Swedish Twin Registry Research Articles

DEMENTIA AFTER SURGERY IN SWEDEN

There is currently a controversy regarding the longterm impact of major surgery on subsequent cognitive performance and risk for dementia. A nested case-control study was performed within the population-based Swedish Twin Registry (STR) based on two samples of individuals: a clinical sample with individuals with a diagnosis of dementia based on clinical assessment within STR studies, and a register sample with dementia diagnosis retrieved from the Swedish National Patient Registry (NPR), Cause of death registry and Prescribed drug registry. All dementia cases were matched with 5 non-demented individuals and combined with information on hospitalizations and surgical procedures recorded in the NPR between 1977-2012. Hospitalizations for surgical or non-surgical conditions are associated with increased risk for dementia, however, hospitalizations for non-surgical reasons or critical illness are associated with a markedly higher risk for dementia than for surgical procedures. The risks of dementia increased with increasing number of non-surgical hospitalizations, and were significant 10 to 20 years past hospitalization. There was no increased risk with surgery after 80 years of age, which may reflect selection bias. Patients and providers should be more concerned about the consequences of repeated hospitalizations or critical illness than about surgery as a major risk factor for dementia.

The association between attention-deficit/hyperactivity (ADHD) symptoms and self-employment.

Attention-deficit/hyperactivity (ADHD) symptoms have been associated with the decision to become self-employed. Although these symptoms are generally regarded as disadvantageous, there may also be a bright side. To our knowledge, however, there has been no systematic, epidemiological evidence to support this claim. This paper examines the association between ADHD symptoms and self-employment in a population-based sample from the STAGE cohort of the Swedish Twin Registry (N = 7208). For replication, we used a sample of Dutch students who participated in the Global University Entrepreneurial Spirit Students’ Survey (N = 13,112). In the Swedish sample, we found a positive association with self-employment for both general ADHD symptoms [odds ratio (OR) 1.13; 95 % confidence intervals (CI) 1.04–1.23] and hyperactivity symptoms [OR 1.19; 95 % CI 1.08–1.32], whereas no association was found for attention-deficit symptoms [OR 0.99; 95 % CI 0.89–1.10]. The positive association between hyperactivity and self-employment was replicated in the Dutch student sample [OR 1.09; 95 % CI 1.03–1.15]. Our results show that certain aspects of ADHD, in particular hyperactivity, can have a bright side, as they are positively associated with self-employment.

A general method for decomposing the causes of socioeconomic inequality in health

We introduce a general decomposition method applicable to all forms of bivariate rank dependent indices of socioeconomic inequality in health, including the concentration index. The technique is based on recentered influence function regression and requires only the application of OLS to a transformed variable with similar interpretation. Our method requires few identifying assumptions to yield valid estimates in most common empirical applications, unlike current methods favoured in the literature. Using the Swedish Twin Registry and a within twin pair fixed effects identification strategy, our new method finds no evidence of a causal effect of education on income-related health inequality.

Genetic overlap between type 2 diabetes and depression in Swedish and Danish twin registries.

A bidirectional association between type 2 diabetes (T2DM) and depression has been consistently reported. Depression is associated with worse biomedical outcomes and increased mortality. The mechanisms underlying the association of T2DM with depression remain unclear. One possible question we can address is the extent to which the co-occurrence of diabetes and depression is due to correlated genetic and/or environmental risk factors. In this study, we performed structural equation model fitting to population-level data from the Swedish (n=68 606) and Danish (n=95 403) twin registries. The primary outcomes were clinical diagnosis of T2DM and depression using national hospital discharge registries. The phenotypic correlation between T2DM and depression is modest in both samples. In the Swedish sample, unique environmental effects explain a greater proportion of the covariance in males, whereas the association is primarily attributed to genetic effects in females. In the Danish sample, genetic effects account for the majority of the covariance in both males and females. Qualitative genetic sex differences are observed in both samples. We believe this is the first study to demonstrate significant genetic overlap between T2DM and depression.

Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women.

A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

Multidimensional assessment of impulsivity in schizophrenia, bipolar disorder, and major depressive disorder: testing for shared endophenotypes.

Impulsivity is associated with bipolar disorder as a clinical feature during and between manic episodes and is considered a potential endophenotype for the disorder. Schizophrenia and major depressive disorder share substantial genetic overlap with bipolar disorder, and these two disorders have also been associated with elevations in impulsivity. However, little is known about the degree of overlap among these disorders in discrete subfacets of impulsivity and whether any overlap is purely phenotypic or due to shared genetic diathesis. We focused on five subfacets of impulsivity: self-reported attentional, motor, and non-planning impulsivity, self-reported sensation seeking, and a behavioral measure of motor inhibition (stop signal reaction time; SSRT). We examined these facets within and across disorder proband and co-twin groups, modeled heritability, and tested for endophenotypic patterning in a sample of twin pairs recruited from the Swedish Twin Registry (N = 420). We found evidence of moderate to high levels of heritability for all five subfacets. All three proband groups and their unaffected co-twins showed elevations on attentional, motor, and non-planning impulsivity. Schizophrenia probands (but not their co-twins) showed significantly lower sensation seeking, and schizophrenia and bipolar disorder probands (but not in their co-twins) had significantly longer SSRTs, compared with healthy controls and the other groups. Attentional, motor, and non-planning impulsivity emerged as potential shared endophenotypes for the three disorders, whereas sensation seeking and SSRT were associated with phenotypic affection but not genetic loading for these disorders.

Somatic Comorbidity in Women with Overactive Bladder Syndrome

We explore the influence of co-occurring somatic illnesses on prevalent overactive bladder in women of premenopausal age. Data for the present study were derived from a nationwide survey on complex diseases among all twins in the Swedish Twin Registry born 1959 to 1985. The present study was limited to female twins participating in the survey (12,850). Generalized estimating equations were used to estimate odds ratios with 95% CIs. Environmental and genetic influences were assessed in co-twin control analysis. Generalized estimating equations analysis showed a significant association between overactive bladder and migraine (OR 1.34, 95% CI 1.15-1.57), fibromyalgia (1.83, 1.54-2.18), chronic fatigue (1.81, 1.49-2.19) and eating disorders (1.56, 1.24-1.96). There was also a significant association with allergic disorders including asthma (1.24, 1.01-1.52) and eczema (1.22, 1.04-1.43). Among reproductive disorders, urinary tract infections (1.60, 1.40-1.84), dysmenorrhea (1.53, 1.33-1.76) and pelvic pain (1.60, 1.31-1.94) showed the strongest association with overactive bladder. Results from co-twin control analysis indicated that the significant associations observed in generalized estimating equations analysis were influenced by environmental and genetic factors without a common pathway model. Our results suggest a multifactorial and complex pathogenesis of overactive bladder in which associations between various somatic illnesses and overactive bladder may be affected by environmental and genetic factors.

Self-reported psychological demands, skill discretion and decision authority at work: A twin study.

To examine the contribution of genetic factors to self-reported psychological demands (PD), skill discretion (SD) and decision authority (DA) and the possible importance of such influence on the association between these work variables and depressive symptoms. 11,543 participants aged 27-54 in the Swedish Twin Registry participated in a web survey. First of all, in multiple regressions, phenotypic associations between each one of the three work environment variables and depressive symptoms were analysed. Secondly, by means of classical twin analysis, the genetic contribution to PD, SD and DA was assessed. After this, cross-twin cross-trait correlations were computed between PD, SD and DA, on the one hand, and depressive symptom score, on the other hand. The genetic contribution to self-reported PD, DS and DA ranged from 18% for decision authority to 30% for skill discretion. Cross-twin cross-trait correlations were very weak (r values < .1) and non-significant for dizygotic twins, and we lacked power to analyse the genetic architecture of the phenotypic associations using bivariate twin modelling. However, substantial genetic contribution to these associations seems unlikely. CONCLUSIONS GENETIC CONTRIBUTIONS TO THE SELF-REPORTED WORK ENVIRONMENT SCORES WERE 18-30%.

Applying the demand-control-support model on burnout in managers and non-managers

Purpose – The purpose of this paper is to study the demand-control-support (DCS) model on burnout in male and female managers and non-managers, taking into account genetic and shared family environmental factors, contributing to the understanding of mechanisms of how and when work stress is related to burnout. Design/methodology/approach – A total of 5,510 individuals in complete same-sex twin pairs from the Swedish Twin Registry were included in the analyses. Co-twin control analyses were performed using linear mixed modeling, comparing between-pairs and within-pair effects, stratified by zygosity and sex. Findings – Managers scored higher on demands and control in their work than non-managers, and female managers seem to be particularly at risk for burnout facing more demands which are not reduced by a higher control as in their male counterparts. Co-twin analyses showed that associations between control and burnout as well as between demands and burnout seem to be affected by shared family environmental factors in male non-managers but not in male managers in which instead the associations between social support and burnout seem to be influenced by shared family environment. Practical implications – Taken together, the study offers knowledge that shared environment as well as sex and managerial status are important factors to consider in how DCS is associated to exhaustion. Originality/value – Using twin data with possibilities to control for genetics, shared environment, sex and age, this study offers unique insight into the DCS research, which focusses primarily on the workplace environment rather than individual factors.

Risks of Myocardial Infarction, Death, and Diabetes in Identical Twin Pairs With Different Body Mass Indexes.

Observational studies have shown that obesity is a major risk factor for cardiovascular disease and death. The extent of genetic confounding in these associations is unclear. To compare the risk of myocardial infarction (MI), type 2 diabetes, and death in monozygotic (MZ) twin pairs discordant for body mass index (BMI). A cohort of 4046 MZ twin pairs with discordant BMIs (difference >0.01) was identified using the nationwide Swedish twin registry. The study was conducted from March 17, 1998, to January 16, 2003, with follow-up regarding incident outcomes until December 31, 2013. The combined primary end point of death or MI and the secondary end point of incident diabetes were evaluated in heavier compared with leaner twins in a co-twin control analysis using multivariable conditional logistic regression. Mean (SD) baseline age for both cohorts was 57.6 (9.5) years (range, 41.9-91.8 years). During a mean follow-up period of 12.4 (2.5) years, 203 MIs (5.0%) and 550 deaths (13.6%) occurred among heavier twins (mean [SD] BMI, 25.9 [3.6] [calculated as weight in kilograms divided by height in meters squared]) compared with 209 MIs (5.2%) and 633 deaths (15.6%) among leaner twins (mean [SD] BMI, 23.9 [3.1]; combined multivariable adjusted odds ratio [OR], 0.75; 95% CI, 0.63-0.91). Even in twin pairs with BMI discordance of 7.0 or more (mean [SE], 9.3 [0.7]), where the heavier twin had a BMI of 30.0 or more (n = 65 pairs), the risk of MI or death was not greater in heavier twins (OR, 0.42; 95% CI, 0.15-1.18). In contrast, in the total cohort of twins, the risk of incident diabetes was greater in heavier twins (OR, 2.14; 95% CI, 1.61-2.84). Finally, increases in BMI since 30 years before baseline were not associated with the later risk of MI or death (OR, 0.97; 95% CI, 0.89-1.05) but were associated with the risk of incident diabetes (OR, 1.13; 95% CI, 1.01-1.26). In MZ twin pairs, higher BMI was not associated with an increased risk of MI or death but was associated with the onset of diabetes. These results may suggest that lifestyle interventions to reduce obesity are more effective in decreasing the risk of diabetes than the risk of cardiovascular disease or death.

Protective effect of HLA-DRB1*13 alleles during specific phases in the development of ACPA-positive RA

ObjectiveHuman leucocyte antigen (HLA)-DRB1*13 alleles are associated with protection from anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). It is, however, unknown at which phase of disease development (seroconversion, ACPA maturation,...

Antemortem Prediction of Braak Stage.

We examined the extent to which tauopathy distribution, as determined by Braak staging, might be predicted by various risk factors in older individuals. The Swedish Twin Registry provided extensive information on neuropsychological function, lifestyle, and cardiovascular risk factors of 128 patients for whom autopsy data including Braak staging were available. Logistic regression was used to develop a prognostic model that targeted discrimination between Braak stages 0 to II and III to VI. The analysis showed that Braak stages III to VI were significantly predicted by having 1 or more APOE ε4 alleles, older age, high total cholesterol, absence of diabetes and cardiovascular disease, and poorer scores on the Wechsler Adult Intelligence Score Information test, verbal fluency, and recognition memory but better verbal recall. The algorithm predicted Braak stages III to VI well (receiver-operating characteristic area under curve, 0.897; 95% confidence interval, 0.842-0.951). Using a cutoff of 50% risk or more, the sensitivity was 85%, the specificity was 70%, and the negative predictive value was 69%. This study demonstrates that tauopathy distribution can be accurately predicted using a combination of antemortem patient data. These results provide further insight into tauopathy development and AD-related disease mechanisms and suggest a prognostic model that predicts the spread of neurofibrillary tangles above the transentorhinal stage.

A Swedish Population-Based Multivariate Twin Study of Externalizing Disorders

In epidemiological and twin populations, prior interview studies have identified an externalizing spectrum of disorders. Could this be detected utilizing objective registry data? In 20,603 twin pairs from the Swedish Twin Registry, we obtained information from national medical, criminal and pharmacy records on drug abuse (DA), criminal behavior (CB) and alcohol use disorders (AUD). Multivariate twin modeling was performed with the OpenMx package. A common pathway model with quantitative but not qualitative sex effects fit best with twin resemblance for the latent liability to externalizing syndromes due to both genetic and shared environmental factors. Heritability of the liability was higher in females (76 vs. 62%) while shared environmental influences were considerably stronger in males (23 vs. 3%). In both sexes, this latent liability was most strongly indexed by DA and least by CB. All three syndromes had specific genetic influences (especially CB and AUD in males, and CB in females) and specific shared environmental effects (especially DA and CB in males, and AUD in females). For DA, CB and AUD in men, and DA and AUD in women, at least 75% of the genetic risk arose through the common factor. The best fit model assumed that genetic and environmental influences on these externalizing syndromes in males and females were the same. We identified, in registry data, a highly heritable externalizing spectrum. DA, CB and AUD share substantial genetic and modest to moderate shared environmental influences. The nature of the externalizing spectrum differed meaningfully between the sexes.

Etiological overlap between obsessive‐compulsive disorder and anorexia nervosa: a longitudinal cohort, multigenerational family and twin study

Obsessive-compulsive disorder (OCD) often co-occurs with anorexia nervosa (AN), a comorbid profile that complicates the clinical management of both conditions. This population-based study aimed to examine patterns of comorbidity, longitudinal risks, shared familial risks and shared genetic factors between OCD and AN at the population level. Participants were individuals with a diagnosis of OCD (N=19,814) or AN (N=8,462) in the Swedish National Patient Register between January 1992 and December 2009; their first-, second- and third-degree relatives; and population-matched (1:10 ratio) unaffected comparison individuals and their relatives. Female twins from the population-based Swedish Twin Register (N=8,550) were also included. Females with OCD had a 16-fold increased risk of having a comorbid diagnosis of AN, whereas males with OCD had a 37-fold increased risk. Longitudinal analyses showed that individuals first diagnosed with OCD had an increased risk for a later diagnosis of AN (risk ratio, RR=3.6), whereas individuals first diagnosed with AN had an even greater risk for a later diagnosis of OCD (RR=9.6). These longitudinal risks were about twice as high for males than for females. First- and second-degree relatives of probands with OCD had an increased risk for AN, and the magnitude of this risk tended to increase with the degree of genetic relatedness. Bivariate twin models revealed a moderate but significant degree of genetic overlap between self-reported OCD and AN diagnoses (ra =0.52, 95% CI: 0.26-0.81), but most of the genetic variance was disorder-specific. The moderately high genetic correlation supports the idea that this frequently observed comorbid pattern is at least in part due to shared genetic factors, though disorder-specific factors are more important. These results have implications for current gene-searching efforts and for clinical practice.

Genetic Differences Between Perinatal and Nonperinatal Depression

Although many etiologically heterogeneous conditions are often lumped together as major depressive disorder, teasing apart these pathogenically discrete entities could be enlightening. In this largest-ever study, investigators conducted two analyses to assess the heritability of perinatal versus nonperinatal depression. The first study relied on Swedish Twin Registry data from some 1500 monozygotic and 1900 same-sex dizygotic female twins; the second employed a sibling …

Importance of Cohort Study in Military Medicine: An International Overview

Observational studies have a great place in the modern research. Randomized controlled trials are not always the best choice or ethical solution to address some research questions in military medicine. Moreover, the validity of small size sampled cross-sectional and casecontrol studies, which usually lack quality control and use paper base questionnaires for main data collection, are under question. Mostly, the results of these small studies are not practical and confined to the shelves of libraries. On the other hand, a well-defined cohort study with combination of questionnaires and biologic sample for data collection, even with small sample size, can provide strong and valid results (1). In a classical cohort study, first a disease-free population is identified by the status of exposure of interest and followed during time until the disease of interest happens. The military environment provides unique opportunity for cohort studies on military personnel and students. Because this population is always available, follow up is easy, and medical documents are collected in recruitment time. In the first stage, with standardization of routine data collection forms and in advanced stages with collecting biologic samples, the possibility of cohort studies is provided. The importance of cohort studies in military population is growing worldwide. Our electronic search in PubMed database shows the growing trend of publications that mentioned ‘military’ and ‘cohort’ words in their title and abstract. Figure 1 shows the number of publications (across time) that mentioned the cohort study design and military related health issue in the world. The figure shows significant jump in the number of publication since 2002. Also, as the number of published papers may be biased criteria for scientometrics, we plotted the median of citation time of published papers during 50 years for military related publications with cohort design (worldwide) compared to the published articles from Swedish Twin Registry (one of the largest studies in the field of medical sciences) (Figure 2).

Engagement in dance is associated with emotional competence in interplay with others.

This study has explored the relation between dance achievement and alexithymia in a larger Swedish population sample (Swedish Twin Registry) with a study sample of 5431 individuals. Dance achievement (CAQ) was assessed in relation to Alexithymia (Toronto Alexithymia Scale, TAS-20) including the three subscales: Difficulty Identifying Feelings (DIF), Difficulty Describing Feelings (DDF), and Externally Oriented Thinking (EOT). The results show a significant negative association between the TAS subscale (EOT) and creative achievement in dance. A high EOT score corresponds to poor ability to communicate feelings to the environment. There was no consistent association between the other factors DIF and DDF and dance achievement. Dance activity and training seem to be involved in the body’s emotional interplay with others. Embodied cognition, emotional perception, and action are discussed as factors relevant to measuring the skill of a dancer.

The association between intelligence and lifespan is mostly genetic.

Background: Several studies in the new field of cognitive epidemiology have shown that higher intelligence predicts longer lifespan. This positive correlation might arise from socioeconomic status influencing both intelligence and health; intelligence leading to better health behaviours; and/or some shared genetic factors influencing both intelligence and health. Distinguishing among these hypotheses is crucial for medicine and public health, but can only be accomplished by studying a genetically informative sample. Methods: We analysed data from three genetically informative samples containing information on intelligence and mortality: Sample 1, 377 pairs of male veterans from the NAS-NRC US World War II Twin Registry; Sample 2, 246 pairs of twins from the Swedish Twin Registry; and Sample 3, 784 pairs of twins from the Danish Twin Registry. The age at which intelligence was measured differed between the samples. We used three methods of genetic analysis to examine the relationship between intelligence and lifespan: we calculated the proportion of the more intelligent twins who outlived their co-twin; we regressed within-twin-pair lifespan differences on within-twin-pair intelligence differences; and we used the resulting regression coefficients to model the additive genetic covariance. We conducted a meta-analysis of the regression coefficients across the three samples. Results: The combined (and all three individual samples) showed a small positive phenotypic correlation between intelligence and lifespan. In the combined sample observed r = .12 (95% confidence interval .06 to .18). The additive genetic covariance model supported a genetic relationship between intelligence and lifespan. In the combined sample the genetic contribution to the covariance was 95%; in the US study, 84%; in the Swedish study, 86%, and in the Danish study, 85%. Conclusions: The finding of common genetic effects between lifespan and intelligence has important implications for public health, and for those interested in the genetics of intelligence, lifespan or inequalities in health outcomes including lifespan.

Coping Styles in Twins Discordant for Schizophrenia, Bipolar Disorder, and Depression.

Schizophrenia, bipolar disorder, and major depression share several clinical and etiological factors. Coping is a critical mediator of the relationship between stress and psychopathology and a point of clinical intervention for all three disorders. However, little is known about their degree of overlap in coping style, or the influence of unique or shared genetic diathesis. In this study, we examined five factors of coping within and across disorder proband and co-twin groups, modeled heritability, and tested for endophenotypic pattern in a sample of twin pairs recruited from the Swedish Twin Registry (N = 420). Although there was substantial phenotypic overlap across disorders, including low levels of Productive, Problem-Focused coping and high levels of Disengagement, each disorder was associated with a unique profile across other dimensions of coping. We also found evidence of heritability for three of five factors, yet little evidence of genotypic overlap among disorders contributing to similar strategy-use.

Personality traits and the risk for Parkinson disease: a prospective study.

In this study, we explored the association between the personality traits, neuroticism and introversion, and risk of Parkinson disease (PD). A population-based cohort study was conducted using questionnaire data from the Swedish Twin Registry for twins born 1926–1958 (n > 29,000). Personality traits were assessed in 1973 by a short form of Eysenck’s Personality Inventory. The cohort was followed from 1974 to 2012 through Swedish patient and cause of death registers for PD ascertainment. Cox proportional hazards regression was used to estimate subsequent risk of PD, adjusting for attained age, sex and smoking. A mediation analysis was performed to further explore the role of smoking in the relationship between personality trait and PD. Confounding by familial factors was explored using a within-pair analysis. During a mean follow-up time of 36.8 years, 197 incident PD cases were identified. Both neuroticism and introversion were associated with an increased risk of PD after adjustment. Smoking was a significant mediator in the relationship between personality traits and PD that partly accounted for the effect of introversion, whereas it acted as a suppressor for the effect of neuroticism on PD risk. In the within-pair analyses, associations for neuroticism and introversion were attenuated. In conclusion, our study provides evidence that neuroticism is associated with an increased risk of PD that is in part suppressed by smoking. There was a weak association between introversion and PD and this effect was at least partly mediated through smoking. The observed effects may partly be explained by familial factors shared by twins.