Laura Portas

Sleep is essential for health and regulated by genetic and environmental factors. We perform genome-wide association studies of device-measured sleep duration, efficiency, and accelerometer-derived rapid eye movement (REM) and non-rapid eye movement (NREM) sleep in 80,013 UK Biobank participants. We identify 20 autosomal loci, 12 of which have not been previously reported, including genome-wide significant associations for REM and NREM sleep duration. MEIS1 shows strong opposing effects on REM and NREM durations and is intolerant to loss-of-function mutations, suggesting an essential role in the regulation of REM/NREM sleep balance. Functional enrichment analysis identifies statistically significant pathways related to chromatin remodelling, lipid metabolism, and metal ion homeostasis while tissue enrichment analysis highlights significant signals in the hypothalamus and frontal cortex. Sex-stratified analyses identify distinct loci, including FOXP2 and NRXN3 in females and LRP1B , NPBWR2 , and PABPC4 in males. Mendelian randomization supports associations between shorter sleep duration and higher cardiometabolic risk. These findings highlight sex- and phase-specific regulators of human sleep architecture, providing biological insights and potential therapeutic targets.

Sleep is essential for health and regulated by genetic and environmental factors. We performed genome-wide association studies of device-measured sleep duration, efficiency, and REM/NREM phases in 80,013 UK Biobank participants using accelerometer measurements separately validated against polysomnography. We identified 20 autosomal loci, 12 of which were novel, and report the first genome-wide significant signals for REM and NREM sleep duration. MEIS1 showed strong opposing effects on REM and NREM durations and is intolerant to loss-of-function mutations, suggesting a regulatory role. Functional enrichment implicated chromatin remodelling, lipid metabolism, and metal ion homeostasis; tissue enrichment highlighted regions including the hypothalamus and frontal cortex. Sex-stratified analyses identified distinct loci: FOXP2 and NRXN3 in females and LRP1B, NPBWR2, and PABPC4 in males. Mendelian randomization supported associations between shorter sleep duration and higher cardiometabolic risk. Our findings highlight novel sex- and phase-specific regulators of human sleep architecture, offering biological insights and potential therapeutic targets.

Background: The association between lower adult lung function and increased cardiovascular comorbidity has not been adequately explained. We investigated whether shared developmental signalling pathways, critical to lung development and repair, could partly explain it. Methods: In UK Biobank (UKB), we performed pairwise colocalisation analysis of variants in 55 lung development genes associated with adult forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV₁)/FVC, to see if these are also associated with coronary heart disease (CHD), blood pressure (systolic, diastolic, hypertension), pulse pressure, Arterial Stiffness index and carotid intima-media thickness. For CHD, we meta-analysed data from UKB and the CARDIoGRAM consortium. Results: We found that 12 of the 55 genes shared the same variant between one (or more) lung function trait and one (or more) cardiovascular trait (H4colocalisation). The direction of effects was always in keeping with our hypothesis (lower lung function–higher cardiovascular risk) for FVC, but not always for FEV₁/FVC. The seven signals for hypertension and CHD all replicated nominally in the FinnGen study, while replication was poor in the China Kadoorie Biobank (CKB) study. In addition, we found a further 10 genes where genetic associations with lung function and cardiovascular traits were within the same gene but involved different variants (H3 colocalisation). Interestingly, six of all 22 genes (H4 and H3 colocalisation) were novel for cardiovascular traits; four replicated in FinnGen, three in CKB. Conclusion: Lung function and cardiovascular traits have shared developmental pathways that may partly explain why lower lung function, especially FVC, is associated with increased cardiovascular risk.

Background: Vitamin A, an essential micronutrient obtained through the diet, plays a crucial role in lung development and contributes to lung regeneration. We aimed to investigate its effect on adult lung function using triangulation of evidence from both observational and genetic data. Methods: Using data on 150 000 individuals from UK Biobank and correcting for measurement error (generalised structural equation modelling), we first investigated the association of dietary vitamin A intake (total vitamin A, carotene and retinol) with lung function (forced vital capacity (FVC), forced expiratory volume in 1 s (FEV ₁ )/FVC)). We then assessed the causality of these associations using Mendelian randomisation (MR), and we investigated the effects on adult lung function of 39 genes related to vitamin A, and their interaction with vitamin A intake. Findings: Our observational analysis suggests a positive association between carotene intake and FVC only (13.3 mL per 100 µg/day; p=2.9×10 ⁻⁹ ), with stronger associations in smokers, but no association of retinol intake with FVC or FEV ₁ /FVC. The MR similarly shows a beneficial effect of serum beta-carotene on FVC only, with no effect of serum retinol on FVC nor FEV ₁ /FVC. Nine of the vitamin A-related genes were associated with adult lung function, six of which have not been previously identified in genome-wide studies and three ( NCOA2, RDH10, RXRB ) in any type of genetic study of lung function. Five genes showed possible gene-vitamin A intake interactions. Interpretation: Our triangulation study provides convincing evidence for a causal effect of vitamin A, carotene in particular, on adult lung function, suggesting a beneficial effect of a carotene-rich diet on adult lung health.

Background Low physical activity (PA) has been shown to be associated with higher risk of non-alcoholic fatty liver disease (NAFLD). However, the strength and shape of this association are currently uncertain due to a reliance on self-reported PA measures. This report aims to investigate the relationship of PA with NAFLD using accelerometer-derived step count from a large prospective cohort study. Methods The wrist-worn accelerometer sub-study of the UK Biobank (N=∼100,000) was used to characterise median daily step count over a seven-day period. NAFLD cases were ascertained via record linkage with hospital inpatient data and death registers or by using a measure of liver fat from imaging. Cox proportional hazards models were employed to assess the association between step count and NAFLD, adjusting for age, sociodemographic, and lifestyle factors. Mediation analyses were conducted. Results Among 91,031 participants (709,440 person-years of follow-up), there were 762 incident NAFLD cases. Higher step count was log-linearly and inversely associated with risk of NAFLD. A 1000 step increase (representing 10 minutes of walking) was associated with a 12% (95% CI: 10%–14%) lower hazard of NAFLD. When using imaging to identify NAFLD, a 1,000-step increase was associated with a 6% (95% CI: 6%–7%) lower risk. There was evidence for some mediation by adiposity. Conclusion Physical activity, a modifiable risk factor, is log-linearly and inversely associated with NAFLD. This association was only partially explained by adiposity. These findings from a large cohort study may have important implications for strategies to lower NAFLD risk.

Background: Symptoms, severity, and acuteness of peripheral artery disease (PAD) are major determinants of severe limb symptoms, subsequent risk of cardiovascular events, and mortality. Lower-extremity revascularization (LER) is a key option to relieve symptoms and to prevent limb loss in symptomatic patients with PAD. This study aimed to quantify the burden of disease among patients with PAD-LER in England. Methods: A retrospective population-based study of linked primary and secondary care electronic health records, included 13,869 adult patients (aged ⩾ 18 years) with PAD-LER from 2003 to 2018. The incidence of first ever PAD-LER was estimated both overall and by type of procedure (endovascular/surgical). Health resource utilization associated with PAD-related complications and treatment patterns were assessed. Results: A high annual incidence of lower-limb revascularization (41.2 per 1000 person years) and a nearly double incidence of endovascular first revascularization compared with open surgery were observed. More than 70% of patients with PAD-LER had a history of hyperlipidemia and hypertension and roughly one-third were diabetic and had a history of coronary artery disease. Cardiovascular mortality accounted for one-third (34.1 per 1000 person years) of all-cause mortality. Over 93% of patients were hospitalized for any reason and the commonest reasons for hospitalization were cardiovascular diseases and PAD with about one-third hospitalized for revascularization reoccurrence. Conclusion: There is a significant burden of PAD-LER to the individual and society with ongoing healthcare resource utilization, treatment, and increasing mortality.

Background and Aims Communication of personalised disease risk can motivate smoking cessation. We assessed whether routine implementation of this intervention by general practitioners (GPs) in England is cost-effective or whether we need further research to better establish its effectiveness. Design Cost-effectiveness analysis (CEA) with value of information (VoI) analysis from the UK National Health Service perspective, using GP communication of personalised disease risk on smoking cessation versus usual care. Setting GP practices in England. Study population Healthy smokers aged 35-60 years attending the GP practice. Measurements Effectiveness of GP communication of personalised disease risk on smoking cessation was estimated through systematic review and meta-analysis. A Bayesian CEA was then performed using a lifetime Markov model on smokers aged 35-60 years that measured lifetime costs and quality-adjusted life-years (QALYs) assigned to the four diseases contributing the most to smoking-related morbidity, mortality and costs: chronic obstructive pulmonary disease, lung cancer, myocardial infarction and stroke. Costs and QALYs for each disease state were obtained from the literature. VoI analysis identified sources of uncertainty in the CEA and assessed how much would be worth investing in further research to reduce this uncertainty. Findings The meta-analysis odds ratio for the effectiveness estimate of GP communication of personalised disease risk was 1.48 (95% credibility interval, 0.91-2.26), an absolute increase in smoking cessation rates of 3.84%. The probability of cost-effectiveness ranged 89-94% depending on sex and age. VoI analysis indicated that: (i) uncertainty in the effectiveness of the intervention was the driver of the overall uncertainty in the CEA; and (ii) a research investment to reduce this uncertainty is justified if lower than 27.6 pound million (7 pound per smoker). Conclusions Evidence to date shows that, in England, incorporating disease risk communication into general practitioners' practices to motivate smoking cessation is likely to be cost-effective compared with usual care.

Background: Determining the proportion of susceptible workers can represent a first step to the biological risk assessment related to measles, mumps, rubella and varicella exposure. This study aimed to assess the immunity against measles, mumps, rubella and varicella viruses in a cohort of female school workers. Methods: A cross-sectional seroepidemiological study in a sample of 263 school workers undergoing routine annual workplace health surveillance program was conducted. As part of the health surveillance program, serum samples were collected and tested for measles, mumps, rubella and varicella IgG antibodies. Results: Overall seropositivity was 90.5%, 85.2%, 94.7% and 97.3% for measles, mumps, rubella and varicella, respectively. In relation to mumps occupation-specific seropositivity, a statistically significant difference was observed, showing the lowest prevalence of protected individuals in other occupation groups. Moreover, in relation to rubella, school workers born in Centre Italy had the lowest seropositivity of protective antibodies and the difference between groups was statistically significant. Measles and rubella seropositivity showed a significant decrease after 2015. Conclusions: This study showed a relevant proportion of school workers susceptible to the aforementioned diseases. These results highlighted the need for proper health surveillance and immunological controls in school workers, especially for females, and provided useful insights to policymakers to select effective strategies aimed at containing the risk of vaccine-preventable diseases at schools.

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10-8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.