Twin and family studies on the development of cognitive and externalizing problems

Cognitive and externalizing problems are responsible for much personal suffering, as well as large monetary costs for society. Intervention and prevention efforts have often failed in reduction of unwanted behaviors, perhaps due to lack of understanding of the development of these complex traits. Studies on risk factors often treat the associations naively by not considering potential unmeasured common causes of the risk factor and the outcome. These common causes may be shared within families; i.e., the association is subject to familial confounding. Analyses informed of family belonging can help to further the knowledge regarding causality. Therefore, in this thesis, I used existing, and developed novel, methodologies to assess familial confounding. Models to adjust for familial confounding, as well as models identifying sources of familial confounding, were implemented. Further, I developed a genetically sensitive longitudinal design with multiple raters and time-points. In study I, advancing paternal age was associated with offspring violent offending. Advancing paternal age was found to increase the incidence of violent criminal convictions among re-offending offspring when siblings were compared; a result congruent with causal inference. Contrary, and congruent with non-causal inference, advancing paternal age did not increase the probability to ever be convicted a violent criminal offence Study II identified an association between maternal smoking during pregnancy (SDP) and offspring stress coping in late adolescence. However, the association did not persist when exposure-discordant siblings were compared. This result is compatible with anon-causal interpretation, and suggests that the association is due to familial confounding; other factors shared between siblings accounts for the association. In a quantitative genetic analysis these factors were found to be of genetic origin. Study III continued the investigation of SDP, this time as a risk factor for cognitive outcomes (general cognitive ability and poor academic achievement), externalizing outcomes (criminal convictions, violent criminal convictions, and drug misuse), and pregnancy related outcomes (birth weight, preterm birth, and born small for gestational age). SDP was associated with all outcomes, but within-sibling analyses found that the association persisted only for pregnancy related outcomes, and disappeared for cognitive and externalizing outcomes. Quantitative genetic analyses found that genetics accounted for the majority of the association between SDP and cognitive and externalizing outcomes. In study IV externalizing traits in mid-childhood were found to predict ADHD-like traits in adolescence when pre-existing associations were adjusted for. Further, ADHD- like traits in late adolescence predicted externalizing behavior in young adult age. The two traits were correlated in mid-childhood (age 8-9), and become even more correlated through early (age 13-14) and late (age 16-17) adolescence and young adult age (age 19-20). Stable and new factors accounted for approximately half of the correlation between the traits each, throughout development. Genetic variation explained two thirds of the correlations. In conclusion, advancing paternal age might increase the rate of violent offending among violent re-offenders. SDP does not seem to be causing offspring cognitive and externalizing problems in adolescence and adulthood; the observed associations are better explained by shared genetic factors. Externalizing behavior predicts ADHD early in development, and ADHD predicts externalizing behavior late in development. And, although new sources of covariance arise throughout development, ADHD- like and externalizing traits become even more correlated from childhood to young adulthood

Codevelopment of ADHD and externalizing behavior from childhood to adulthood

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) frequently co-occurs with externalizing disorders, but a clear understanding of the etiologic underpinnings is hampered by the limited understanding of the codevelopment of the traits from childhood into early adulthood. METHODS: Using a birth cohort of 2600 twins, the Swedish Twin study of Child and Adolescent Development study, assessed at ages 8-9, 13-14, 16-17, and 19-20, we investigated the codevelopment of ADHD and externalizing behavior from childhood to adulthood. The analyses examined ADHD-like and externalizing traits, as rated by twins and their parents using the Attention Problems scale and Externalizing scale of the Child Behavior Checklist, and estimated cross-lagged effects (one trait at one time-point predicting the other at the next). The covariation between the traits were decomposed into stable (effects carried over from the prior time-points) and innovative (new effects for each time-point) sources; each source was further decomposed into additive genetics, shared and nonshared environment. RESULTS: The analysis suggested that externalizing traits in middle childhood (age 8-9) predicted ADHD-like traits in early adolescence (age 13-14), whereas the reverse association was nonsignificant. In contrast, ADHD-like traits in lateadolescence (age 16-17) predicted externalizing traits in early adulthood (age 19-20). The correlation between ADHD-like and externalizing traits increased over time. At all time-points, innovative sources contributed substantially to maintained comorbidity. Genetic effects explained 67% of the covariation at each time-point; importantly, nearly 50% of these effects were innovative. CONCLUSIONS: This study challenges the belief that ADHD generally precedes externalizing behaviors; rather, change in the etiologic factors across the development is the rule. The effects were due to both new genetic and environmental factors emerging up to young adulthood. Clinicians and researchers needs to consider complex etiologic and developmental models for the comorbidity between ADHD and externalizing behaviors.The Swedish Research CouncilThe Swedish Research Council for Health, Working Life and WelfareThe Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM)National Institute of Child Health and Human DevelopmentAccepte

Paternal antisocial behavior and sons' cognitive ability : a population-based quasiexperimental study

Parents’ antisocial behavior is associated with developmental risks for the offspring but effects on cognitive ability are unknown. We used linked Swedish register data for a large sample of adolescent men (N = 1,177,173) and their parents to estimate associations between fathers’ criminal convictions and sons’ cognitive ability assessed at compulsory military conscription. Mechanisms behind the association were tested in children-of-siblings models across three types of sibling fathers (half-siblings, full-siblings, and monozygotic twins) with increasing genetic relatedness, and in quantitative genetic models. Fathers’ convictions associated with lower cognitive ability in sons (any crime: Cohen’s d = -.28; violent crimes: Cohen’s d = -.49). Adjusting for more genetic factors gradually reduced and eventually eliminated the association. Nuclear family environmental factors did not contribute to the association. Our results suggest that the association between paternal antisocial behavior and offspring cognitive ability is not causal but mostly due to underlying genetic factors.The Alfred Kordelin FoundationThe Swedish Research CouncilThe Swedish Research Council for Health, Working Life and WelfareAccepte

Cognitive ability and risk for substance misuse in men : genetic and environmental correlations in a longitudinal nation-wide family study.

Aims. To investigate the association between cognitive ability in late adolescence and subsequent substance misuse-related events in men, and to study the underlying genetic and environmental correlations. Design. A population-based longitudinal study with three different family-based designs. Cox proportional hazards models were conducted to investigate the association at the individual level. Bivariate quantitative genetic modeling in (1) full brothers and maternal half-brothers, (2) full brothers reared together and apart, and (3) monozygotic and dizygotic twin brothers was used to estimate genetic and environmental correlations. Setting. Register-based study in Sweden. Participants. The full sample included 1,402,333 Swedish men born 1958-1991 and conscripted at mean age 18.2 (SD=0.5) years. 1,361,066 men who had no substance misuse events before cognitive assessment at mandatory military conscription were included in the Cox regression models with a follow-up time of up to 35.6 years. Measures. Cognitive ability was assessed at conscription with the Swedish Enlistment Battery. Substance misuse events included alcohol and drug related court convictions, medical treatments, and deaths, available from governmental registries Findings. Lower cognitive ability in late adolescence predicted an increased risk for substance misuse events (hazard ratio [HR] for a 1-stanine unit decrease in cognitive ability: 1.29, 95% CI: 1.29-1.30). The association was somewhat attenuated within clusters of full brothers (HR=1.21, 95% CI: 1.20-1.23). Quantitative genetic analyses indicated that the association was primarily due to genetic influences; the genetic correlations ranged between -.39 (95% CI: -.45, -.34) and -.52 (-.55, -.48) in the three different designs. Conclusions. Our findings from different family designs indicate that shared genetic influences underlie the association between low cognitive ability and subsequent risk for substance misuse events.The Academy of FinlandThe Swedish Research Council for Health, Working Life and Welfare.The Swedish Research CouncilThe Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM)Manuscrip

Parental criminality and children's educational attainment : A population-based extended family study

Objectives: We examine how parental criminality is associated with offspring education at different educational stages from primary to tertiary education and conduct separate analyses for non-violent and violent crimes and incarceration, and for paternal and maternal criminality.Methods: We use Swedish total population register data of 513,886 children and their parents and estimate both population-level linear probability models and cousin fixed-effects models.Results: Parental criminality was negatively associated with all stages of offspring education. In population-level models accounting for parental education, the strongest associations were observed for parental violent crimes and incarceration with offspring secondary education completion (beta: -0.16 to -0.18). Cousin fixed-effects models suggested that family-level unobserved heterogeneity played a role in the associations as they were reduced when analyzing cousins differently exposed to parental criminality.Conclusions: Parental criminality is negatively associated with offspring educational attainment, and the associations are in part due to shared familial factors. The association is different at different educational stages and for parental violent vs. non-violent crime.Peer reviewe

Shared etiology of type 1 diabetes and Hashimoto’s thyroiditis: a population-based twin study

Objective Type 1 diabetes and Hashimoto’s thyroiditis frequently cluster in individuals and in families, indicating shared origins. The objective of this study was to investigate familial co-aggregation of these diseases and to quantify shared genetic and environmental factors. Design This study is a twin cohort study. Methods National health registers were used to identify cases among 110 814 Swedish twins. Co-aggregation was calculated as risk ratios for type 1 diabetes among co-twins of individuals with Hashimoto’s thyroiditis, and vice-versa. Variance explained by genetics (i.e. heritability), and the proportions thereof shared between the diseases, was estimated by contrasting associations in monozygotic and dizygotic twins using structural equation models. Results Individuals with one disease were at a high risk for the other disease (adjusted risk ratio: 11.4 (95% CI: 8.5–15.3)). Co-aggregation was more common in monozygotic than in dizygotic pairs, with adjusted risk ratios of 7.0 (95% CI: 3.2–15.1) and 1.7 (95% CI: 0.7–4.1), respectively. Genetic effects shared across diseases accounted for 11% of the variance for type 1 diabetes and 9% of the variance for Hashimoto’s thyroiditis, while environmental factors unique to individual twins, but shared across diseases, accounted for 10% of the variance for type 1 diabetes and 18% of the variance for Hashimoto’s thyroiditis. Conclusions Both genes and environment unique to individual twins contribute to considerable etiologic overlap between type 1 diabetes and Hashimoto’s thyroiditis. These findings add to the current knowledge on the mechanisms behind autoimmune disease clustering and could guide future research aimed at identifying pathophysiological mechanisms and intervention targets.publishedVersio

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.Swedish Research Council (project grant 2018-02640)Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework (grant no 340-2013-5867)Stockholm County Council (ALF-projects)Strategic Research Program in Epidemiology at Karolinska InstituteSwedish Heart-Lung FoundationSwedish Asthma and Allergy Association's Research FoundationPublishe

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 longitudinal study of resting heart rate and violent criminality in more than 700000 men

IMPORTANCE: Low resting heart rate is a well-replicated physiological correlate of aggressive and antisocial behavior in children and adolescents, but whether low resting heart rate increases the risk of violence and other antisocial and risk-taking behaviors in adulthood has not been studied in representative samples. OBJECTIVE: To study the predictive association of resting heart rate with violent and nonviolent criminality and with fatal and nonfatal injuries owing to assaults and unintentional injuries in the population. DESIGN, SETTING, AND PARTICIPANTS: We conducted a study of data from several Swedish national registers on 710264 Swedish men in the general population born from 1958 to 1991, with a follow-up of up to 35.7 years. Outcome data were available and analyzed from January 1, 1973, through December 31, 2009. Resting heart rate was measured together with blood pressure at mandatory military conscription testing at a mean (SD) age of 18.2 (0.5) years. MAIN OUTCOMES AND MEASURES: Violent and nonviolent criminal convictions and medical treatments or deaths owing to assaults and unintentional injuries. RESULTS: In models adjusted for physical, cardiovascular, psychiatric, cognitive, and socioeconomic covariates, compared with 139511 men in the highest quintile of the distribution of resting heart rate (>/=83 beats/min), 132595 men with the lowest quintile (heart rate, </=60 beats/min) had a 39% (95% CI, 35%-44%) higher hazard of being convicted of violent crimes and a 25% (95% CI, 23%-28%) higher hazard of being convicted of nonviolent crimes. The corresponding hazard was 39% higher for assault injuries (95% CI, 33%-46%) and for unintentional injuries (95% CI, 38%-41%). Further adjustment for cardiorespiratory fitness in a subset of 572610 men with data from an exercise test did not reduce the associations. Similar associations were found between low systolic blood pressure and violent and nonviolent criminality and for assault injuries when systolic blood pressure was studied instead of resting heart rate in more than 1 million men. CONCLUSIONS AND RELEVANCE: Among men, low resting heart rate in late adolescence was associated with an increased risk for violent criminality, nonviolent criminality, exposure to assault, and unintentional injury in adulthood. Most of these results were replicated with low systolic blood pressure. Resting heart rate and other autonomic measures merit further study in the development and prevention of violence and antisocial behavior.The Alfred Kordelin FoundationThe Academy of FinlandThe Swedish Research Council for Health, Working Life and WelfareThe Swedish Research CouncilThe Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM)Accepte

Heritability of mammographic breast density, density change, microcalcifications, and masses

Background: Mammographic features influence breast cancer risk and are used in risk prediction models. Understanding how genetics influence mammographic features is important since the mechanisms through which they are associated with breast cancer are not well known. Methods: Mammographic screening history and detailed questionnaire data for 56,820 women from the KARMA prospective cohort study were used. The heritability of mammographic features such as dense area (MD), microcalcifications, masses, and density change (MDC – cm2/year) were estimated using 1,940 sister pairs. We investigated the association between a genetic predisposition to breast cancer and mammographic features, among women with family history of breast cancer information (N=49,674) and a polygenic risk score (PRS, N=9,365). Results: Heritability was estimated at 58% (95% CI: 48%, 67%) for MD, 23% (2%, 45%) for microcalcifications, and 13% (1%, 25%) for masses. The estimated heritability for MDC was essentially null (2%, 95% CI: -8%, 12%). The association between a genetic predisposition to breast cancer (using PRS) and MD and microcalcifications was positive, while for masses this was borderline significant. In addition, for MDC, having a family history of breast cancer was associated with slightly greater MD reduction. Conclusions: We confirmed previous findings of heritability in MD, and also found heritability of the number of microcalcifications and masses at baseline. Since these features are associated with breast cancer risk, and can improve detecting women at short-term risk of breast cancer, further investigation of common loci associated with mammographic features is warranted to better understand the etiology of breast cancer.Swedish Research Council, 2018-02547Swedish Cancer Society, CAN 19 0266Stockholm County Council, LS 1211-1594Swedish Research Council, 70867902Accepte