Cohort profile : Swedish Twin Study on Prediction and Prevention of Asthma (STOPPA)

Asthma is a common childhood disease and several risk factors have been identified, however the impact of genes and environment is not fully understood. The aim of the Swedish Twin study On Prediction and Prevention of Asthma (STOPPA) is to identify environmental (birth characteristics and early life) and genetic (including epigenetic) factors as determinants for asthmatic disease. Based on the Child and Adolescent Twin Study in Sweden (parental interview at 9 or 12 years, N~23,900) and an asthma and/or wheezing algorithm, we identified a sample of monozygotic (MZ) and dizygotic (DZ) same-sexed twin pairs. The twin pairs were identified as asthma concordant (ACC), asthma discordant (ADC) and healthy concordant (HCC). A sample of 9- to 14-year-old twins and their parents were invited to participate in a clinical examination. Background characteristics were collected in questionnaires and obtained from the National Health Registers. A clinical examination was performed to test lung function and capacity (spirometry with reversibility test and exhaled nitric oxide) and collect blood (serology and DNA), urine (metabolites), feces (microbiota) and saliva (cortisol). In total, 376 twin pairs (752 individual twins) completed the study, response rate 52%. All participating twins answered the questionnaire and >90% participated in lung function testing, blood and saliva sampling. This article describes the design, recruitment, data collection, measures, background characteristics as well as ongoing and planned analyses in STOPPA. Potential gains of the study include the identification of biomarkers, the emergence of candidates for drug development and new leads for prevention of asthma and allergic disease.NonePublishe

Heritability and the Equal Environments Assumption: Evidence from Multiple Samples of Misclassified Twins

The final publication is available at Springer via https://doi.org/10.1007/s10519-013-9602-1Classically derived estimates of heritability from twin models have been plagued by the possibility of genetic-environmental covariance. Survey questions that attempt to measure directly the extent to which more genetically similar kin (such as monozygotic twins) also share more similar environmental conditions represent poor attempts to gauge a complex underlying phenomenon of GE-covariance. The present study exploits a natural experiment to address this issue: Self-misperception of twin zygosity in the National Longitudinal Survey of Adolescent Health (Add Health). Such twins were reared under one “environmental regime of similarity” while genetically belonging to another group, reversing the typical GE-covariance and allowing bounded estimates of heritability for a range of outcomes. In addition, we examine twins who were initially misclassified by survey assignment—a stricter standard—in three datasets: Add Health, the Minnesota Twin Family Study and the Child and Adolescent Twin Study in Sweden. Results are similar across approaches and datasets and largely support the validity of the equal environments assumption

Heritability of Oral Microbiota and Immune Responses to Oral Bacteria

Maintaining a symbiotic oral microbiota is essential for oral and dental health, and host genetic factors may affect the composition or function of the oral microbiota through a range of possible mechanisms, including immune pathways. The study included 836 Swedish twins divided into separate groups of adolescents (n= 418) and unrelated adults (n= 418). Oral microbiota composition and functions of non-enzymatically lysed oral bacteria samples were evaluated using 16S rRNA gene sequencing and functional bioinformatics tools in the adolescents. Adaptive immune responses were assessed by testing for serum IgG antibodies against a panel of common oral bacteria in adults. In the adolescents, host genetic factors were associated with both the detection and abundance of microbial species, but with considerable variation between species. Host genetic factors were associated with predicted microbiota functions, including several functions related to bacterial sucrose, fructose, and carbohydrate metabolism. In adults, genetic factors were associated with serum antibodies against oral bacteria. In conclusion, host genetic factors affect the composition of the oral microbiota at a species level, and host-governed adaptive immune responses, and also affect the concerted functions of the oral microbiota as a whole. This may help explain why some people are genetically predisposed to the major dental diseases of caries and periodontitis

A New Method for Detecting Associations with Rare Copy-Number Variants

Copy number variants (CNVs) play an important role in the etiology of many diseases such as cancers and psychiatric disorders. Due to a modest marginal effect size or the rarity of the CNVs, collapsing rare CNVs together and collectively evaluating their effect serves as a key approach to evaluating the collective effect of rare CNVs on disease risk. While a plethora of powerful collapsing methods are available for sequence variants (e.g., SNPs) in association analysis, these methods cannot be directly applied to rare CNVs due to the CNV-specific challenges, i.e., the multi-faceted nature of CNV polymorphisms (e.g., CNVs vary in size, type, dosage, and details of gene disruption), and etiological heterogeneity (e.g., heterogeneous effects of duplications and deletions that occur within a locus or in different loci). Existing CNV collapsing analysis methods (a.k.a. the burden test) tend to have suboptimal performance due to the fact that these methods often ignore heterogeneity and evaluate only the marginal effects of a CNV feature. We introduce CCRET, a random effects test for collapsing rare CNVs when searching for disease associations. CCRET is applicable to variants measured on a multi-categorical scale, collectively modeling the effects of multiple CNV features, and is robust to etiological heterogeneity. Multiple confounders can be simultaneously corrected. To evaluate the performance of CCRET, we conducted extensive simulations and analyzed large-scale schizophrenia datasets. We show that CCRET has powerful and robust performance under multiple types of etiological heterogeneity, and has performance comparable to or better than existing methods when there is no heterogeneity

A genome-wide association study of the frailty index highlights brain pathways in ageing

Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60–70 years) and Swedish TwinGene participants (n = 10,616, 41–87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10−8). Many FI-associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on pathways in the brain

Examining neurodevelopmental problems in 15q11.2 ( BP1‐BP2 ) copy number variation carriers at ages 9/12 and 18 in a Swedish twin sample

Background: Several copy number variations (CNVs) are associated with increased risk for neurodevelopmental and psychiatric disorders. The CNV 15q11.2 (BP1‐BP2) deletion has been associated with learning difficulties, attention deficit hyperactivity disorder (ADHD), epilepsy, and brain morphology; however, many carriers present mild or no symptoms. Carrying the reciprocal duplication does not seem to confer risk for these disorders or traits. Our aim was to examine the impact of carrying either 15q11.2 deletion and reciprocal duplication on neurodevelopmental problems in a population‐based sample of children. Methods: Twins with genotype and phenotype information in the Child and Adolescent Twin Study in Sweden (CATSS) were included (N = 12,040). We included measures of neurodevelopmental problems (NDPs), including learning problems, from the questionnaire Autism–Tics, ADHD, and other Comorbidities inventory (A‐TAC) at age 9/12, ADHD and autism spectrum disorder (ASD) questionnaires at age 18, as well as information about lifetime psychiatric diagnoses and epileptic seizures. We tested the association between these phenotypic measurements and carrying the 15q11.2 deletion, the reciprocal duplication, and other CNVs with previously reported strong associations with neurodevelopmental and psychiatric disorders (i.e., psychiatric CNVs). Results: We identified 57 carriers of the 15q11.2 deletion, 75 carriers of the reciprocal duplication, and 67 carriers of other psychiatric CNVs. We did not find an increased risk for NDPs or psychiatric diagnoses in the 15q11.2 deletion carriers. For 15q11.2 duplication carriers, we found an increased risk for math learning problems and fewer self‐reported ADHD symptoms at age 18 but not for other NDPs. In line with previous studies, we found an increased risk of NDPs and other evaluated phenotypes in carriers of psychiatric CNVs. Conclusions: Our results support previous findings that carrying 15q11.2 deletion does not have a large effect on NDPs in children

Most Reported Genetic Associations with General Intelligence Are Probably False Positives

General intelligence (g) and virtually all other behavioral traits are heritable. Associations between g and specific single-nucleotide polymorphisms (SNPs) in several candidate genes involved in brain function have been reported. We sought to replicate published associations between g and 12 specific genetic variants (in the genes DTNBP1, CTSD, DRD2, ANKK1, CHRM2, SSADH, COMT, BDNF, CHRNA4, DISC1, APOE, and SNAP25) using data sets from three independent, well-characterized longitudinal studies with samples of 5,571, 1,759, and 2,441 individuals. Of 32 independent tests across all three data sets, only 1 was nominally significant. By contrast, power analyses showed that we should have expected 10 to 15 significant associations, given reasonable assumptions for genotype effect sizes. For positive controls, we confirmed accepted genetic associations for Alzheimer’s disease and body mass index, and we used SNP-based calculations of genetic relatedness to replicate previous estimates that about half of the variance in g is accounted for by common genetic variation among individuals. We conclude that the molecular genetics of psychology and social science requires approaches that go beyond the examination of candidate genes.Economic

Utilizing Twins as Controls for Non-Twin Case-Materials in Genome Wide Association Studies

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Utilizing Twins as Controls for Non-Twin Case-Materials in Genome Wide Association Studies

Twin registries around the globe have collected DNA samples from large numbers of monozygotic and dizygotic twins. The twin sample collections are frequently used as controls in disease-specific studies together with non-twins. This approach is unbiased under the hypothesis that twins and singletons are comparable in terms of allele frequencies; i.e. there are no genetic variants associated with being a twin per se. To test this hypothesis we performed a genome-wide association study comparing the allele frequency of 572,352 single nucleotide polymorphisms (SNPs) in 1,413 monozygotic (MZ) and 5,451 dizygotic (DZ) twins with 3,720 healthy singletons. Twins and singletons have been genotyped using the same platform. SNPs showing association with being a twin at P-value < 1 × 10-5 were selected for replication analysis in 1,492 twins (463 MZ and 1,029 DZ) and 1,880 singletons from Finland. No SNPs reached genome-wide significance (P-value < 5 × 10-8) in the main analysis combining MZ and DZ twins. In a secondary analysis including only DZ twins two SNPs (rs2033541 close to ADAMTSL1 and rs4149283 close to ABCA1) were genome-wide significant after meta-analysis with the Finnish population. The estimated proportion of variance on the liability scale explained by all SNPs was 0.08 (P-value=0.003) when MZ and DZ were considered together and smaller for MZ (0.06, P-value=0.10) compared to DZ (0.09, P-value=0.003) when analyzed separately. In conclusion, twins and singletons can be used in genetic studies together with general population samples without introducing large bias. Further research is needed to explore genetic variances associated with DZ twinning

Mental health indicators in Sweden over a 12-month period during the COVID-19 pandemic – Baseline data of the Omtanke2020 Study

Funding Information: This study was funded with grants from NordForsk (CovidMent, 105668 ), Horizon 2020 (CoMorMent, 847776 ), and the Karolinska Institutet . Funding Information: The Omtanke2020 study is supported by NordForsk (project No. 105668 ) and Karolinska Institute (Strategic Research Area in Epidemiology and Senior Researcher Award). We acknowledge The Swedish Twin Registry for access to contact information to participating twins. The Swedish Twin Registry is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no 2017-00641. The Funding Sources had no direct or indirect impact on the analysis and interpretation of the results. Publisher Copyright: © 2022 The AuthorsBackground: The ongoing COVID-19 pandemic has had an unprecedented impact on the lives of people globally and is expected to have profound effects on mental health. Here we aim to describe the mental health burden experienced in Sweden using baseline data of the Omtanke2020 Study. Method: We analysed self-reported, cross-sectional baseline data collected over a 12-month period (June 9, 2020–June 8, 2021) from the Omtanke2020 Study including 27,950 adults in Sweden. Participants were volunteers or actively recruited through existing cohorts and, after providing informed consent, responded to online questionnaires on socio-demographics, mental and physical health, as well as COVID-19 infection and impact. Poisson regression was fitted to assess the relative risk of demonstrating high level symptoms of depression, anxiety, and COVID-19 related distress. Result: The proportion of persons with high level of symptoms was 15.6 %, 9.5 % and 24.5 % for depression, anxiety, and COVID-19 specific post-traumatic stress disorder (PTSD), respectively. Overall, 43.4 % of the participants had significant, clinically relevant symptoms for at least one of the three mental health outcomes and 7.3 % had significant symptoms for all three outcomes. We also observed differences in the prevalence of these outcomes across strata of sex, age, recruitment type, COVID-19 status, region, and seasonality. Conclusion: While the proportion of persons with high mental health burden remains higher than the ones reported in pre-pandemic publications, our estimates are lower than previously reported levels of depression, anxiety, and PTSD during the pandemic in Sweden and elsewhere.Peer reviewe