Mohammad Talaei

In observational studies, an unhealthy dietary pattern during pregnancy is associated with an increased likelihood of offspring ADHD. We investigated whether such associations may be partly attributable to genetic confounding. Polygenic scores (PGSs) for a healthy dietary pattern were calculated for mother, father, and child trios in the COPSAC ₂₀₁₀ cohort. Diagnoses and trait scores of ADHD were assessed in the children at age 10. Using trio models, we tested whether the association between maternal genetic liability to a healthy dietary pattern and offspring ADHD could be accounted for by genetic confounding. In COPSAC ₂₀₁₀ trio models (N-trio=437), a maternal healthy dietary pattern PGS was associated with reduced ADHD trait score after adjustment for child and paternal dietary pattern PGS, suggesting indirect genetic effects consistent with causal effects from maternal diet. However, this was not replicated in MoBa (N-trio=41 580) or ALSPAC (N-trio=1 211), where direct genetic effect estimates implied an important role for genetic confounding. Collectively, these genetic results indicate a potential pathway by which genetic confounding can inflate observed associations between maternal dietary pattern in pregnancy and offspring ADHD, and do not provide any robust evidence consistent with a causal pathway between the two. These findings should be interpreted in the light of both the limited predictive power of the dietary pattern PGS, which accounted for only a small proportion of pregnancy diet variance, and the multi-faceted nature of diet as an exposure.

The positive association between childhood asthma and attention deficit hyperactivity disorder (ADHD) has not been adequately explained. We aimed to investigate whether it is causal or whether shared genetics and/or shared early-life risk factors explain the link. We used a two-sample Mendelian randomization (MR) to test whether there is a causal relationship between asthma and ADHD. In the Avon Longitudinal Study of Parents and Children (ALSPAC), we defined doctor-diagnosed asthma, its endotypes according to atopy determined by skin-prick tests, and the risk of ADHD by using the Strengths and Difficulties Questionnaire, all at 7 years of age. We explored whether the asthma-ADHD association was attenuated when controlling for an extensive number of early-life risk factors (N = 7165). Child polygenic risk scores (PRSs) for asthma and ADHD were calculated by using published genome-wide association studies across seven P-value thresholds (<5 × 10-8 to <.5) (N = 5425-5503). We found little evidence of a causal effect between asthma and ADHD in both directions. In ALSPAC, asthma [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.10 - 1.65], particularly non-atopic asthma (OR 1.51, 95% CI 1.09 - 2.08), was associated with ADHD in crude models, while atopic asthma was not (OR 1.00, 95% CI 0.69 - 1.45). These associations were largely attenuated after adjusting for 15 shared early-life risk factors (OR 1.14, 95% CI 0.92 - 1.41 for asthma and OR 1.24, 95% CI 0.88 - 1.74 for non-atopic asthma). There was little evidence of association between asthma PRSs and ADHD at any P-value threshold. We found evidence of an association between ADHD PRSs and asthma and non-atopic asthma at most thresholds; the strongest association was at P < 5 × 10-3 (OR 1.12, 95% CI 1.04 - 1.22, P = .004) for asthma and at P < 5 × 10-2 (OR 1.18, 95% CI 1.04 - 1.34, P = .01) for non-atopic asthma. The association between asthma and ADHD in childhood is unlikely to be causal and is largely explained by shared early-life risk factors, with some evidence for a shared genetic background.

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.

Introduction: Hypertension is the most prominent established risk factor for adverse cardiovascular outcomes. The influence of hypertension in combination with other major cardiovascular disease risk factors (CVD‐RFs) on mortality and cardiovascular events has not been fully comprehended yet due to their overlapping and interconnected nature. This study was conducted to evaluate the impact of CVD‐RFs quantity on the occurrence of cardiovascular events, CVD‐related mortality, and all‐cause mortality rates in hypertensive patients. Design and Method: In a secondary analysis of the Isfahan Cohort Study, demographic information, anthropometric measures, and laboratory results of participants were extracted. During the 15 years of follow‐up, all‐cause mortality, CVD‐related mortality, and the occurrence of nonfatal cardiovascular events were assessed by separate panels of experts. Data analysis was performed using Cox proportional hazard models to estimate adjusted hazard ratios (HRs) among normotensive and hypertensive individuals in two subgroups of 3 CVD‐RFs and≥ 3 CVD‐RFs. Results: Among 5432 eligible participants, hypertensive patients ( n = 1509) had 1.3, 2, and 1.4 times higher HRs for all‐cause mortality, CVD‐related mortality, and nonfatal cardiovascular events, respectively. Compared to the normotensives, HRs for the mentioned outcomes were 1.2, 1.7, and 1.3 for hypertensive participants with < 3 CVD‐RFs and 1.7, 3.4, and 2.3 for hypertensive participants with≥ 3 CVD‐RFs. These rises were shown to be highly significant ( p = 0.003, p = 0.001) for CVD‐related mortality and nonfatal cardiovascular events in hypertensives with ≥ 3 CVD‐RFs compared with hypertensives with < 3 CVD‐RFs. Conclusions: Hypertension alone or combined with other CVD‐RFs increases the chance of all‐cause mortality, CVD‐related mortality, and nonfatal cardiovascular events. Rises in the quantity of other CVD‐RFs (specifically to≥ 3) result in highly significant increases in fatal and nonfatal cardiovascular events. Therefore, to reduce mortality and cardiovascular events, hypertensive patients should be thoroughly evaluated for coexisting CVD‐RFs, aiming to limit the synergistic effects of multiple CVD‐RFs by properly managing modifiable RFs.

Lower lung function is associated with lower cognitive function and an increased risk of dementia. This has not been adequately explained and may partly reflect shared developmental pathways. In UK Biobank participants of European ancestry, we tested the association between lung function measures (forced vital capacity and forced expiratory volume in one second to forced vital capacity ratio; N=306,476) and cognitive traits including nine cognitive function test scores (N=32,321-428,609), all-cause dementia, Alzheimer’s disease, and vascular dementia (6,805, 2,859 and 1,544 cases, respectively, and ∼421,241 controls). In the same population, we derived summary statistics for associations between common genetic variants in 55 lung development genes, and lung function measures and cognitive traits using adjusted linear/logistic regression models. Using a hypothesis-driven Bayesian colocalisation analysis, we finally investigated the presence of shared genetic signals between lung function measures and cognitive traits at each of these 55 genes. Higher lung function measures were generally associated with higher scores of cognitive function tests as well as lower risk of dementia, with the strongest association between forced vital capacity and vascular dementia. The strongest association was between forced vital capacity and vascular dementia (adjusted hazard ratio 0.74 per standard deviation increase, 95% CI 0.67-0.83). Of the 55 genes of interest, we found shared variants in four genes, namely: CSNK2B rs9267531 (forced vital capacity and forced expiratory volume in one second to forced vital capacity ratio with fluid intelligence and pairs matching); NFATC3 rs548092276 & rs11275011 (forced expiratory volume in one second to forced vital capacity ratio with fluid intelligence); PTCH1 rs2297086 & rs539078574 (forced expiratory volume in one second to forced vital capacity ratio with reaction time); and KAT8 rs138259061 (forced vital capacity with pairs matching). However, the direction of effects was not in keeping with our hypothesis, i.e. variants associated with lower lung function were associated with better cognitive function or vice versa. We also found distinct variants associated with lung function and cognitive function in KAT8 (forced vital capacity and Alzheimer’s disease) and PTCH1 (forced vital capacity and forced expiratory volume in one second to forced vital capacity ratio with fluid intelligence and reaction time). The links between CSNK2B and NFATC3 and cognitive traits have not been previously reported by genome-wide association studies. Despite shared genes and variants, our findings do not support the hypothesis that shared developmental signalling pathways explain the association of lower adult lung function with poorer cognitive function.

Background: The positive association between asthma and attention deficit hyperactivity disorder (ADHD) has not been adequately explained. Aims: To investigate whether it is causal or whether shared genetics and/or shared early-life risk factors (RFs) explain the link. Methods: We used 2-sample Mendelian Randomization (MR) to test the causal relationship between asthma and ADHD. In the Avon Longitudinal Study of Parents and Children (ALSPAC), we defined doctor-diagnosed asthma, its endotypes according to atopy determined by skin-prick tests, and ADHD using the Strengths and Difficulties Questionnaire, all at seven years of age. We explored whether the asthma-ADHD association was attenuated when controlling for an extensive number of early-life RFs. Child polygenic risk scores (PRSs) for asthma and ADHD were calculated using published genome-wide association studies across 7 P-value thresholds (<5×10−08 to <0.5). Results: We found little evidence of a causal effect between asthma and ADHD in both directions. In ALSPAC, asthma (OR 1.35, 95% CI 1.10−1.65), particularly non-atopic asthma (1.51, 1.09−2.08), was associated with ADHD in crude models, while atopic asthma was not (1.00, 0.69−1.45). These associations were largely attenuated after adjusting for 14 shared early-life risk factors (1.15, 0.93−1.42 for asthma and 1.24, 0.88−1.75 for non-atopic asthma). Asthma PRSs were not associated with ADHD at any P-value threshold, whereas ADHD PRSs were associated with asthma and non-atopic asthma at most thresholds. Conclusions: The association between asthma and ADHD in childhood is unlikely to be causal and is largely explained by shared early-life RFs, with some evidence for a shared genetic background.

Background: In several countries, COVID-19 booster vaccinations are offered annually to priority groups, but many people have not been vaccinated in over a year. We aimed to assess the association between time since booster vaccination and characteristics of breakthrough infection. We also assessed whether incident COVID-19 continued to associate with asthma exacerbations in boosted individuals, and whether risk of COVID-19-associated exacerbation was affected by time since vaccination. Methods: COVIDENCE UK is a prospective, longitudinal, population-based study of COVID-19. We included adult participants who had received ≥1 booster vaccination. Time since vaccination was binarised at 6 months or 12 months according to vaccine eligibility subgroup. We used logistic, Cox, and linear regression to obtain adjusted estimates for the association between time since vaccination and breakthrough infection severity, symptom duration, and acute changes to health-related quality of life (measured by the EQ-5D-3L Index). We then assessed the association of incident COVID-19 with asthma exacerbations using multilevel mixed models, by time since vaccination. Results: 7391 boosted participants reported a breakthrough infection. Across all eligibility subgroups, greater time since vaccination associated with increased odds of infection requiring bedrest ( vs milder symptoms), with the highest odds for adults aged 65–75 years (1.83 [95% CI 1.51–2.23] when vaccinated >6 months vs ≤6 months prior). However, we observed little evidence of association between time since vaccination and symptom duration. Vaccination >12 months prior ( vs ≤12 months) was associated with a small decrease in EQ-5D-3L Index among participants younger than 65 years (-0.03 points [-0.04 to -0.01]). Among 2100 participants with asthma, incident COVID-19 associated with increased risk of asthma exacerbation, both ≤12 months after vaccination (OR 5.31 [4.36–6.48]) and later (6.06 [3.23–11.38]), with a greater difference in point estimates when specifically considering severe asthma exacerbations (6.82 [4.88–9.54] for ≤12 months vs 10.06 [3.90–25.92] for >12 months). Conclusion: Longer time since booster vaccination consistently associates with more severe breakthrough infections, and may potentially increase risk of severe asthma exacerbations. These findings highlight the importance of ensuring those currently eligible receive their booster vaccinations, and the need for research on further vaccinations in people with asthma no longer eligible for boosters.

Background: Many mothers in high-income countries (HIC) do not breastfeed to the World Health Organisation’s recommendation of two years. This is particularly true for low-income women (LIW). They often face additional socio-structural barriers that encourage early discontinuation and are inadequately supported by current healthcare interventions. Teleinterventions are flexible and widely used following the global pandemic and increase maternal autonomy over intervention delivery. They show promise in improving other maternal conditions in LIW, including postpartum depression. Teleinterventions can increase breastfeeding rates in the wider maternal population, however their efficacy for this underserved population has not yet been systematically assessed. This meta-analysis aimed to identify if teleinterventions increase ‘exclusive’ or ‘any’ breastfeeding by LIW in HIC at 1-, 3–4, and 6-months postpartum. Methods: We searched five online databases for randomised controlled trials assessing breastfeeding teleinterventions for LIW in HIC. Risk ratios (RR) were used to calculate the average effect of teleinterventions on ‘any’ and ‘exclusive’ breastfeeding at at 1-, 3–4, and 6-months postpartum using random effects meta-analysis. Study bias was assessed using the Revised Cochrane risk-of-bias tool for randomised trials (RoB2), and outcome quality was evaluated against GRADE criteria. Results: Nine studies met inclusion criteria: six providing telephone calls, two text messages and one an online support group. All the studies were conducted in the United States, with small sample sizes and a high risk of bias. Pooled results indicate teleinterventions modestly increase ‘any’ and ‘exclusive’ breastfeeding at all time points, with a statistically significant increase in ‘exclusive’ breastfeeding after 3–4 months (RR 1.12, 95% CI [1.00,1.25]). At 3–4 months teleinterventions providing peer support were more effective than educational teleinterventions at promoting any and exclusive breastfeeding. Evidence for all outcomes were rated ‘low’ or ‘very low’ quality using the GRADE tool, mainly due to high attrition and low power. Conclusions: Despite insufficient high-quality research into breastfeeding teleinterventions for LIW, our results suggest teleinterventions may improve exclusive and any breastfeeding. Given breastfeeding is particularly low in LIW population from HIC, our findings are promising and require further exploration by larger, methodologically sound trials in other HIC.