Swedish Twin Registry Research Articles

Polygenic Risk Scores and Twin Concordance for Schizophrenia and Bipolar Disorder

Schizophrenia and bipolar disorder are highly heritable psychiatric disorders with strong genetic and phenotypic overlap. Twin and molecular methods can be leveraged to predict the shared genetic liability to these disorders. To investigate whether twin concordance for psychosis depends on the level of polygenic risk score (PRS) for psychosis and zygosity and compare PRS from cases and controls from several large samples and estimate the twin heritability of psychosis. In this case-control study, psychosis PRS were generated from a genome-wide association study (GWAS) combining schizophrenia and bipolar disorder into a single psychosis phenotype and compared between cases and controls from the Schizophrenia and Bipolar Twin Study in Sweden (STAR) project. Further tests were conducted to ascertain if twin concordance for psychosis depended on the mean PRS for psychosis. Structural equation modeling was used to estimate heritability. This study constituted an analysis of existing clinical and population datasets with genotype and/or twin data. Included were twins from the STAR cohort and from the Swedish Twin Registry. Data were collected during the 2006 to 2013 period and analyzed from March 2023 to June 2024. PRS for psychosis based on the most recent GWAS of combined schizophrenia/bipolar disorder. Psychosis case status was assessed by clinical interviews and/or Swedish National Register data. The final cohort comprised 87 pairs of twins with 1 or both affected and 59 unaffected pairs from the STAR project (for a total of 292 twins) as well as 443 pairs with 1 or both affected and 20 913 unaffected pairs from the Swedish Twin Registry. Among the 292 twins (mean [SD] birth year, 1960 [10.8] years; 158 female [54.1%]; 134 male [45.9%]), 134 were monozygotic twins, and 158 were dyzygotic twins. PRS for psychosis was higher in cases than in controls and associated with twin concordance for psychosis (1-SD increase in PRS, odds ratio [OR], 2.12; 95% CI, 1.23-3.87 on case status in monozygotic twins and OR, 2.74; 95% CI, 1.56-5.30 in dizygotic twins). The association between PRS for psychosis and concordance was not modified by zygosity. The twin heritability was estimated at 0.73 (95% CI, 0.30-1.00), which overlapped with the estimate in the full Swedish Twin Registry (0.69; 95% CI, 0.43-0.85). In this case-control study, using the natural experiment of twins, results suggest that twins with greater inherited liability for psychosis were more likely to have an affected co-twin. Results from twin and molecular designs largely aligned. Even as illness vulnerability is not solely genetic, PRS carried predictive power for psychosis even in a modest sample size.

Tilts, developmental modules, and cognitive differentiation-integration effort: A multi-study response to

Sorjonen et al. (2024) critique a recently published finding that cognitive tilts are heritable, which was advanced as a line of evidence supporting their substantive (rather than artefactual) nature. These researchers claim: i) that the heritability of tilts is simply a function of the heritabilities of the specific cognitive dimensions used in their estimation, and ii) that spuriously heritable tilts can be recovered using difference scores between psychometric, anthropometric, and even random number variables. Here, multiple studies employing three behavior genetic datasets are used to test these claims. Even when cognitive tilts are residualized for their association with their constituent abilities, they still exhibit small, but non-zero heritabilities. Shared environmentality (C) accounts for the largest proportion of variance among these residuals. Tilts generated using random numbers are, by contrast, in all cases associated with AE models, exhibiting near 100 % E variance, corresponding to error. In the Swedish Twin Registry, the tilt residual is positively correlated with a measure of life history speed (Mini-K score), suggesting that tilts capture cognitive differentiation-integration effort conditioned developmentally by C variance. Distinct latent factors among psychometric and anthropometric variables in the Georgia Twin Study are also found. These indicate the presence of distinct developmental modules, meaning that tilts estimated using manifest variables associated with different modules lack theoretical credibility, as also evidenced by weak cross loadings.

The causal effect of genetic variants linked to cognitive and non-cognitive skills on education and labor market outcomes

We estimate the effect of genetic variants that are associated with differences in cognitive and non-cognitive skills on labor market and education outcomes by linking genetic data from individuals in the Swedish Twin Registry to government registry data. Genes are fixed over the life cycle and genetic differences between full siblings are random, making it possible to establish the causal effects of within-family genetic variation. We show that polygenic indices associated with cognitive skills and personality traits significantly affect income, occupation, and educational attainment. By comparing estimates that use only within-family variation to OLS estimates with and without socioeconomic controls, our results also provide indications of the degree of (residual) confounding, which can be useful for research conducted in datasets that do not contain sibling pairs. Overall, our results indicate that education and labor market outcomes are partially the result of a genetic lottery.

Researchers consider links between genetics and psychosis in teen use of psychedelics

Genetics may be more responsible for an association between psychedelic use by teens and manic symptoms than the use of the drug itself. A recent study of 16,255 adolescent twins found that psychedelic use was associated with lower rates of psychotic symptoms when adjusting for other drug use. However, psychedelic use was associated with more manic symptoms in teens with a higher genetic vulnerability to schizophrenia or bipolar I disorder. The findings are focused on psychedelic‐assisted therapy, which has shown promise in treating some psychiatric disorders. However, little is known about the risk of psychotic or manic symptoms in teens who use psychedelics recreationally, not therapeutically. This study used the Swedish Twin Registry to investigate links between recreational psychedelic use and self‐reported psychotic or manic symptoms in adolescents. Among the 16,255 participants included in the analyses, 541 reported past use of psychedelics, most of whom (535 of 541 [99%]) also reported past use of other drugs. The findings come with significant limitations and should be interpreted with caution, the researchers concluded. Among the conflicts of interest reported, the lead author was the founder of Eudelics, a company which markets mindfulness, leadership, and psychedelics. Simonsson, O., et al. (2024, Mar 13). Adolescent psychedelic use and psychotic or manic symptoms. JAMA Psychiatry. Published online. https://doi.org/10.1001/jamapsychiatry.2024.0047.

Adolescent Psychedelic Use and Psychotic or Manic Symptoms

While psychedelic-assisted therapy has shown promise in the treatment of certain psychiatric disorders, little is known about the potential risk of psychotic or manic symptoms following naturalistic psychedelic use, especially among adolescents. To investigate associations between naturalistic psychedelic use and self-reported psychotic or manic symptoms in adolescents using a genetically informative design. This study included a large sample of adolescent twins (assessed at age 15, 18, and 24 years) born between July 1992 and December 2005 from the Swedish Twin Registry and cross-sectionally evaluated the associations between past psychedelic use and psychotic or manic symptoms at age 15 years. Individuals were included if they answered questions related to past use of psychedelics. Data were analyzed from October 2022 to November 2023. Primary outcome measures were self-reported psychotic and manic symptoms at age 15 years. Lifetime use of psychedelics and other drugs was also assessed at the same time point. Among the 16 255 participants included in the analyses, 8889 were female and 7366 were male. Among them, 541 participants reported past use of psychedelics, most of whom (535 of 541 [99%]) also reported past use of other drugs (ie, cannabis, stimulants, sedatives, opioids, inhalants, or performance enhancers). When adjusting for substance-specific and substance-aggregated drug use, psychedelic use was associated with reduced psychotic symptoms in both linear regression analyses (β, -0.79; 95% CI, -1.18 to -0.41 and β, -0.39; 95% CI, -0.50 to -0.27, respectively) and co-twin control analyses (β, -0.89; 95% CI, -1.61 to -0.16 and β, -0.24; 95% CI, -0.48 to -0.01, respectively). In relation to manic symptoms, likewise adjusting for substance-specific and substance-aggregated drug use, statistically significant interactions were found between psychedelic use and genetic vulnerability to schizophrenia (β, 0.17; 95% CI, 0.01 to 0.32 and β, 0.17; 95% CI, 0.02 to 0.32, respectively) or bipolar I disorder (β, 0.20; 95% CI, 0.04 to 0.36 and β, 0.17; 95% CI, 0.01 to 0.33, respectively). The findings in this study suggest that, after adjusting for other drug use, naturalistic use of psychedelic may be associated with lower rates of psychotic symptoms among adolescents. At the same time, the association between psychedelic use and manic symptoms seems to be associated with genetic vulnerability to schizophrenia or bipolar I disorder. These findings should be considered in light of the study's limitations and should therefore be interpreted with caution.

Adverse Childhood Experiences and Adult Mental Health Outcomes

Exposure to adverse childhood experiences (ACEs) has consistently been associated with multiple negative mental health outcomes extending into adulthood. However, given that ACEs and psychiatric disorders cluster within families, it remains to be comprehensively assessed to what extent familial confounding contributes to associations between ACEs and clinically confirmed adult psychiatric disorders. To investigate whether associations between ACEs and adult mental health outcomes remain after adjusting for familial (genetic and environmental) confounding. This Swedish twin cohort study used a discordant twin pair design based on monozygotic (MZ) and dizygotic (DZ) twins. A total of 25 252 adult twins (aged 18-47 years) from the Swedish Twin Registry born between 1959 and 1998 were followed up from age 19 years until 2016, with a maximum follow-up time of 39 years. Data were analyzed from April 2022 to November 2023. A total of 7 ACEs, including family violence, emotional abuse or neglect, physical neglect, physical abuse, sexual abuse, rape, and hate crime, were assessed with items from the Life Stressor Checklist-Revised in a web-based survey. Adult (ages >18 years) clinical diagnosis of psychiatric disorders (ie, depressive, anxiety, alcohol or drug misuse, or stress-related disorders) were obtained from the Swedish National Patient Register. Of 25 252 twins included in the study (15 038 female [59.6%]; mean [SD] age at ACE assessment, 29.9 [8.7] years), 9751 individuals (38.6%) reported exposure to at least 1 ACE. A greater number of ACEs was associated with increased odds of any psychiatric disorder in the full cohort (odds ratio [OR] per additional ACE, 1.52; 95% CI, 1.48-1.57). The association remained but ORs per additional ACE were attenuated in DZ (1.29; 95% CI, 1.14-1.47) and MZ (1.20; 95% CI, 1.02-1.40) twin pairs. Individuals who were exposed to sexual abuse compared with those who were not exposed had increased odds of any clinically confirmed psychiatric disorder in all comparisons: full cohort (OR, 3.09; 95% CI, 2.68-3.56), DZ twin pairs (OR, 2.10; 95% CI, 1.33-3.32), and MZ twin pairs (1.80; 95% CI, 1.04-3.11). This study found that associations between ACEs and adult mental health outcomes remained after controlling for shared genetic and environmental factors, which was particularly evident after multiple ACEs or sexual abuse. These findings suggest that targeted interventions may be associated with reduced risks of future psychopathology.

Surgically treated degenerative disk disease in twins.

Previous studies have suggested that genetic factors are important in the development of degenerative disk disease (DDD). However, the concordance rates for the phenotypes requiring surgery are unknown. The purpose of this study was to determine the concordance rates for DDD requiring surgery by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. Patients, aged between 18 and 85years, operated for DDD between 1996 and 2022 were identified in the national Swedish spine register (Swespine) and matched with the Swedish twin registry (STR) to identify MZ and DZ twins. Pairwise and probandwise concordance rates were calculated. We identified 11,207 patients, 53% women, operated for DDD. By matching the Swespine patients with the STR, we identified 121 twin pairs (37 MZ and 84 DZ) where one or both twins were surgically treated for DDD. The total twin incidence for operated DDD was 1.1%. For DDD requiring surgery, we found no concordant MZ pair and no concordant DZ pair where both twins were operated for DDD. When we evaluated pairs where at least one twin was operated for DDD, we found two concordant MZ pairs (the co-twins were operated for spinal stenosis) and two concordant DZ pairs (one co-twin operated for spinal stenosis and one (co-twin operated for disk herniation). Our findings suggest that genetic factors are probably not a major etiologic component in most cases of DDD requiring surgery. The findings of this study can be used for counseling patients about the risk for requiring DDD surgery.

Surgically Treated Degenerative Lumbar Spine Diseases in Twins.

There is growing evidence to suggest a potential genetic component underlying the development and progression of lumbar spine diseases. However, the heritability and the concordance rates for the phenotypes requiring surgery for the common spine diseases lumbar spinal stenosis (LSS) and lumbar disc herniation (LDH) are unknown. The aim of this study was to determine the heritability and the concordance rates for LSS and LDH requiring surgery by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. Patients between 18 and 85 years of age who underwent surgery for LSS or LDH between 1996 and 2022 were identified in the national Swedish spine registry (LSS: 45,110 patients; LDH: 39,272 patients), and matched with the Swedish Twin Registry to identify MZ and DZ twins. Pairwise and probandwise concordance rates, heritability estimates, and MZ/DZ concordance ratios were calculated. We identified 414 twin pairs (92 MZ and 322 DZ pairs) of whom 1 or both twins underwent surgery for LSS. The corresponding number for LDH was 387 twin pairs (118 MZ and 269 DZ pairs). The probandwise concordance rate for LSS requiring surgery was 0.25 (26 of 105) (95% confidence interval [CI], 0.14 to 0.34) for MZ twins and 0.04 (12 of 328) (95% CI, 0.01 to 0.07) for DZ twins. The corresponding values for LDH requiring surgery were 0.03 (4 of 120) (95% CI, 0 to 0.08) and 0.01 (4 of 271) (95% CI, 0 to 0.04), respectively. The probandwise MZ/DZ concordance ratio was 6.8 (95% CI, 2.9 to 21.5) for LSS and 2.3 (95% CI, 0 to 8.9) for LDH. The heritability was significantly higher in LSS compared with LDH (0.64 [95% CI, 0.50 to 0.74] versus 0.19 [95% CI, 0.08 to 0.35]). Our findings suggest that genetic factors may play an important role in the risk of developing LSS requiring surgery, whereas heredity seems to be of less importance in LDH requiring surgery. Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Age effects on autism heritability and etiological stability of autistic traits.

Autism and autistic traits onset in childhood but persist into adulthood. Little is known about how genetic and environmental factors influence autism and autistic traits into adulthood. We aimed to determine age effects on the heritability of clinically diagnosed autism and the etiological stability of autistic traits from childhood to adulthood using twin methods. From 23,849 twin pairs in the Swedish Twin Register born between 1959 and 2010, we identified 485 individuals (1.01%, 31.5% female) with a clinical autism diagnosis. We estimated and compared the relative contribution of genetic, shared, and nonshared environmental influences to autism in childhood and adulthood. We further used multivariate twin analysis with four measurement points among 1,348 twin pairs in the longitudinal Twin Study of Child and Adolescent Development to assess the phenotypic and etiological stability of autistic traits - measured with three scales from the Child Behavior Checklist - from childhood to adulthood. Autism heritability was comparable from childhood, (96% [95% CI, 76-99%]) to adulthood (87% [67-96%]). Autistic traits were moderately stable (phenotypic correlation = 0.35-0.61) from childhood to adulthood, and their heritability varied between 52 and 71%. We observed stable as well as newly emerging genetic influences on autistic traits from ages 8-9 to 19-20, and unique nonshared environmental influences at each age. Genetic factors are important for autism and autistic traits in adulthood and separate genetic studies in adults are warranted.

Association of cardiometabolic multimorbidity with risk of late-life depression: a nationwide twin study.

Cardiometabolic diseases (CMDs) including heart disease, stroke, and type 2 diabetes have been individually linked to depression. However, their combined impact on depression risk is unclear. We aimed to examine the association between cardiometabolic multimorbidity and depression and explore the role of genetic background in this association. Within the Swedish Twin Registry, 40,080 depression-free individuals (mean age 60years) were followed for 18years. Cardiometabolic multimorbidity was defined as having ≥2 CMDs. CMDs and depression were ascertained based on the National Patient Register. Cox regression was used to estimate the CMD-depression association in a classical cohort study design and a matched co-twin design involving 176 twin pairs. By comparing the associations between monozygotic and dizygotic co-twins, the contribution of genetic background was estimated. At baseline, 4809 (12.0%) participants had one CMD and 969 (2.4%) had ≥2 CMDs. Over the follow-up period, 1361 participants developed depression. In the classical cohort design, the multi-adjusted hazard ratios (95% confidence interval [CIs]) of depression were 1.52 (1.31-1.76) for those with one CMD and 1.83 (1.29-2.58) for those with ≥2 CMDs. CMDs had a greater risk effect on depression if they developed in mid-life (<60years) as opposed to late life (≥60years). In matched co-twin analysis, the CMD-depression association was significant among dizygotic twins (HR=1.63, 95% CI, 1.02-2.59) but not monozygotic twins (HR=0.90, 95% CI, 0.32-2.51). Cardiometabolic multimorbidity is associated with an elevated risk of depression. Genetic factors may contribute to the association between CMDs and depression.

WITHIN TWIN PAIR DIFFERENCES INDICATE GENETIC EFFECTS OF SES INDICATORS ON LONGITUDINAL CHANGES IN PHYSICAL AGING

Abstract Socioeconomic status (SES) predicts change in health status over age, even after accounting for measured confounders such as environmental and biological risk factors. Nonetheless, the source of SES-health associations continues to be heavily debated. Twin studies offer a method for testing causal hypotheses by incorporating within and between twin pair differences in longitudinal latent growth curve models (LGCM) of physical aging on both level of functioning and rate of change with age. Three longitudinal twin studies of aging from the Swedish Twin Registry (N = 2059) included up to 27 years of follow-up on a Functional Aging Index (FAI) consisting of lung function, grip strength, walking speed, and self-report sensory functioning. SES indicators included education, financial strain, and occupation. Pair means (between family effect) and within pair differences (within family effect) were included as covariates of both intercept and slopes in a two-slope LGCM (intercept at age 75); models were corrected for sex and parental SES. LGCM results were compared across full sample, monozygotic twins, and dizygotic twins. For the FAI intercept, MZ within pair effects in all SES variables were strongly attenuated, indicating genetic confounding. For slope 1, only MZ within pair effect for education was attenuated, and no SES indicators were related to rate of change in FAI after age 75. Thus, results suggest shared genetic factors explain the association between education and change in physical aging in early aging processes. In other words, genes that impact educational achievement may also influence health behaviors and physical aging.

Combining Mendelian randomization with the sibling comparison design.

Mendelian randomization (MR) is a popular epidemiologic study design that uses genetic variants as instrumental variables (IVs) to estimate causal effects, while accounting for unmeasured confounding. The validity of the MR design hinges on certain IV assumptions, which may sometimes be violated due to dynastic effects, population stratification, or assortative mating. Since these mechanisms act through parental factors it was recently suggested that the bias resulting from violations of the IV assumptions can be reduced by combing the MR design with the sibling comparison design, which implicitly controls for all factors that are constant within families. In this article, we provide a formal discussion of this combined MR-sibling design. We derive conditions under which the MR-sibling design is unbiased, and we relate these to the corresponding conditions for the standard MR and sibling comparison designs. We proceed by considering scenarios where all three designs are biased to some extent, and discuss under which conditions the MR-sibling design can be expected to have less bias than the other two designs. We finally illustrate the theoretical results and conclusions with an application to real data, in a study of low-density lipoprotein and diastolic blood pressure using data from the Swedish Twin Registry.

Pregnancy‐Related Cardiometabolic Disease and Dementia Risk: A Twin Study

AbstractBackgroundPregnancy related complications such as gestational diabetes mellitus (GDM) and pregnancy‐induced hypertension (PIH) have been shown to increase risk of cardiometabolic disease and may subsequently contribute to all cause dementia. While GDM and PIH have been genetically associated with their later life, non‐pregnancy related counterparts, it remains to be seen if these conditions independently contribute to dementia risk. This study investigated the degree to which GDM and PIH are genetically associated with dementia.MethodData were analyzed from 5,930 females in the Swedish Twin Registry who reported at least one pregnancy. Traditional twin analyses were conducted to determine the degree to which GDM and PIH are genetically influenced, as well as the degree of genetic and environmental overlap with the non‐pregnancy related variant of these conditions. Survival analyses examined relationships between 1) GDM and dementia and 2) PIH and dementia. Hypertension and diabetes outside of pregnancy were included in their respective models as covariates.ResultFor individuals who reported having been pregnant, risk of later life cardiometabolic risk factors were significantly increased if the similar conditions were experienced during pregnancy (P&lt;.001). Both GDM and PIH showed evidence of significant familial associations, with a higher OR in MZ twins for both conditions (GDM OR = 6.74; 95% CI, 1.06 to 2.76; PIH OR = 8.27; 95% CI, 1.89 to 2.38). The survival models indicated that while neither pregnancy‐related condition was independently associated with dementia risk, diabetes outside of pregnancy was associated with a more than three‐fold increase in dementia risk (HR = 3.77, 95% CI = 1.17 – 1.63).ConclusionIn this large, population‐based cohort we found significant associations between pregnancy conditions and their respective cardiometabolic conditions. Cross‐twin associations further indicated that the association between pregnancy and non‐pregnancy cardiometabolic risk factors was driven by genetic influences. However, GDM and PIH did not appear to convey risk for dementia. These findings suggest that mechanisms driving diabetes and hypertension during pregnancy, while related to their later‐life counterparts, do not increase risk of neurocognitive decline.

Attention-deficit/hyperactivity disorder symptoms and subsequent cardiometabolic disorders in adults: investigating underlying mechanisms using a longitudinal twin study

BackgroundEmerging research suggests that attention-deficit/hyperactivity disorder (ADHD) increases the risk for cardiovascular (CVDs) and metabolic disorders (i.e., cardiometabolic disorders) in adulthood. Yet, available studies are scarce and have mainly been focused on individuals receiving clinical ADHD diagnoses. We aimed to investigate the prospective associations of ADHD symptoms in young and mid-adulthood with subsequent cardiometabolic disorders and the underlying mechanisms.MethodsWe studied 10,394 twins from the Swedish Twin Registry (STR), born between 1958 and 1985 without previous medical history of cardiometabolic disorders. They provided self-assessment of ADHD symptoms (score range 0–36) via a validated, DSM-IV-based scale in a web-based questionnaire/telephone interview within the Study of Twin Adults: Genes and Environment (STAGE), in 2005–2006 (aged 19–47 years), and were followed until the end of 2018 (33–59 years) to identify incident clinical diagnoses/medication prescriptions for cardiometabolic disorders acquired from Swedish national registers. We used Cox regression models to investigate the associations between ADHD symptoms score and cardiometabolic outcomes, with and without adjustment for relevant covariates, and a co-twin control design to study familial confounding.ResultsA one-unit increase in the level of ADHD symptoms was associated with a 2% increase in the rate of CVDs (hazard ratio [HR] = 1.02, 95% confidence interval 1.01–1.04) and a 3% increase in the rate of metabolic disorders (HR = 1.03, 1.02–1.05), after adjusting for birth year and sex. The associations were no longer significant after adjusting for educational attainment, lifestyle factors, and comorbid psychiatric disorders. The associations remained significant after adjusting for familial factors shared by dizygotic twin pairs but became nonsignificant after adjusting for factors shared by monozygotic twin pairs. However, the strength of the associations attenuated significantly in monozygotic twins compared to dizygotic twins for CVDs only, suggesting genetic confounding.ConclusionsADHD symptom score is associated with a higher risk for cardiometabolic disorders, which may be explained by lower educational attainment, adverse lifestyle factors, and psychiatric comorbidities. Moreover, the associations appear to be partly confounded by shared genetic factors, especially for CVDs. Further research is needed to investigate the identified associations at the level of individual cardiometabolic disorders and to follow-up participants until a more advanced older age.

Educational Influences on Late-Life Health: Genetic Propensity and Attained Education.

The educational gradient in late-life health is well established. Despite this, there are still ambiguities concerning the role of underlying confounding by genetic influences and gene-environment (GE) interplay. Here, we investigate the role of educational factors (attained and genetic propensities) on health and mortality in late life using genetic propensity for educational attainment (as measured by a genome-wide polygenic score, PGSEdu) and attained education. By utilizing genetically informative twin data from the Swedish Twin Registry (n = 14,570), we investigated influences of the educational measures, familial confounding as well as the possible presence of passive GE correlation on both objective and subjective indicators of late-life health, that is, the Frailty Index, Multimorbidity, Self-rated health, cardiovascular disease, and all-cause mortality. Using between-within models to adjust for shared familial factors, we found that the relationship between educational level and health and mortality later in life persisted despite controlling for familial confounding. PGSEdu and attained education both uniquely predicted late-life health and mortality, even when mutually adjusted. Between-within models of PGSEdu on the health outcomes in dizygotic twins showed weak evidence for passive GE correlation (prGE) in the education-health relationship. Both genetic propensity to education and attained education are (partly) independently associated with health in late life. These results lend further support for a causal education-health relationship but also raise the importance of genetic contributions and GE interplay.

The heritability of ability tilts

Tilts arise from within-subject differences in performance between two distinct cognitive ability measures (e.g., verbal minus quantitative). These are independent of general cognitive ability (GCA) and are likely a function of differential investment of time and other resources into the cultivation of one ability, at the expense of another. There is some debate about the meaning and measurement of tilts among psychometricians, but a body of research is emerging demonstrating that these are predictive of real-world outcomes independent of GCA. An open question concerns the heritability of tilts. Since nearly all phenotypic individual differences are heritable, tilts, if substantive, should not be an exception. It was found that tilts are modestly heritable (after controlling for participant age and residual correlations with GCA) in three samples (US children, Georgia Twin Study; Swedish adults, Swedish Twin Registry; US adults, MIDUS II). AE models better fit the tilt data in all but one case (Verbal - Reasoning, in the GTS, where an ACE model better fit the data). Comparatively large (non-shared) environmentalities were noted in all cases, potentially consistent with models predicting a role for niche-picking and experience-producing-drive dynamics in generating tilts. A Wilson-like effect was observed when the tilt heritabilities in the GTS were compared with their equivalent parameters in the other two (older) samples. The finding that tilts exhibit non-zero heritability in different age ranges and in two countries strengthens their external validity, and weakens claims that they are measurement artifacts, as predisposing genetic and environmental factors are part of their nomological network.

A twin study of genetic and environmental contributions to attention-deficit/hyperactivity disorder over time.

Attention-deficit/hyperactivity disorder (ADHD) is an increasingly commonly diagnosed neurodevelopmental condition. One possibility is that this reflects a genuine increase in the prevalence of ADHD due to secular environmental changes, yet this hypothesis remains untested. We therefore investigated whether the genetic and environmental variance underlying ADHD, and traits of ADHD, has changed over time. We identified twins born from 1982 to 2008 from the Swedish Twin Registry (STR). We linked the STR with the Swedish National Patient Register and Prescribed Drug Register to identify diagnoses of ADHD and prescriptions of ADHD medication for these twins. We also utilized data collected from participants in the Child and Adolescent Twin Study in Sweden (CATSS), born from 1992 to 2008. Their parents completed a structured ADHD screening tool, which was used to measure traits of ADHD and assign broad screening diagnoses of ADHD. We used the classical twin design to test whether the degree to which variation in these measures was influenced by genetic and environmental variation changed over time. We included 22,678 twin pairs from the STR and 15,036 pairs from CATSS. The heritability of ADHD in the STR ranged from 66% to 86% over time, although these fluctuations were not statistically significant. We observed a modest increase in variance in ADHD traits, from 0.98 to 1.09. This was driven by small increases in the underlying genetic and environmental variance, with heritability estimated as 64%-65%. No statistically significant changes in variance in screening diagnoses were observed. The relative contribution of genetic and environmental factors to ADHD has remained stable over time, despite its increasing prevalence. Thus, changes in the underlying etiology of ADHD over time are unlikely to explain the increase in ADHD diagnoses.

In search of environmental risk factors for obsessive-compulsive disorder: study protocol for the OCDTWIN project

BackgroundThe causes of obsessive-compulsive disorder (OCD) remain unknown. Gene-searching efforts are well underway, but the identification of environmental risk factors is at least as important and should be a priority because some of them may be amenable to prevention or early intervention strategies. Genetically informative studies, particularly those employing the discordant monozygotic (MZ) twin design, are ideally suited to study environmental risk factors. This protocol paper describes the study rationale, aims, and methods of OCDTWIN, an open cohort of MZ twin pairs who are discordant for the diagnosis of OCD.MethodsOCDTWIN has two broad aims. In Aim 1, we are recruiting MZ twin pairs from across Sweden, conducting thorough clinical assessments, and building a biobank of biological specimens, including blood, saliva, urine, stool, hair, nails, and multimodal brain imaging. A wealth of early life exposures (e.g., perinatal variables, health-related information, psychosocial stressors) are available through linkage with the nationwide registers and the Swedish Twin Registry. Blood spots stored in the Swedish phenylketonuria (PKU) biobank will be available to extract DNA, proteins, and metabolites, providing an invaluable source of biomaterial taken at birth. In Aim 2, we will perform within-pair comparisons of discordant MZ twins, which will allow us to isolate unique environmental risk factors that are in the causal pathway to OCD, while strictly controlling for genetic and early shared environmental influences. To date (May 2023), 43 pairs of twins (21 discordant for OCD) have been recruited.DiscussionOCDTWIN hopes to generate unique insights into environmental risk factors that are in the causal pathway to OCD, some of which have the potential of being actionable targets.

Dementia mediates the association of life‐course depression with mortality: A nationwide twin study

AbstractBackgroundAlthough the association between depression and mortality has been investigated, the impact of depression in different periods of life on mortality remains inconclusive. We aimed to examine the association of depression with all‐cause mortality from a life‐course perspective, and to explore the roles of dementia, as well as genetic and early‐life environmental factors shared by twins, in this association.MethodFrom the Swedish Twin Registry, 44,919 twin individuals were followed for up to 18 years. Depression and dementia were ascertained using the Swedish National Patient Registry. Early‐life (&lt;45 years), midlife (45‐64 years), and late‐life (≥ 65 years) depression were categorized according to the age of the first depression diagnosis. Deaths were identified through the Cause of Death Register. Generalized estimating equation model was used for unmatched analysis among all individuals. The mediating effect of dementia on the depression‐mortality association was estimated using generalized structural equation modeling. Conditional logistic regression model was used for co‐twin matched analysis among death‐discordant twin pairs.ResultAmong all the participants (mean age 59.34 years), 1,179 had a history of depression at baseline and 12,761 died during the follow‐up. In the unmatched analysis, the multivariate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of all‐cause mortality were 1.71 (1.46–2.00) for depression at any age, 1.72 (1.36–2.17) for early‐life, 1.51 (1.19–1.90) for midlife, and 4.10 (2.02‐8.34) for late‐life depression. Mortality was significantly higher in individuals with late‐life depression than those with earlier‐life depression (P&lt;0.05). Depression at any age was also associated with an increased risk of mortality with dementia (OR 1.62, 95% CI 1.28–2.05). In the mediation analysis, 56.74% of the depression‐mortality association was mediated by dementia. In the co‐twin matched analysis, the OR (95% CI) for the depression‐mortality association was 1.70 (1.22–2.38). No statistically significant difference in ORs between the unmatched and co‐twin matched analyses was observed (P = 0.09).ConclusionDepression, especially occurring in late life, is associated with an increased all‐cause mortality. Dementia in late life mediates over 50% of the depression‐mortality association, but genetic and early‐life environmental factors appear not to account for this association.

Injurious falls before, during, and after dementia diagnosis: A population‐based study

AbstractBackgroundFalls are common among older adults with dementia, but the timing of incident injurious falls at different stages of dementia diagnosis is unclear. We aimed to examine injurious falls before, during, and after dementia diagnosis to detect when the occurrence of falls starts to increase prior to dementia onset, when people with dementia are at highest risk of falls, and which factors are associated with falls among people with dementia.MethodThis study included 4874 participants aged ≥55, consisting of 2437 incident dementia cases detected in a dementia‐free cohort from the Swedish Twin Registry and 2437 1:1 matched (i.e., same birth year and sex) non‐demented controls from the cohort. Dementia diagnosis and date of onset were identified from the National Patient Registry (NPR) and the Swedish Cause of Death Register. Information on injurious falls, including date of occurrence and history of chronic disease, was obtained from the NPR. Data on demographics, lifestyle, and anthropometrics were collected through a self‐reported questionnaire. Data were analyzed using conditional Poisson regression and generalized estimating equation (GEE) models.ResultIn Poisson regression analysis, the adjusted incidence rates of injurious falls among dementia cases and controls were similar (around 3.65‐9.08 per 1,000 person‐years) in the 6‐10 years preceding dementia diagnosis. Compared to controls, the incidence of falls in dementia cases started to increase beginning 5 years prior to dementia diagnosis (incidence rate ratio [IRR] 1.50, 95% confidence interval [CI] 1.11‐2.03), reaching a peak (IRR 3.37, 95% CI 2.85–3.97) in the year of dementia diagnosis, and declining rapidly 3 years after dementia diagnosis (IRR 1.38, 95% CI 1.05–1.79). In multi‐adjusted GEE models, alcohol consumption, living alone, and stroke were significantly associated with incident falls among people with dementia.ConclusionCompared to dementia‐free people, those with dementia have a greater incidence of injurious falls that increases in the 5 years leading up to dementia diagnosis and peaks during the year of dementia diagnosis. Alcohol consumption, living alone, and stroke may predict falls among people with dementia. Our findings highlight the importance of a tailored preventive strategy against falls among people with dementia, especially in the diagnosis stage.