Jessica Tyrrell

Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci

Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.

Associations between socioeconomic status and environmental toxicant concentrations in adults in the USA: NHANES 2001-2010.

Low level chronic exposure to toxicants is associated with a range of adverse health effects. Understanding the various factors that influence the chemical burden of an individual is of critical importance to public health strategies. We investigated the relationships between socioeconomic status (SES) and bio-monitored chemical concentration in five cross-sectional waves of the U.S. National Health and Nutrition Examination Survey (NHANES). We utilised adjusted linear regression models to investigate the association between 179 toxicants and the poverty income ratio (PIR) for five NHANES waves. We then selected a subset of chemicals associated with PIR in 3 or more NHANES waves and investigated potential mediating factors using structural equation modelling. PIR was associated with 18 chemicals in 3 or more NHANES waves. Higher SES individuals had higher burdens of serum and urinary mercury, arsenic, caesium, thallium, perfluorooctanoic acid, perfluorononanoic acid, mono(carboxyoctyl) phthalate and benzophenone-3. Inverse associations were noted between PIR and serum and urinary lead and cadmium, antimony, bisphenol A and three phthalates (mono-benzyl, mono-isobutyl, mono-n-butyl). Key mediators included fish and shellfish consumption for the PIR, mercury, arsenic, thallium and perfluorononanoic acid associations. Sunscreen use was an important mediator in the benzophenone-3/PIR relationship. The association between PIR and cadmium or lead was partially mediated by smoking, occupation and diet. These results provide a comprehensive analysis of exposure patterns as a function of socioeconomic status in US adults, providing important information to guide future public health remediation measures to decrease toxicant and disease burdens within society.

Height, body mass index, and socioeconomic status: mendelian randomisation study in UK Biobank

Objective To determine whether height and body mass index (BMI) have a causal role in five measures of socioeconomic status. Design Mendelian randomisation study to test for causal effects of differences in stature and BMI on five measures of socioeconomic status. Mendelian randomisation exploits the fact that genotypes are randomly assigned at conception and thus not confounded by non-genetic factors. Setting UK Biobank. Participants 119 669 men and women of British ancestry, aged between 37 and 73 years. Main outcome measures Age completed full time education, degree level education, job class, annual household income, and Townsend deprivation index. Results In the UK Biobank study, shorter stature and higher BMI were observationally associated with several measures of lower socioeconomic status. The associations between shorter stature and lower socioeconomic status tended to be stronger in men, and the associations between higher BMI and lower socioeconomic status tended to be stronger in women. For example, a 1 standard deviation (SD) higher BMI was associated with a £210 (€276;

The relationship between protoporphyrin IX photobleaching during real-time dermatological methyl-aminolevulinate photodynamic therapy (MAL-PDT) and subsequent clinical outcome.

300; 95% confidence interval £84 to £420; P=6×10−3) lower annual household income in men and a £1890 (£1680 to £2100; P=6×10−15) lower annual household income in women. Genetic analysis provided evidence that these associations were partly causal. A genetically determined 1 SD (6.3 cm) taller stature caused a 0.06 (0.02 to 0.09) year older age of completing full time education (P=0.01), a 1.12 (1.07 to 1.18) times higher odds of working in a skilled profession (P=6×10−7), and a £1130 (£680 to £1580) higher annual household income (P=4×10−8). Associations were stronger in men. A genetically determined 1 SD higher BMI (4.6 kg/m2) caused a £2940 (£1680 to £4200; P=1×10−5) lower annual household income and a 0.10 (0.04 to 0.16) SD (P=0.001) higher level of deprivation in women only. Conclusions These data support evidence that height and BMI play an important partial role in determining several aspects of a person’s socioeconomic status, especially women’s BMI for income and deprivation and men’s height for education, income, and job class. These findings have important social and health implications, supporting evidence that overweight people, especially women, are at a disadvantage and that taller people, especially men, are at an advantage.

Prevalence, associated factors, and comorbid conditions for Ménière's disease.

The relationship between protoporphyrin IX (PpIX) photobleaching and cellular damage during aminolevulinic (ALA) photodynamic therapy (PDT) has been studied at the cellular level. This study assessed the capability of a non‐invasive fluorescence imaging system (Dyaderm, Biocam, Germany), to monitor changes in PpIX during real time methyl‐aminolevulinate (MAL) PDT in dermatological lesions, and thus to act as a predictive tool in terms of observed clinical outcome post‐treatment.

Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5–CHRNA3–CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight

Objectives: The aims of this study were to estimate the prevalence of Ménière’s disease and investigate its relationship with: demographic factors; symptoms and conditions that are known or hypothesized to be associated with Ménière’s disease; other physical diseases; mental health. Design: The authors used cross-sectional data from the UK Biobank to compare 1376 self-reported Ménière’s participants with over 500,000 without Ménière’s. The data set has comprehensive anthropometric measures, questionnaire data investigating health, well-being, diet, and medical and drug-prescribing history for each participant. The authors used logistic regression models to investigate the relationship of Ménière’s disease with: demographic factors; symptoms and conditions that are known or hypothesized to be associated with Ménière’s disease; other physical diseases; and mental health. Results: Ménière’s disease was more common in participants who were older (adjusted odds ratio per 10-year increase: 1.5 [95% confidence interval:1.4–1.6]), white (odds ratio: 1.7;1.2–2.3), female (1.4;1.3–1.6), and having higher body mass index categories (p < 0.001). The Ménière’s group had greater odds of hearing difficulty (10.9;9.6–12.5), current tinnitus (68.3;47.8–97.5), and had fallen more than once in the last year (2.1;1.8–2.5). Ménière’s participants had greater odds of reporting at least one disease from each grouping of allergic, immune dysfunction, or autonomic dysfunction (2.2;1.8–2.6), and poor mental health (2.1;1.8–2.5). Conclusions: This study provides an evidence base that improves understanding of Ménière’s disease. Associations were noted with a number of diseases, and the authors hypothesize a role for the autonomic nervous system and immune system dysfunction in Ménière’s etiology. The study also highlights the physical and mental health correlates of the condition.

The effect of air cooling pain relief on protoporphyrin IX photobleaching and clinical efficacy during dermatological photodynamic therapy

Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4–36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: −4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.

Gene–obesogenic environment interactions in the UK Biobank study

Methyl aminolevulinate photodynamic therapy (MAL-PDT) is utilized to successfully treat licensed indications (e.g. actinic keratosis (AK), superficial basal cell carcinoma (sBCC) and Bowens disease (BD)) in the UK. Air cooling devices (ACD) are commonly utilized as a method of pain relief, however the effect of this on treatment outcome has never been extensively investigated. This non-randomized, retrospective observational controlled study investigated whether the application of the ACD limited photosensitiser (protoporphyrin IX - PpIX) photobleaching during irradiation and/or subsequent clinical outcome. Patients utilizing the ACD throughout treatment were observed to undergo significantly less PpIX photobleaching than the control group (P<0.001) and complete clinical clearances observed at 3 months were also reduced within the ACD group. Separate analysis of the different lesion types indicated that significantly less photobleaching occurred in AK lesions with ACD and all lesion types failed to fully utilize the accumulated PpIX when ACD was employed. The application of the ACD as pain relief during light irradiation therefore resulted in lower PpIX photobleaching which corresponded to a reduction in the efficacy of PDT treatment. Whilst the ACD is an effective method of dermatological PDT analgesia it should be utilized as sparingly as possible to minimize any deleterious effects on treatment outcome.

Genetic Evidence for a Link Between Favorable Adiposity and Lower Risk of Type 2 Diabetes, Hypertension, and Heart Disease.

Abstract Background: Previous studies have suggested that modern obesogenic environments accentuate the genetic risk of obesity. However, these studies have proven controversial as to which, if any, measures of the environment accentuate genetic susceptibility to high body mass index (BMI). Methods: We used up to 120 000 adults from the UK Biobank study to test the hypothesis that high-risk obesogenic environments and behaviours accentuate genetic susceptibility to obesity. We used BMI as the outcome and a 69-variant genetic risk score (GRS) for obesity and 12 measures of the obesogenic environment as exposures. These measures included Townsend deprivation index (TDI) as a measure of socio-economic position, TV watching, a ‘Westernized’ diet and physical activity. We performed several negative control tests, including randomly selecting groups of different average BMIs, using a simulated environment and including sun-protection use as an environment. Results: We found gene–environment interactions with TDI (Pinteraction = 3 × 10–10), self-reported TV watching (Pinteraction = 7 × 10–5) and self-reported physical activity (Pinteraction = 5 × 10–6). Within the group of 50% living in the most relatively deprived situations, carrying 10 additional BMI-raising alleles was associated with approximately 3.8 kg extra weight in someone 1.73 m tall. In contrast, within the group of 50% living in the least deprivation, carrying 10 additional BMI-raising alleles was associated with approximately 2.9 kg extra weight. The interactions were weaker, but present, with the negative controls, including sun-protection use, indicating that residual confounding is likely. Conclusions: Our findings suggest that the obesogenic environment accentuates the risk of obesity in genetically susceptible adults. Of the factors we tested, relative social deprivation best captures the aspects of the obesogenic environment responsible.

Parental diabetes and birthweight in 236 030 individuals in the UK Biobank Study

Recent genetic studies have identified some alleles that are associated with higher BMI but lower risk of type 2 diabetes, hypertension, and heart disease. These “favorable adiposity” alleles are collectively associated with lower insulin levels and higher subcutaneous–to–visceral adipose tissue ratio and may protect from disease through higher adipose storage capacity. We aimed to use data from 164,609 individuals from the UK Biobank and five other studies to replicate associations between a genetic score of 11 favorable adiposity variants and adiposity and risk of disease, to test for interactions between BMI and favorable adiposity genetics, and to test effects separately in men and women. In the UK Biobank, the 50% of individuals carrying the most favorable adiposity alleles had higher BMIs (0.120 kg/m2 [95% CI 0.066, 0.174]; P = 1E-5) and higher body fat percentage (0.301% [0.230, 0.372]; P = 1E-16) compared with the 50% of individuals carrying the fewest alleles. For a given BMI, the 50% of individuals carrying the most favorable adiposity alleles were at lower risk of type 2 diabetes (odds ratio [OR] 0.837 [0.784, 0.894]; P = 1E-7), hypertension (OR 0.935 [0.911, 0.958]; P = 1E-7), and heart disease (OR 0.921 [0.872, 0.973]; P = 0.003) and had lower blood pressure (systolic −0.859 mmHg [−1.099, −0.618]; P = 3E-12 and diastolic −0.394 mmHg [−0.534, −0.254]; P = 4E-8). In women, these associations could be explained by the observation that the alleles associated with higher BMI but lower risk of disease were also associated with a favorable body fat distribution, with a lower waist-to-hip ratio (−0.004 cm [95% CI −0.005, −0.003] 50% vs. 50%; P = 3E-14), but in men, the favorable adiposity alleles were associated with higher waist circumference (0.454 cm [0.267, 0.641] 50% vs. 50%; P = 2E-6) and higher waist-to-hip ratio (0.0013 [0.0003, 0.0024] 50% vs. 50%; P = 0.01). Results were strengthened when a meta-analysis with five additional studies was conducted. There was no evidence of interaction between a genetic score consisting of known BMI variants and the favorable adiposity genetic score. In conclusion, different molecular mechanisms that lead to higher body fat percentage (with greater subcutaneous storage capacity) can have different impacts on cardiometabolic disease risk. Although higher BMI is associated with higher risk of diseases, better fat storage capacity could reduce the risk.