Bidirectional association between autoimmune disease and perinatal depression: a nationwide study with sibling comparison.

Although major depression, characterized by a pro-inflammatory profile, genetically overlap with autoimmune disease (AD) and the perinatal period involve immune system adaptations and AD symptom alterations, the bidirectional link between perinatal depression (PND) and AD is largely unexplored. Hence, the objective of this study was to investigate the bidirectional association between PND and AD. Using nationwide Swedish population and health registers, we conducted a nested case-control study and a matched cohort study. From 1,347,901 pregnancies during 2001-2013, we included 55,299 incident PND, their unaffected full sisters, and 10 unaffected matched women per PND case. We identified 41 subtypes of AD diagnoses recorded in the registers and compared PND with unaffected population-matched women and full sisters, using multivariable regressions. Women with an AD had a 30% higher risk of subsequent PND (95% CI 1.2-1.5) and women exposed to PND had a 30% higher risk of a subsequent AD (95% CI 1.3-1.4). Comparable associations were found when comparing exposed women with their unaffected sisters (nested case-control OR: 1.3, 95% CI 1.2-1.5, matched cohort HR: 1.3, 95% CI 1.1-1.6), and when studying antepartum and postpartum depression. The bidirectional association was more pronounced among women without psychiatric comorbidities (nested case-control OR: 1.5, 95% CI 1.4-1.6, matched cohort HR: 1.4, 95% CI 1.4-1.5) and strongest for multiple sclerosis (nested case-control OR: 2.0, 95% CI 1.6-2.3, matched cohort HR: 1.8, 95% CI 1.0-3.1). These findings demonstrate a bidirectional association between AD and PND independent of psychiatric comorbidities, suggesting possibly shared biological mechanisms. If future translational science confirms the underlying mechanisms, healthcare providers need to be aware of the increased risk of PND among women with ADs and vice versa.

Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study.

RATIONALE: Early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. OBJECTIVES: To assess the accuracy of gas chromatography-mass spectrometry based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. METHODS: This study encompassed a discovery (SysPharmPediA) and validation phase (U-BIOPRED, PANDA). Firstly, exhaled VOCs that discriminated asthma control levels were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled, based on asthma control test scores and number of severe attacks in the past year. Additionally, potential of VOCs in predicting two or more future severe asthma attacks in SysPharmPediA was evaluated. MEASUREMENTS AND MAIN RESULTS: Complete data were available for 196 children (SysPharmPediA=100, U-BIOPRED=49, PANDA=47). In SysPharmPediA, after randomly splitting the population into training (n=51) and test sets (n=49), three compounds (acetophenone, ethylbenzene, and styrene) distinguished between uncontrolled and controlled asthmatics. The area under the receiver operating characteristic curve (AUROCC) for training and test sets were respectively: 0.83 (95% CI: 0.65-1.00) and 0.77 (95% CI: 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ±0.06 (UBIOPRED) and 0.68 ±0.05 (PANDA). Attacks prediction tests, resulted in AUROCCs of 0.71 (95% CI 0.51-0.91) and 0.71 (95% CI 0.52-0.90) for training and test sets. CONCLUSIONS: Exhaled metabolites analysis might enable asthma control classification in children. This should stimulate further development of exhaled metabolites-based point-of-care tests in asthma.

Use of inhaled corticosteroids and the risk of hospitalisation for pneumonia in children with asthma: a nationwide cohort study.

BACKGROUND: The potential association between the use of inhaled corticosteroids (ICS) and the risk of pneumonia among adults is disputed and paediatric-specific evidence is scarce. AIM: To assess the potential association between ICS, use and the risk of hospitalisation for pneumonia among children (age 2-17 years) with asthma. METHODS: This was a cohort study based on nationwide data from routine clinical practice in Sweden (January 2007 to November 2021). From 425 965 children with confirmed asthma, episodes of new ICS use and no use were identified using records of dispensed drugs. We adjusted for potential confounders with propensity score overlap weighting and the risk of a hospitalisation with pneumonia as primary diagnosis was estimated. Multiple subgroup and sensitivity analyses were also performed. RESULTS: We identified 249 351 ICS (mean follow-up of 0.9 years) and 214 840 no-use (mean follow-up of 0.7 years) episodes. During follow-up, 369 and 181 events of hospitalisation for pneumonia were observed in the ICS and no-use episodes, respectively. The weighted incidence rates of hospitalisation for pneumonia was 14.5 per 10 000 patient-years for ICS use episodes and 14.6 for no-use episodes. The weighted HR for hospitalisation for pneumonia associated with ICS use was 1.06 (95% CI 0.88 to 1.28) and the absolute rate difference was -0.06 (95% CI -2.83 to 2.72) events per 10 000 patient-years, compared with no use. CONCLUSIONS: In this nationwide cohort study, we found no evidence of an association between ICS use and the risk of hospitalisation for pneumonia among children with asthma, as compared with no use.

Congenital Hypothyroidism and School Achievement in Adolescence: A Population-Based Sibling Control Study.

OBJECTIVE: To study school achievement in grade 9 of compulsory school in children with congenital hypothyroidism (CH), both those detected by the national screening program and those with a normal screening result and thus diagnosed later. STUDY DESIGN: Nationwide study of children in the Swedish Medical Birth Register (n = 1 547 927) from 1982 through 1997, linked to the neonatal screening CH cohort and the National School Register. Dried blood spot (DBS) samples are collected from all newborn infants, according to the neonatal screening program. Thyroid-stimulating hormone was used for CH screening. CH was defined as either having an abnormal screening result (DBS+) and treatment with levothyroxine (LT4+) or having a normal screening result but a CH diagnosis in the National Patient Register and treatment with LT4 (DBS-/ICD+/LT4+). Regression models were used to study school performance, which as measured as grade point sum and national test results. Sibling analysis also was performed to account for unmeasured familial factors. RESULTS: There were 448 children who were DBS+/LT4+ and 475 children who were DBS-/ICD+/LT4+. Children with CH had lower grade point sum, adjusted ß = - 6.34 (95% CI -11.7 to -1.01) and adjusted ß = -10.3 (95% CI -15.5 to -5.20) for those with abnormal (DBS+/LT4+) and normal screening (DBS-/ICD+/LT4+) results, respectively. CH also was associated with lower result on the national tests, especially in mathematics. These associations remained in the sibling analyses. CONCLUSIONS: Youth with CH had slightly lower school achievements compared with those without CH and compared with their siblings. CH children with a normal screening result, and thus diagnosed later, presented the lowest results on grade point sum and national tests.

Infant lung function and early skin barrier impairment in the development of asthma at age 3 years.

BACKGROUND: Largely unexplored, we investigated if lower lung function, impaired skin barrier function by transepidermal water loss (TEWL), eczema, and filaggrin (FLG) mutations in infancy were associated with asthma in early childhood. METHODS: From the factorially designed randomized controlled intervention study PreventADALL, we evaluated 1337/2394 children from all randomization groups with information on asthma at age 3 years, and at age 3 months either lung function, TEWL, eczema, and/or FLG mutations. Lower lung function was defined as the time to peak tidal expiratory flow to expiratory time (tPTEF /tE ) <0.25, and skin barrier impairment as a high TEWL >9.50 g/m2 /h. Eczema was clinically observed, and DNA genotyped for FLG mutations. Asthma was defined as asthma-like symptoms (≥3 episodes of bronchial obstruction) between age 2-3 years as well as a history of doctor-diagnosed asthma and/or asthma medication use. Associations were analyzed in logistic regression models, presented with adjusted ORs (aOR) and 95% confidence intervals (CI). RESULTS: Lower lung function and skin barrier impairment were associated with asthma in general; aOR (95% CI) 5.4 (2.1, 13.7) and 1.6 (1.1, 2.5), while eczema and FLG mutations were associated with asthma in children with atopic dermatitis or allergic sensitization only. Stratifying for sex, the risk of asthma was only increased in boys with lower lung function; aOR (95% CI) 7.7 (2.5, 23.6), and in girls with FLG mutations; aOR (95% CI) 3.5 (1.5, 8.2). CONCLUSION: Lower lung function and impaired skin barrier function in infancy may increase the risk of asthma at age 3 years.

Maternal mental health disorders and offspring asthma and allergic diseases: The role of child mental health.

BACKGROUND: Maternal psychological stress during pregnancy and postnatally has been shown to be associated with offspring atopic diseases (asthma, atopic dermatitis and allergic rhinitis). The aim of this study was to assess whether this association may be attributable to the child's own mental health disorders. METHOD: The study population included 15,092 twin children born 2002-2010 in Sweden. Questionnaire data at age 9 years was linked to national patient- and prescription registers. Maternal mental health during pregnancy and 3 years postnatally were identified from diagnosis and medication data (depression, anxiety and stress disorders). Atopic diseases in children were identified from questionnaires, diagnosis and medication data. Child mental health status (depression and anxiety) was identified from questionnaires. Three-way decomposition methods tested for mediation or interaction by child mental health disorders. RESULTS: Maternal mental health disorders were associated with most child atopic diseases including asthma aRR1.36 (95% CI 1.12, 1.60), and child mental health disorders, aRR1.73 (95% CI 1.56, 1.92). Children with mental health disorders were comorbid for atopic diseases with only asthma reaching statistical significance, aRR1.29 (95% CI 1.14, 1.47). Three-way decomposition found that mediation or interaction by child mental health disorders did not account for the mother mental health and child atopy associations except in parent-report asthma, where child mental health disorders mediated 13.4% (95% CI 2.1, 24.7) of the effect, but not for objectively defined (diagnosis and medication) asthma. CONCLUSION: The associations between maternal mental health and child asthma and allergic diseases do not appear to be attributable to child mental health disorders.

Genetic meta-analysis of twin birth weight shows high genetic correlation with singleton birth weight.

Birth weight (BW) is an important predictor of newborn survival and health and has associations with many adult health outcomes, including cardiometabolic disorders, autoimmune diseases and mental health. On average, twins have a lower BW than singletons as a result of a different pattern of fetal growth and shorter gestational duration. Therefore, investigations into the genetics of BW often exclude data from twins, leading to a reduction in sample size and remaining ambiguities concerning the genetic contribution to BW in twins. In this study, we carried out a genome-wide association meta-analysis of BW in 42 212 twin individuals and found a positive correlation of beta values (Pearson's r = 0.66, 95% confidence interval [CI]: 0.47-0.77) with 150 previously reported genome-wide significant variants for singleton BW. We identified strong positive genetic correlations between BW in twins and numerous anthropometric traits, most notably with BW in singletons (genetic correlation [rg] = 0.92, 95% CI: 0.66-1.18). Genetic correlations of BW in twins with a series of health-related traits closely resembled those previously observed for BW in singletons. Polygenic scores constructed from a genome-wide association study on BW in the UK Biobank demonstrated strong predictive power in a target sample of Dutch twins and singletons. Together, our results indicate that a similar genetic architecture underlies BW in twins and singletons and that future genome-wide studies might benefit from including data from large twin registers.

Understanding the relationship between asthma and autism spectrum disorder: a population-based family and twin study.

BACKGROUND: There is some evidence that autism spectrum disorder (ASD) frequently co-occurs with immune-mediated conditions including asthma. We aimed to explore the familial co-aggregation of ASD and asthma using different genetically informed designs. METHODS: We first examined familial co-aggregation of asthma and ASD in individuals born in Sweden from 1992 to 2007 (n = 1 569 944), including their full- and half-siblings (n = 1 704 388 and 356 544 pairs) and full cousins (n = 3 921 890 pairs), identified using Swedish register data. We then applied quantitative genetic modeling to siblings (n = 620 994 pairs) and twins who participated in the Child and Adolescent Twin Study in Sweden (n = 15 963 pairs) to estimate the contribution of genetic and environmental factors to the co-aggregation. Finally, we estimated genetic correlations between traits using linkage disequilibrium score regression (LDSC). RESULTS: We observed a within-individual association [adjusted odds ratio (OR) 1.33, 95% confidence interval (CI) 1.28-1.37] and familial co-aggregation between asthma and ASD, and the magnitude of the associations decreased as the degree of relatedness decreased (full-siblings: OR 1.44, 95% CI 1.38-1.50, maternal half-siblings: OR 1.28, 95% CI 1.18-1.39, paternal half-siblings: OR 1.05, 95% CI 0.96-1.15, full cousins: OR 1.06, 95% CI 1.03-1.09), suggesting shared familial liability. Quantitative genetic models estimated statistically significant genetic correlations between ASD traits and asthma. Using the LDSC approach, we did not find statistically significant genetic correlations between asthma and ASD (coefficients between -0.09 and 0.12). CONCLUSIONS: Using different genetically informed designs, we found some evidence of familial co-aggregation between asthma and ASD, suggesting the weak association between these disorders was influenced by shared genetics.

Associations of parental and perinatal factors with subsequent risk of stress-related disorders: a nationwide cohort study with sibling comparison.

Little is known about the contribution of pregnancy-related parental and perinatal factors to the development of stress-related disorders. We aimed to investigate whether parental/perinatal adversities entail higher risks of stress-related disorders in the offspring, later in life, by accounting for genetic and early environmental factors. Based on the nationwide Swedish registers, we conducted a population-based cohort study of 3,435,747 singleton births (of which 2,554,235 were full siblings), born 1973-2008 and survived through the age of 5 years. Using both population- and sibling designs, we employed Cox regression to assess the association between parental and perinatal factors with subsequent risk of stress-related disorders. We identified 55,511 individuals diagnosed with stress-related disorders in the population analysis and 37,433 in the sibling analysis. In the population-based analysis we observed increased risks of stress-related disorders among offspring of maternal/paternal age <25, single mothers, parity ≥4, mothers with BMI ≥ 25 or maternal smoking in early pregnancy, gestational diabetes, and offspring born moderately preterm (GA 32-36 weeks), or small-for-gestational-age. These associations were significantly attenuated toward null in the sibling analysis. Cesarean-section was weakly associated with offspring stress-related disorders in population [hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.06-1.12] and sibling analyses (HR 1.10, 95% CI 1.02-1.20). Our findings suggest that most of the observed associations between parental and perinatal factors and risk of stress-related disorders in the population analysis are driven by shared familial environment or genetics, and underscore the importance of family designs in epidemiological studies on the etiology of psychiatric disorders.

Association of maternal snuff use and smoking with Sudden Infant Death Syndrome: a national register study.

BACKGROUND: The aim was to study whether non-combustible nicotine (Swedish snuff) use in pregnancy is associated with elevated risk of post neonatal mortality, Sudden Infant Death Syndrome (SIDS), and Sudden Unexpected Infant Death (SUID) and to study how cessation before the antenatal booking influenced these risks. METHODS: This was a population-based register study of all infants with information on tobacco exposure in early pregnancy born in Sweden 1999-2019, n = 2,061,514. Self-reported tobacco use in early pregnancy was categorized as nonuse, snuff use, and moderate and heavy smoking. Multiple logistic regression models were used to estimate crude and adjusted odds ratios (aORs) with 95% confidence intervals (CIs). RESULTS: Maternal snuff use was associated with increased risks of post neonatal mortality, SIDS, and SUID. The risks of snuff use and moderate smoking were of similar magnitude. Heavy smoking was associated with the highest risks. Cessation of smoking and snuff use before the antenatal booking was associated with lower risks of SIDS and SUID compared to that of continuous usage. CONCLUSIONS: Maternal snuff use was associated with increased risks of post neonatal mortality, SIDS, and SUID. Nicotine is the common substance in cigarette smoke and snuff. These findings support the hypothesis that nicotine contributes to an elevated risk of SIDS. IMPACT: Maternal snuff use and smoking in early pregnancy were associated with increased risks of post neonatal mortality, SIDS, and SUID. Cessation of smoking and snuff use before the first antenatal visit was associated with reduced risks of SIDS and SUID. The common substance in cigarette smoke and snuff is nicotine. Our findings suggest that nicotine contributes to an elevated risk of SIDS and SUID. The implication of our findings is that all forms of nicotine should be avoided in pregnancy.

Mode of delivery and offspring atopic dermatitis in a Swedish nationwide study.

BACKGROUND: Atopic dermatitis is a common chronic childhood disease associated with significant morbidity and healthcare costs. There is a known association between caesarean section and asthma, but the relationship between caesarean section and offspring atopic dermatitis remains uncertain. METHODS: We conducted a register-based nationwide cohort study including children born in Sweden between January 2006 and December 2018. Data on health and socioeconomic variables were extracted from the national registers for children aged ≤5 years. Time-to-event analyses were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) adjusting for confounders and familial factors. RESULTS: 1,399,406 children were included (6,029,542 person-years at risk). Atopic dermatitis was observed in 17.2% of the 1,150,896 children born by vaginal delivery and 18.3% of the 248,510 born by caesarean section. The mean age of onset of atopic dermatitis was 2.72 years (SD 1.8). Birth by caesarean section was associated with a higher risk of atopic dermatitis (adj-HR 1.12, 95% CI: 1.10-1.14). A higher risk of atopic dermatitis was found in children born by instrumental vaginal delivery (adj-HR 1.10, 1.07-1.13); emergency caesarean section (adj-HR 1.12, 1.10-1.15), and elective caesarean section (adj-HR 1.13, 1.10-1.16) than uncomplicated vaginal delivery in children <1 year of age. Similar hazards were observed in those ≥1 year of age. In sibling control analysis, greater risks remained in children aged <1 year but not in age ≥1 year. CONCLUSIONS: In our study population, it was observed that children born by caesarean section or instrumental vaginal delivery were at higher risk of early childhood atopic dermatitis. Although familial confounding attenuates the risk in children aged ≥1 year, this was not observed in the first year of life.

The Fear of Asthma Symptoms Scale and the Asthma Behavior Checklist: preliminary validity of two novel patient reported outcome measures.

Objective: The aim of this study was to investigate the preliminary validity of two novel scales, the Fear of Asthma Symptoms scale (FAS) and the Asthma Behavior Checklist (ABC). Methods: Using cross-sectional design, data was collected online from 188 adult participants (Age 18-71 years) with a diagnosis of asthma and self-reported anxiety related to asthma, recruited through social media. Confirmatory factor analysis, internal consistency and test-retest reliability were ascertained to address validity.Results: The confirmatory factor analysis demonstrated convergent validity for both the FAS (average variance extracted; AVE=.57) and the item-reduced ABC-8 (AVE=.61) as well as divergent validity for both scales. Both scales demonstrated high internal consistency (FAS: α = 0.94; ABC-8: α = 0.92). Test-retest reliability assessed after 1 week was good (FAS: r=.85; ABC-8: r=.88).Conclusions: We observed promising psychometric properties of the FAS and the ABC-8. The two novel scales could be useful to identify excessive fear and avoidance in patients with asthma and to investigate putative mechanisms in clinical research on anxiety related to asthma. Further evaluation of psychometric properties in independent samples are needed.

Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

Early-Life Adversity Due to Bereavement and Inflammatory Diseases in the Next Generation: A Population Study in Transgenerational Stress Exposure.

Emerging evidence suggests that trauma experienced in childhood has negative transgenerational implications for offspring mental and physical health. We aimed to investigate whether early-life adversity experienced as bereavement is associated with chronic inflammatory health in offspring. The study population included 3 generations of Swedish families with a base population of 453,516 children (generation 3) born in 2001-2012. Exposure was defined as the middle generation's (generation 2) experiencing bereavement in childhood due to the death of a parent (generation 1). Outcomes in generation 3 included 2 diagnoses of inflammatory diseases, including asthma, allergic diseases, eczema, and autoimmune diseases. Survival analysis was used to identify causal pathways, including investigation of mediation by generation 2 mood disorders and socioeconomic status (SES). We found that early-life bereavement experienced by women was associated with early-onset offspring asthma (hazard ratio = 1.15, 95% confidence interval: 1.08, 1.23); mediation analysis revealed that 28%-33% of the association may be mediated by SES and 9%-20% by mood disorders. Early-life bereavement experienced by men was associated with autoimmune diseases in offspring (hazard ratio = 1.31, 95% confidence interval: 1.06, 1.62), with no evidence of mediation. In conclusion, adversity experienced early in life may contribute to an increased risk of inflammatory diseases which is partly mediated by mood disorders and SES.

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.

The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h2g = 25.6%) than for AOA (onset at ages between 20 and 60 years; h2g = 10.6%). The genetic correlation (rg) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h2g = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.

Changing genetic architecture of body mass index from infancy to early adulthood: an individual based pooled analysis of 25 twin cohorts.

BACKGROUND: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. METHODS: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. RESULTS: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. CONCLUSIONS: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.

Parental socioeconomic status and asthma in children: Using a population-based cohort and family design.

BACKGROUND: The observed association between the parental socioeconomic status (SES, measured as education/income) and asthma or wheezing in offspring may be explained by confounding of unmeasured factors (shared genes and family environment). We aimed to study the association between parental SES and asthma/wheeze using cousin comparison. METHOD: Data were collected on individuals born in Sweden 2001-2013. Parental SES (education and income) was gathered from Statistics Sweden. Asthma/wheeze was identified using national health registers. The association between parental SES at birth and incident asthma/wheeze was estimated using Cox regression also comparing differently exposed cousins. The association between parental SES at 5 years and current asthma was estimated using logistic regression. RESULTS: Included were 955,371 individuals. Mothers with compulsory school only (lowest education group) compared with those with further education (highest education group) was associated with incident asthma/wheeze below 1 year of age HRadj = 1.45 (1.38-1.52) and over 1 year of age HRadj = 1.17 (1.13-1.20). The corresponding estimates for the lowest income group were HRadj = 1.61 (1.54-1.69) and HRadj = 0.94 (0.92-0.97), respectively. In maternal cousin comparisons, the associations for asthma/wheeze over 1 year of age was HRadj = 1.21 (1.05-1.40) for compulsory school only and HRadj = 0.94 (0.84-1.07) for the lowest income group. The ORadj for current asthma at 5 years was 1.05 (1.00-1.11) for mother's compulsory school only and 0.98 (0.94-1.02) for mother's lowest income group. Results for estimates were similar for father's SES. CONCLUSION: We confirm an association between low parental SES (measured as education) and asthma/wheeze. Cousin comparison suggests that this association is not wholly due to confounding of unknown familial factors, therefore supporting a causal relationship. The relationship between parental income and asthma/wheeze is less clear. This study is important for understanding risk factors for asthma/wheeze and for future prevention strategies. Further research is warranted to investigate the possible mechanisms for association between parental education and asthma/wheeze.

Comorbidity of atopic diseases and gastro-oesophageal reflux: evidence of a shared cause.

INTRODUCTION: Gastro-oesophageal reflux disease (GERD) is the most common non-allergic comorbidity in adults with asthma; however, comorbidity with other atopic diseases such as eczema and hay fever is unclear. The objective was to assess the comorbidity of GERD with asthma and atopic diseases and to investigate possible mechanisms, including genetic and/or affective factors. METHODS: A co-twin control study harnessing 46 583 adult twins. Questionnaires on health status were linked to national patient and prescribed drug register data. Analyses tested associations of comorbidity between multiple definitions of atopic diseases (self-report and register-based) with GERD. Comparisons were made between unpaired, monozygotic (MZ) and dizygotic (DZ) twins to assess genetic liability. Affective traits (depression, anxiety and neuroticism) were added to models as possible explanatory factors. RESULTS: The risk of GERD in those with asthma was OR (odds ratio) 1.52 (95% CI 1.38, 1.68), hay fever OR 1.22 (95%CI 1.12, 1.34) and eczema OR 1.23 (95%CI 1.10, 1.38). Adjusting for affective traits completely attenuated the comorbidity associations for hay fever and eczema with GERD, and partly for asthma with GERD. Co-twin control associations attenuated suggesting a shared cause for both GERD and atopic diseases. For example, all twins adjOR 1.32 (95%CI 1.00, 1.74), 0.97 (95% CI 0.76-1.23) and 1.11 (95%CI 0.85-1.45) for self-report asthma, hay fever and eczema with GERD respectively. CONCLUSIONS: GERD is a common comorbidity in adults with asthma, hay fever and/or eczema. We found evidence for shared mechanisms suggesting common underlying causes that may involve affective traits requiring further investigation.

Paediatric asthma and non-allergic comorbidities: A review of current risk and proposed mechanisms.

It is increasingly recognized that children with asthma are at a higher risk of other non-allergic concurrent diseases than the non-asthma population. A plethora of recent research has reported on these comorbidities and progress has been made in understanding the mechanisms for comorbidity. The goal of this review was to assess the most recent evidence (2016-2021) on the extent of common comorbidities (obesity, depression and anxiety, neurodevelopmental disorders, sleep disorders and autoimmune diseases) and the latest mechanistic research, highlighting knowledge gaps requiring further investigation. We found that the majority of recent studies from around the world demonstrate that children with asthma are at an increased risk of having at least one of the studied comorbidities. A range of potential mechanisms were identified including common early life risk factors, common genetic factors, causal relationships, asthma medication and embryologic origins. Studies varied in their selection of population, asthma definition and outcome definitions. Next, steps in future studies should include using objective measures of asthma, such as lung function and immunological data, as well as investigating asthma phenotypes and endotypes. Larger complex genetic analyses are needed, including genome-wide association studies, gene expression-functional as well as pathway analyses or Mendelian randomization techniques; and identification of gene-environment interactions, such as epi-genetic studies or twin analyses, including omics and early life exposure data. Importantly, research should have relevance to clinical and public health translation including clinical practice, asthma management guidelines and intervention studies aimed at reducing comorbidities.

Associations Between Maternal Distress, Cortisol Levels, and Perinatal Outcomes.

OBJECTIVE: Stress during pregnancy may decrease gestational age at birth and birth size. We aimed to investigate the associations between maternal subjective stress measures, salivary cortisol, and perinatal outcomes. METHODS: A cohort of pregnant women (n = 1693) was recruited from eight antenatal care clinics in Stockholm, Sweden. Questionnaires on subjective distress (perceived stress, worry, depression symptoms, sleep quality) and saliva samples for cortisol measurement (morning and evening) were collected in early and late pregnancy. Perinatal outcomes were birth weight, birth length, gestational age, and birth weight for gestational age. We used linear regression to estimate associations adjusted for maternal characteristics. RESULTS: All associations between subjective distress and cortisol levels were close to null and nonsignificant, for example, exp(ß) = 1.001 (95% confidence interval = 0.995 to 1.006) for the morning cortisol level and perceived stress in early pregnancy. Likewise, most associations between distress (subjective and cortisol) and perinatal outcomes were weak and not statistically significant, for example, ß = 1.95 (95% confidence interval = -4.16 to 8.06) for perceived stress in early pregnancy and birth weight. An exception was a statistically significant association between birth weight for gestational age and depression symptoms in early pregnancy, with somewhat higher weight with more symptoms (ß = 0.08; 95% CI = 0.04 to 0.13). The results were similar for stress in early and late pregnancy. CONCLUSIONS: We found no association between subjective distress and cortisol measures irrespective of when in pregnancy the measures were taken. Furthermore, we found no evidence for a longitudinal association between psychological measures of stress or cortisol with lower birth weight, birth weight for gestational age, or gestational age.