Phenotypic associations with the HMOX1 GT(n) repeat in European populations

HO-1 is a key enzyme in the management of heme in humans. A GT(n) repeat length in the gene HMOX1, has previously been widely associated with a variety of phenotypes, including susceptibility and outcomes in diabetes, cancer, infections, and neonatal jaundice. However, studies are generally small and results inconsistent. In this study, we imputed the GT(n) repeat length in two European cohorts (UK Biobank, UK, n = 463,005, recruited 2006-onwards; and Avon Longitudinal Study of Parents and Children, ALSPAC, UK, n = 937, recruited 1990 onwards), with the reliability of imputation tested in other cohorts (1000 Genomes, Human Genome Diversity Project and UK-Personal Genome Project). Subsequently, we measured the relationship between repeat length and previously identified associations (diabetes, COPD, pneumonia and infection related mortality in UK Biobank; neonatal jaundice in ALSPAC) and performed a phenome-wide association study (PheWAS) in UK Biobank. Despite high quality imputation (correlation between true repeat length and imputed repeat length >0.9 in test cohorts), clinical associations were not identified in either the PheWAS or specific association studies. These findings are robust to definitions of repeat length and sensitivity analyses. Despite multiple smaller studies identifying associations across a variety of clinical settings; we could not replicate or identify any relevant phenotypic associations with the HMOX1 GT(n) repeat

Is Height2.7 Appropriate for Indexation of Left Ventricular Mass in Healthy Adolescents? The Importance of Sex Differences

BACKGROUND: Left ventricular mass (LVM) is an important predictor of cardiovascular risk. In adolescence, LVM is commonly indexed to height2.7, although some evidence suggests that this may not fully account for sex differences. METHODS: We investigated appropriate allometric scaling of LVM to height, total lean mass, and body surface area, in a UK birth cohort of 2039 healthy adolescents (17±1 years). Allometric relationships were determined by linear regression stratified by sex, following log transformation of x and y variables [log(y)=a+b×log(x)], b is the allometric exponent. RESULTS: Log (LVM) showed linear relationships with log(height) and log(lean mass). Biased estimates of slope resulted when the sexes were pooled. The exponents were lower than the conventional estimate of 2.7 for males (mean [95% CI]=1.66 [1.30-2.03]) and females (1.58 [1.27-1.90]). When LVM was indexed to lean mass, the exponent was 1.16 (1.05-1.26) for males and 1.07 (0.97-1.16) for females. When LVM was indexed to estimated body surface area, the exponent was 1.53 (1.40-1.66) for males and 1.34 (1.24-1.45) for females. CONCLUSIONS: Allometric exponents derived from pooled data, including men and women without adjustment for sex were biased, possibly due to sex differences in body composition. We suggest that when assessing LVM, clinicians should consider body size, body composition, sex, and age. Our observations may also have implications for the identification of young individuals with cardiac hypertrophy

Clustered Environments and Randomized Genes: A Fundamental Distinction between Conventional and Genetic Epidemiology

In a cross-sectional study Davey Smith and colleagues show why observational studies can produce misleading claims regarding potential causal factors for disease, and illustrate the use of mendelian randomization to study environmentally modifiable risk factors

Psychological distress, depression, anxiety and life satisfaction following COVID-19 infection: Evidence from 11 UK longitudinal population studies

Background: Evidence on associations between COVID-19 illness and mental health is mixed. We aimed to examine whether COVID-19 is associated with deterioration in mental health while considering pre-pandemic mental health, time since infection, subgroup differences, and confirmation of infection via self-reported test and serology data. Methods: We obtained data from 11 UK longitudinal studies with repeated measures of mental health (psychological distress, depression, anxiety, and life satisfaction; mental health scales were standardised within each study across time) and COVID-19 status between April, 2020, and April, 2021. We included participants with information available on at least one mental health outcome measure and self-reported COVID-19 status (suspected or test-confirmed) during the pandemic, and a subset with serology-confirmed COVID-19. Furthermore, only participants who had available data on a minimum set of covariates, including age, sex, and pre-pandemic mental health were included. We investigated associations between having ever had COVID-19 and mental health outcomes using generalised estimating equations. We examined whether associations varied by age, sex, ethnicity, education, and pre-pandemic mental health, whether the strength of the association varied according to time since infection, and whether associations differed between self-reported versus confirmed (by test or serology) infection. Findings: Between 21 Dec, 2021, and July 11, 2022, we analysed data from 54 442 participants (ranging from a minimum age of 16 years in one study to a maximum category of 90 years and older in another; including 33 200 [61·0%] women and 21 242 [39·0%] men) from 11 longitudinal UK studies. Of 40 819 participants with available ethnicity data, 36 802 (90·2%) were White. Pooled estimates of standardised differences in outcomes suggested associations between COVID-19 and subsequent psychological distress (0·10 [95% CI 0·06 to 0·13], I2=42·8%), depression (0·08 [0·05 to 0·10], I2=20·8%), anxiety (0·08 [0·05 to 0·10], I2=0·0%), and lower life satisfaction (–0·06 [–0·08 to –0·04], I2=29·2%). We found no evidence of interactions between COVID-19 and sex, education, ethnicity, or pre-pandemic mental health. Associations did not vary substantially between time since infection of less than 4 weeks, 4–12 weeks, and more than 12 weeks, and were present in all age groups, with some evidence of stronger effects in those aged 50 years and older. Participants who self-reported COVID-19 but had negative serology had worse mental health outcomes for all measures than those without COVID-19 based on serology and self-report. Participants who had positive serology but did not self-report COVID-19 did not show association with mental health outcomes. Interpretation: Self-reporting COVID-19 was longitudinally associated with deterioration in mental health and life satisfaction. Our findings emphasise the need for greater post-infection mental health service provision, given the substantial prevalence of COVID-19 in the UK and worldwide. Funding: UK Medical Research Council and UK National Institute for Health and Care Research

The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants

Background: It is unclear whether C-reactive protein (CRP) is causally related to coronary heart disease (CHD). Genetic variants that are known to be associated with CRP levels can be used to provide causal inference of the effect of CRP on CHD. Our objective was to examine the association between CRP genetic variant +1444C>T (rs1130864) and CHD risk in the largest study to date of this association.Methods and Results: We estimated the association of CRP genetic variant +1444C>T (rs1130864) with CRP levels and with CHD in five studies and then pooled these analyses (N= 18,637 participants amongst whom there were 4,610 cases). CRP was associated with potential confounding factors (socioeconomic position, physical activity, smoking and body mass) whereas genotype (rs1130864) was not associated with these confounders. The pooled odds ratio of CHD per doubling of circulating CRP level after adjustment for age and sex was 1.13 (95% CI: 1.06, 1.21), and after further adjustment for confounding factors it was 1.07 (95% CI: 1.02, 1.13). Genotype (rs1130864) was associated with circulating CRP; the pooled ratio of geometric means of CRP level among individuals with the TT genotype compared to those with the CT/CC genotype was 1.21 (95% CI: 1.15, 1.28) and the pooled ratio of geometric means of CRP level per additional T allele was 1.14 (95% CI: 1.11, 1.18), with no strong evidence in either analyses of between study heterogeneity (I-2 = 0%, p>0.9 for both analyses). There was no association of genotype (rs1130864) with CHD: pooled odds ratio 1.01 (95% CI: 0.88, 1.16) comparing individuals with TT genotype to those with CT/CC genotype and 0.96 (95% CI: 0.90, 1.03) per additional T allele (I-2<7.5%, p. 0.6 for both meta-analyses). An instrumental variables analysis (in which the proportion of CRP levels explained by rs1130864 was related to CHD) suggested that circulating CRP was not associated with CHD: the odds ratio for a doubling of CRP level was 1.04 (95% CI: 0.61, 1.80).Conclusions: We found no association of a genetic variant, which is known to be related to CRP levels, (rs1130864) and having CHD. These findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out

Geometric and algebraic classification of quadratic differential systems with invariant hyperbolas

Let QSH be the whole class of non-degenerate planar quadratic differential systems possessing at least one invariant hyperbola. We classify this family of systems, modulo the action of the group of real affine transformations and time rescaling, according to their geometric properties encoded in the configurations of invariant hyperbolas and invariant straight lines which these systems possess. The classification is given both in terms of algebraic geometric invariants and also in terms of affine invariant polynomials and it yields a total of 205 distinct such configurations. We have 162 configurations for the subclass QSH(η>0) of systems which possess three distinct real singularities at infinity, and 43 configurations for the subclass QSH(η=0) of systems which possess either exactly two distinct real singularities at infinity or the line at infinity filled up with singularities. The algebraic classification, based on the invariant polynomials, is also an algorithm which makes it possible to verify for any given real quadratic differential system if it has invariant hyperbolas or not and to specify its configuration of invariant hyperbolas and straight lines

Managing clinically significant findings in research:the UK10K example

Recent advances in sequencing technology allow data on the human genome to be generated more quickly and in greater detail than ever before. Such detail includes findings that may be of significance to the health of the research participant involved. Although research studies generally do not feed back information on clinically significant findings (CSFs) to participants, this stance is increasingly being questioned. There may be difficulties and risks in feeding clinically significant information back to research participants, however, the UK10K consortium sought to address these by creating a detailed management pathway. This was not intended to create any obligation upon the researchers to feed back any CSFs they discovered. Instead, it provides a mechanism to ensure that any such findings can be passed on to the participant where appropriate. This paper describes this mechanism and the specific criteria, which must be fulfilled in order for a finding and participant to qualify for feedback. This mechanism could be used by future research consortia, and may also assist in the development of sound principles for dealing with CSFs

Worldwide population differentiation at disease-associated SNPs

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association (GWA) studies have provided compelling evidence of association between genetic variants and common complex diseases. These studies have made use of cases and controls almost exclusively from populations of European ancestry and little is known about the frequency of risk alleles in other populations. The present study addresses the transferability of disease associations across human populations by examining levels of population differentiation at disease-associated single nucleotide polymorphisms (SNPs).</p> <p>Methods</p> <p>We genotyped ~1000 individuals from 53 populations worldwide at 25 SNPs which show robust association with 6 complex human diseases (Crohn's disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, coronary artery disease and obesity). Allele frequency differences between populations for these SNPs were measured using Fst. The Fst values for the disease-associated SNPs were compared to Fst values from 2750 random SNPs typed in the same set of individuals.</p> <p>Results</p> <p>On average, disease SNPs are not significantly more differentiated between populations than random SNPs in the genome. Risk allele frequencies, however, do show substantial variation across human populations and may contribute to differences in disease prevalence between populations. We demonstrate that, in some cases, risk allele frequency differences are unusually high compared to random SNPs and may be due to the action of local (i.e. geographically-restricted) positive natural selection. Moreover, some risk alleles were absent or fixed in a population, which implies that risk alleles identified in one population do not necessarily account for disease prevalence in all human populations.</p> <p>Conclusion</p> <p>Although differences in risk allele frequencies between human populations are not unusually large and are thus likely not due to positive local selection, there is substantial variation in risk allele frequencies between populations which may account for differences in disease prevalence between human populations.</p

Genome-Wide Meta-Analysis of Cotinine Levels in Cigarette Smokers Identifies Locus at 4q13.2

Genome-wide association studies (GWAS) of complex behavioural phenotypes such as cigarette smoking typically employ self-report phenotypes. However, precise biomarker phenotypes may afford greater statistical power and identify novel variants. Here we report the results of a GWAS meta-analysis of levels of cotinine, the primary metabolite of nicotine, in 4,548 daily smokers of European ancestry. We identified a locus close to UGT2B10 at 4q13.2 (minimum p = 5.89 x 10(-10) for rs114612145), which was consequently replicated. This variant is in high linkage disequilibrium with a known functional variant in the UGT2B10 gene which is associated with reduced nicotine and cotinine glucuronidation activity, but intriguingly is not associated with nicotine intake. Additionally, we observed association between multiple variants within the 15q25.1 region and cotinine levels, all located within the CHRNA5-A3-B4 gene cluster or adjacent genes, consistent with previous much larger GWAS using self-report measures of smoking quantity. These results clearly illustrate the increase in power afforded by using precise biomarker measures in GWAS. Perhaps more importantly however, they also highlight that biomarkers do not always mark the phenotype of interest. The use of metabolite data as a proxy for environmental exposures should be carefully considered in the context of individual differences in metabolic pathways.Peer reviewe