALSPAC: N ≤ 5,608, TEDS: N ≤ 2,691) provided furthermore little support for the contribution of measured common genetic variants during childhood (4-12 years, 0.02 < GCTA-h(2)(Meta) ≤ 0.11) though these influences become stronger in adolescence (13-17 years, 0.14 < GCTA-h (2)(ALSPAC) ≤ 0.27). A subsequent cross-sectional genome-wide screen in ALSPAC (N ≤ 6,000) focussed on peer problems with the highest GCTA-heritability (10, 13 and 17 years, 0.0002 < GCTA-P ≤ 0.03). Single variant signals (P ≤ 10(-5)) were followed up in TEDS (N ≤ 2835, 9 and 11 years) and, in search for autism quantitative trait loci, explored within two autism samples (AGRE: N Pedigrees = 793; ACC: N Cases = 1,453/N Controls = 7,070). There was, however, no evidence for association in TEDS and little evidence for an overlap with the autistic continuum. In summary, our findings suggest that problematic peer relationships are heritable but genetically complex and heterogeneous from age to age, with an increase in common measurable genetic variation during adolescence.

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Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.

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We describe a complete technological system at Imperial College London for Attosecond Science studies. The system comprises a few-cycle, carrier envelope phase stabilized laser source which delivers sub 4 fs pulses to a vibration-isolated attosecond vacuum beamline. The beamline is used for the generation of isolated attosecond pulses in the extreme ultraviolet (XUV) at kilohertz repetition rates through laser-driven high harmonic generation in gas targets. The beamline incorporates: interferometers for producing pulse sequences for pump-probe studies; the facility to spectrally and spatially filter the harmonic radiation; an in-line spatially resolving XUV spectrometer; and a photoelectron spectroscopy chamber in which attosecond streaking is used to characterize the attosecond pulses. We discuss the technology and techniques behind the development of our complete system and summarize its performance. This versatile apparatus has enabled a number of new experimental investigations which we briefly describe.

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Twin studies allow us to estimate the relative contributions of nature and nurture to human phenotypes by comparing the resemblance of identical and fraternal twins. Variation in complex traits is a balance of genetic and environmental influences; these influences are typically estimated at a population level. However, what if the balance of nature and nurture varies depending on where we grow up? Here we use statistical and visual analysis of geocoded data from over 6700 families to show that genetic and environmental contributions to 45 childhood cognitive and behavioral phenotypes vary geographically in the United Kingdom. This has implications for detecting environmental exposures that may interact with the genetic influences on complex traits, and for the statistical power of samples recruited for genetic association studies. More broadly, our experience demonstrates the potential for collaborative exploratory visualization to act as a lingua franca for large-scale interdisciplinary research.

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Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined. In addition to its far-reaching implications for neuroscience and molecular genetics, this finding suggests new ways of thinking about the interface between nature and nurture during the school years. Why, despite life's 'slings and arrows of outrageous fortune', do genetically driven differences increasingly account for differences in general cognitive ability? We suggest that the answer lies with genotype-environment correlation: as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.

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Previous studies have identified abnormalities in the oxidative responses of the neutrophil in cystic fibrosis (CF), but it is unclear whether such changes relate to loss of membrane cystic fibrosis transmembrane conductance regulator (CFTR) or to the inflammatory environment present in this disease. The aim of the present study was to determine whether neutrophils from CF patients demonstrate an intrinsic abnormality of the respiratory burst. The respiratory burst activity of neutrophils isolated from stable DeltaF508 homozygote CF patients and matched healthy controls was quantified by both chemiluminscence and cytochrome C reduction. Expression of NADPH oxidase components and CFTR was determined by Western blotting and RT-PCR. The oxidative output from neutrophils from CF in response to receptor-linked and particulate stimuli did not differ from that of controls. Expression of NADPH oxidase components was identical in CF and non-CF neutrophils. While low levels of CFTR mRNA could be identified in the normal human neutrophil, we were unable to detect CFTR protein in human neutrophil lysates or immunoprecipitates. CFTR has no role in controlling neutrophil oxidative activity; previously reported differences in neutrophil function between CF and non-CF subjects most likely relate to the inflammatory milieu from which the cells were isolated.

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OBJECTIVES: To investigate variability in colony morphology and antibiotic susceptibility in populations of Pseudomonas aeruginosa from sputa of patients with bronchiectasis without cystic fibrosis (CF) compared with P. aeruginosa isolated from patients with CF, and from other infections as controls. METHODS: P. aeruginosa was cultured from 31 patients with non-CF bronchiectasis, 24 with CF, 7 ventilated patients and 9 skin swabs. Four colonies of each morphotype of P. aeruginosa were tested for susceptibility to 12 antibiotics by disc diffusion. The variability in susceptibility between the isolates in each patient's population of P. aeruginosa was investigated. RESULTS: The classic morphotype of P. aeruginosa was cultured from control samples with an average variation in zone size of 2 mm (range 0-4 mm) for the four colonies tested. Non-CF bronchiectasis sputa contained 1-3 colonial morphotypes of P. aeruginosa; the average difference between the largest and smallest zone sizes found in all examples of the morphotypes present in each sample varied from 3 mm (1-9 mm) for colistin to 8 mm (0-24 mm) for piperacillin/tazobactam. CF sputa contained 2-6 morphotypes of P. aeruginosa with a wider variation of susceptibility. There was variation between bacteria of the same morphotype from non-CF bronchiectasis and CF sputa. CONCLUSIONS: Phenotypic variation in colonial form and antibiotic susceptibility is not unique to chronic infection in CF but is also found in non-CF bronchiectasis. This questions the use of current susceptibility testing methods for the complex populations of bacteria found in chronic lung infection.

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BACKGROUND: The modern environment is ubiquitously 'obesogenic', yet people vary enormously in weight. One factor contributing to weight variation could be genetically determined differences in appetite that modulate susceptibility to the environment. We assessed the relative contribution of genes and environment for two aspects of appetite that have been implicated in obesity. METHODS: Parents of a population-based sample of 8- to 11-year-old twins (n=5435 pairs) completed validated, questionnaire measures of responsiveness to satiety and responsiveness to food cues for both children. RESULTS: Quantitative genetic model fitting gave estimates of 63% (95% confidence interval: 39-81%) for the heritability of satiety responsiveness and 75% (52-85%) for food cue responsiveness. Shared and non-shared environmental influences were 21% (0-51%) and 16% (10-21%) for satiety responsiveness, and 10% (0-38%) and 15% (10-18%) for food cue responsiveness, respectively. CONCLUSIONS: The high heritability of appetitive traits that are known to be related to weight suggests that genetic vulnerability to weight gain could operate through behavioural as well as metabolic pathways. Intervention strategies aimed at improving satiety responsiveness and reducing food cue responsiveness in high-risk individuals could help in preventing the development of obesity.

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Sex differences in the frequency and patterns of behaviours are frequently observed and largely unexplained. We have investigated the possible role of X-linked genes in the aetiology of social behaviour problems, including those involved in autistic spectrum disorders. A novel approach has been implemented. This is based on predictions following from stochastic patterns of X-inactivation of lower concordance of monozygous female (MZF) twins than MZM twins for behaviours underpinned by X-linked QTLs and the converse that DZF twins are expected to correlate more strongly for X-linked traits than DZM twins because unlike males, females always have at least one X chromosome in common. These expectations were tested in an ongoing longitudinal cohort study in which all twins born in England and Wales between 1994 and 1996 were invited to take part. 1000 each of MZF, MZM, DZF and DZM pairs from TEDS were tested at 7 and 8 years of age. The results suggest the persistent influence of X-linked genes on cognition and social behaviour problems, including those involved in autistic spectrum disorders, from early to middle childhood. This emphasises the potential importance of X-linked genes in the developmental trajectories of behaviour and mental health and the need to stratify genetic analysis of behaviours by gender.

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We report three cases of Clostridium difficile pancolitis in adults with cystic fibrosis (CF) in whom the presenting symptoms were atypical. All three required treatment with systemic steroids, in addition to oral vancomycin and metronidazole to achieve resolution of the colitis. This experience suggests that C. difficile colitis should be considered in individuals with CF presenting with non-specific abdominal symptoms.

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BACKGROUND: Liver disease is an important cause of death in adults with cystic fibrosis (CF). Ursodeoxycholic acid (UDCA) may slow progression. Managing varices and timely evaluation for liver transplantation are important. METHODS: Adults with CF underwent annual review. Abnormalities of liver function tests or ultrasound prompted referral to the CF/liver clinic where UDCA was commenced. Endoscopic surveillance for varices was undertaken if ultrasound suggested portal hypertension. RESULTS: 154 patients were followed for a median 5 years. 43 had significant liver disease, 29 had cirrhosis with portal hypertension and 14 had ultrasound evidence of cirrhosis without portal hypertension. All started UDCA. Only one patient developed chronic liver failure and none required liver transplantation. 27 underwent endoscopy; 1 required variceal banding, the others had insignificant varices. Ultrasound was normal in 97 patients while five had steatosis; nine further patients had splenomegaly but no other evidence of portal hypertension. Neither spleen size nor platelet count correlated with portal hypertension. CONCLUSIONS: Liver disease was common in adults with CF but disease progression was rare. Thus liver disease detected and closely monitored in adults appeared to have a milder course than childhood CF. Splenomegaly, unrelated to portal hypertension may be a consequence of CF.

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AIMS: The prevalence of diabetes in adults with cystic fibrosis (CF) approximates 25%, yet few studies have defined risk factors. We examined the association between biochemical and clinical factors and CF-related diabetes. METHODS: We performed a study in adults with CF in 2004 in Cambridgeshire, UK. Of 160 individuals, 51 had diabetes (cases) on the basis of medical history or screening using a 75-g oral glucose tolerance test, and 107 did not have diabetes (control subjects); two were excluded. We used logistic regression to model the cross-sectional association between potential risk factors and diabetes. RESULTS: The mean age was 26 (16-58) years, mean body mass index (BMI) was 21 (16-28) kg/m(2), and mean forced expiratory volume in 1 s was 60 +/- 24% (mean +/- sd). All of the cases and 88% of control subjects had pancreatic insufficiency. Cases did not differ from control subjects with respect to age, sex, body mass index, or dose of oral pancreatic enzymes. Cases were more likely to have low serum magnesium, haemoglobin, and pulmonary function, and higher serum gamma-glutamyl transferase (GGT) activity, plasma fibrinogen levels, erythrocyte sedimentation rate, use of oral corticosteroids, and number of CF-related complications. In multivariate analyses, GGT, previous organ transplantation, plasma fibrinogen and the presence of CF-related complications were independently associated with diabetes, after controlling for corticosteroid use. CONCLUSIONS: These data confirm the high prevalence of diabetes in adults with CF, and identify plasma fibrinogen and GGT, and organ transplantation as factors independently associated with CF-related diabetes. A prospective study would clarify the nature of these associations.

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BACKGROUND: To what extent do genetic and environmental influences on reading disability overlap with those on mathematics disability? Multivariate genetic research on the normal range of variation in unselected samples has led to a Generalist Genes Hypothesis which posits that the same genes largely affect individual differences in these abilities in the normal range. However, little is known about the etiology of co-morbidity for the disability extremes of reading and mathematics. METHOD: From 2596 pairs of 10-year-old monozygotic and dizygotic twins assessed on a web-based battery of reading and mathematics tests, we selected the lowest 15% on reading and on mathematics. We conducted bivariate DeFries-Fulker (DF) extremes analyses to assess overlap and specificity of genetic and environmental influences on reading and mathematics disability defined by a 15% cut-off. RESULTS: Both reading and mathematics disability are moderately heritable (47% and 43%, respectively) and show only modest shared environmental influence (16% and 20%). There is substantial phenotypic co-morbidity between reading and mathematics disability. Bivariate DF extremes analyses yielded a genetic correlation of .67 between reading disability and mathematics disability, suggesting that they are affected largely by the same genetic factors. The shared environmental correlation is .96 and the non-shared environmental correlation is .08. CONCLUSIONS: In line with the Generalist Genes Hypothesis, the same set of generalist genes largely affects mathematical and reading disabilities. The dissociation between the disabilities occurs largely due to independent non-shared environmental influences.

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The aim of the current study was to investigate the prevalence and clinical associations of nontuberculous mycobacteria (NTM) in a well-characterised cohort of patients with adult-onset bronchiectasis. The sputum of all patients attending a tertiary referral bronchiectasis clinic between April 2002 and August 2003 was examined for mycobacteria as part of an extensive diagnostic work-up. NTM-positive patients subsequently had further sputa examined. A modified bronchiectasis scoring system was applied to all high-resolution computed tomography (HRCT) scans from NTM-positive patients, and a matched cohort without NTM. Out of 98 patients attending the clinic, 10 had NTM in their sputum on first culture; of those, eight provided multiple positive cultures. Three patients were treated for NTM infection. A higher proportion of NTM-positive than -negative patients were subsequently diagnosed with cystic fibrosis (two out of nine versus two out of 75). On HRCT scoring, more patients in the NTM-positive group had peripheral mucus plugging than in the NTM-negative group. In the current prospective study of a large cohort of patients with bronchiectasis, 10% cultured positive for nontuberculous mycobacteria in a random clinic sputum sample. Few clinical parameters were helpful in discriminating between groups, except for a higher prevalence of previously undiagnosed cystic fibrosis and of peripheral mucus plugging on high-resolution computed tomography in the nontuberculous mycobacteria group.

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We demonstrate a technique that uses high-order harmonic generation in molecules to probe nuclear dynamics and structural rearrangement on a subfemtosecond time scale. The chirped nature of the electron wavepacket produced by laser ionization in a strong field gives rise to a similar chirp in the photons emitted upon electron-ion recombination. Use of this chirp in the emitted light allows information about nuclear dynamics to be gained with 100-attosecond temporal resolution, from excitation by an 8-femtosecond pulse, in a single laser shot. Measurements on molecular hydrogen and deuterium agreed well with calculations of ultrafast nuclear dynamics in the H2+ molecule, confirming the validity of the method. We then measured harmonic spectra from CH4 and CD4 to demonstrate a few-femtosecond time scale for the onset of proton rearrangement in methane upon ionization.