Twin studies on cancer.

Studies on cancer loci by use of twin data reveal sources of variation in risk. The Nordic twin and cancer registries contain the largest cohort of population representative twins ever studied with more than median 40 years of follow-up. This article considers findings that show influences on familial risk and demonstrates the strengths of the matched case co-twin design for unraveling important risk factors of cancers. Studies using twin data will expectedly continue to provide insights into cancer epidemiology and genetics for the benefit of prevention and treatment.

Surgically treated degenerative disk disease in twins.

PURPOSE: 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. METHODS: Patients, aged between 18 and 85 years, 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. RESULTS: 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). CONCLUSIONS: 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.

The Colombo Twin and Singleton Study (COTASS): Piloting the Feasibility of Collecting Nutritional Data and Extension of the Sample to Include Children of Twins.

Nutrition and diet are key modifiable risk factors for the rising burden of non-communicable diseases like cardio-vascular diseases and diabetes in low- and middle- income countries (LMICs). The nutritional transition in dietary behaviours in LMICs has most likely contributed to this problem. Although traditionally assumed to be environmental, dietary choices are also genetically influenced. Twin study designs can be used to investigate the relative influence of genes and environment on nutrition intake, eating behaviours and associated psychological health. The overall aim of this project is to: provide proof-of-concept for the feasibility of using dietary (biomarker) data within the Children-of-Twin design in nutrition studies, develop laboratory skills and statistical genetic skills and establish a Sri Lankan-specific food composition database. Currently, a pilot study is being conducted with 304 individuals (38 Monozygotic twin pairs, 38 Dizygotic twin pairs and their male or female adult offspring). Questionnaire data on nutritional intake, eating behaviours, psychological well-being, physical health, and bio-specimens are being collected. A Sri Lankan-specific food composition database was developed, training sessions on macro and micro element analysis in biological samples and statistical genetics skills development were conducted and Community Engagement and Involvement programs were carried out in two districts of Sri Lanka.

Genotype-Environment Interaction in ADHD: Genetic Predisposition Determines the Extent to Which Environmental Influences Explain Variability in the Symptom Dimensions Hyperactivity and Inattention.

Although earlier research has shown that individual differences on the spectrum of attention deficit hyperactivity disorder (ADHD) are highly heritable, emerging evidence suggests that symptoms are associated with complex interactions between genes and environmental influences. This study investigated whether a genetic predisposition [Note that the term 'genetic predisposition' was used in this manuscript to refer to an estimate based on twin modeling (an individual's score on the latent trait that resembles additive genetic influences) in the particular population being examined.] for the symptom dimensions hyperactivity and inattention determines the extent to which unique-environmental influences explain variability in these symptoms. To this purpose, we analysed a sample drawn from the Twins Early Development Study (TEDS) that consisted of item-level scores of 2168 16-year-old twin pairs who completed both the Strengths and Difficulties Questionnaire (SDQ; Goodman, in J Child Psychol Psychiatry 38:581-586, 1997) and the Strength and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN; Swanson, in Paper presented at the meeting of the American Psychological Association, Los Angeles, 1981) questionnaire. To maximize the psychometric information to measure ADHD symptoms, psychometric analyses were performed to investigate whether the items from the two questionnaires could be combined to form two longer subscales. In the estimation of genotype-environment interaction, we corrected for error variance heterogeneity in the measurement of ADHD symptoms through the application of item response theory (IRT) measurement models. A positive interaction was found for both hyperactivity (e.g., [Formula: see text] = 2.20 with 95% highest posterior density interval equal to [1.79;2.65] and effect size equal to 3.00) and inattention (e.g., [Formula: see text] = 2.16 with 95% highest posterior density interval equal to [1.56;2.79] and effect size equal to 3.07). These results indicate that unique-environmental influences were more important in creating individual differences in both hyperactivity and inattention for twins with a genetic predisposition for these symptoms than for twins without such a predisposition.

The relationship between weight-related indicators and depressive symptoms during adolescence and adulthood: results from two twin studies.

BACKGROUND: The association between weight and depressive symptoms is well established, but the direction of effects remains unclear. Most studies rely on body mass index (BMI) as the sole weight indicator, with few examining the aetiology of the association between weight indicators and depressive symptoms. METHODS: We analysed data from the Twins Early Development Study (TEDS) and UK Adult Twin Registry (TwinsUK) (7658 and 2775 twin pairs, respectively). A phenotypic cross-lagged panel model assessed the directionality between BMI and depressive symptoms at ages 12, 16, and 21 years in TEDS. Bivariate correlations tested the phenotypic association between a range of weight indicators and depressive symptoms in TwinsUK. In both samples, structural equation modelling of twin data investigated genetic and environmental influences between weight indicators and depression. Sensitivity analyses included two-wave phenotypic cross-lagged panel models and the exclusion of those with a BMI <18.5. RESULTS: Within TEDS, the relationship between BMI and depression was bidirectional between ages 12 and 16 with a stronger influence of earlier BMI on later depression. The associations were unidirectional thereafter with depression at 16 influencing BMI at 21. Small genetic correlations were found between BMI and depression at ages 16 and 21, but not at 12. Within TwinsUK, depression was weakly correlated with weight indicators; therefore, it was not possible to generate precise estimates of genetic or environmental correlations. CONCLUSIONS: The directionality of the relationship between BMI and depression appears to be developmentally sensitive. Further research with larger genetically informative samples is needed to estimate the aetiological influence on these associations.

Double Vision: Study of U.K. Twins Provides New Insight Into Human Wellbeing.

Back in 1992, when Prof. Tim Spector of King's College London set up a study to investigate the incidence of osteoporosis and other rheumatologic diseases in monozygotic (identical) twins, little did he know how much the project would expand its horizons. From a few hundred identical twins, the cohort has grown to more than 15,000 identical and nonidentical twins across the U.K., aged between 18 and 100, and a host of diseases and conditions are under the microscope (Figure 1). Now, TwinsUK has one of the most deeply characterized adult twin cohorts anywhere in the world, providing vast quantities of data for longitudinal studies of health and aging.

Case of twin achondroplasia and autism coexistence and literature review.

Achondroplasia and autism spectrum disorder (ASD) are two genetically based disorders. The coexistence of autism with chromosomal abnormalities such as Down syndrome, monogenic syndromes such as tuberous sclerosis, Fragile X, and Rett syndrome, and microdeletion syndromes such as Phelan-McDermid syndrome helps to shed light on the genetic basis of autism spectrum disorder. The association between ASD and achondroplasia has been reported twice in the literature. In this article, we report Turkish patients who were born as identical twins from IVF pregnancy of 34 and 36-year-old parents, clinically and molecularly diagnosed with achondroplasia, and diagnosed with ASD at the age of 39 months. Our case is the first twin patient with the coexistence of achondroplasia and autism. We discuss environmental and genetic factors contributing to the development of ASD.

The Management of Acardiac Twinning: Twin Reverse Arterial Perfusion Sequence - An International Survey.

INTRODUCTION: The optimal approach and therapy method for the acardiac twin with a reverse arterial perfusion sequence has not yet been established. The aim of this study was to determine the clinical practice patterns among international fetal therapy units in their management of these cases. METHODS: A survey was sent to fetal centers across the world via email between December 2020 and December 2021. RESULTS: Responses were obtained from 77% contacted centers. The most frequent ultrasound variables used in the evaluation of twin reverse arterial perfusion sequence include echocardiographic assessment of the pump twin and umbilical artery Doppler waveforms in the acardiac and pump twins, in 90% and 80% of the centers, respectively. Most centers in Europe and Latin America propose an in utero intervention in all cases. Most centers in Europe and Latin America prefer interstitial laser ablation, whereas radiofrequency ablation (RFA) is preferred in North America. The earliest gestational age for an intervention is on mean 13 weeks in Europe, which is earlier than the other geographic areas (p = 0.001). CONCLUSIONS: Most centers agreed that antenatal evaluation should include echocardiography along with the UA Doppler waveform measurements, and the most frequently used interventions were interstitial laser ablation or RFA at a median between 14 and 26 weeks.

Associations between socioeconomic factors and depression in Sri Lanka: The role of gene-environment interplay.

BACKGROUND: Low socioeconomic status is a risk factor for depression. The nature and magnitude of associations can differ cross-culturally and is influenced by a range of contextual factors. We examined the aetiology of socioeconomic indicators and depression symptoms and investigated whether socioeconomic indicators moderate genetic and environmental influences on depression symptoms in a Sri Lankan population. METHODS: Data were from a population-based sample of twins (N = 2934) and singletons (N = 1035) in Colombo, Sri Lanka. Standard of living, educational attainment, and financial strain were used to index socioeconomic status. Depression symptoms were assessed using the Revised Beck Depression Inventory. Structural equation modelling explored genetic and environmental influences on socioeconomic indicators and depression symptoms and moderation of aetiological influences on depression symptoms by socioeconomic status. RESULTS: Depression symptoms were associated with lower standard of living, lower educational attainment, and financial strain. Sex differences were evident in the aetiology of standard of living, with a small contribution of genetic influences in females. Educational attainment was moderately heritable in both males and females. Total variance in depression was greater among less socioeconomically advantaged individuals. Modest evidence of moderation of the aetiology of depression by standard of living and education was observed. LIMITATIONS: While the sample is representative of individuals living in Colombo District, it may not be representative of different regions of Sri Lanka. CONCLUSIONS: The aetiology of depression varies across socioeconomic contexts, suggesting a potential mechanism through which socioeconomic disadvantage increases the risk for depression in Sri Lanka. Findings have implications for cross-cultural investigations of the role of socioeconomic factors in depression and for identifying targets for social interventions.

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

BACKGROUND: The 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. METHODS: OCDTWIN 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. DISCUSSION: OCDTWIN 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.

[A descriptive analysis on hypertension in adult twins in China].

Objective: To describe the distribution characteristics of hypertension among adult twins in the Chinese National Twin Registry (CNTR) and to provide clues for exploring the role of genetic and environmental factors on hypertension. Methods: A total of 69 220 (34 610 pairs) of twins aged 18 and above with hypertension information were selected from CNTR registered from 2010 to 2018. Random effect models were used to describe the population and regional distribution of hypertension in twins. To estimate the heritability, the concordance rates of hypertension were calculated and compared between monozygotic twins (MZ) and dizygotic twins (DZ). Results: The age of all participants was (34.1±12.4) years. The overall self-reported prevalence of hypertension was 3.8%(2 610/69 220). Twin pairs who were older, living in urban areas, married, overweight or obese, current smokers or ex-smokers, and current drinkers or abstainers had a higher self-reported prevalence of hypertension (P<0.05). Analysis within the same-sex twin pairs found that the concordance rate of hypertension was 43.2% in MZ and 27.0% in DZ, and the difference was statistically significant (P<0.001). The heritability of hypertension was 22.1% (95%CI: 16.3%- 28.0%). Stratified by gender, age, and region, the concordance rate of hypertension in MZ was still higher than that in DZ. The heritability of hypertension was higher in female participants. Conclusions: There were differences in the distribution of hypertension among twins with different demographic and regional characteristics. It is indicated that genetic factors play a crucial role in hypertension in different genders, ages, and regions, while the magnitude of genetic effects may vary.

[A descriptive analysis of hyperlipidemia in adult twins in China].

Objective: To describe the distribution characteristics of hyperlipidemia in adult twins in the Chinese National Twin Registry (CNTR) and explore the effect of genetic and environmental factors on hyperlipidemia. Methods: Twins recruited from the CNTR in 11 project areas across China were included in the study. A total of 69 130 (34 565 pairs) of adult twins with complete information on hyperlipidemia were selected for analysis. The random effect model was used to characterize the population and regional distribution of hyperlipidemia among twins. The concordance rates of hyperlipidemia were calculated in monozygotic twins (MZ) and dizygotic twins (DZ), respectively, to estimate the heritability. Results: The age of all participants was (34.2±12.4) years. This study's prevalence of hyperlipidemia was 1.3% (895/69 130). Twin pairs who were men, older, living in urban areas, married,had junior college degree or above, overweight, obese, insufficient physical activity, current smokers, ex-smokers, current drinkers, and ex-drinkers had a higher prevalence of hyperlipidemia (P<0.05). In within-pair analysis, the concordance rate of hyperlipidemia was 29.1% (118/405) in MZ and 18.1% (57/315) in DZ, and the difference was statistically significant (P<0.05). Stratified by gender, age, and region, the concordance rate of hyperlipidemia in MZ was still higher than that in DZ. Further, in within-same-sex twin pair analyses, the heritability of hyperlipidemia was 13.04% (95%CI: 2.61%-23.47%) in the northern group and 18.59% (95%CI: 4.43%-32.74%) in the female group, respectively. Conclusions: Adult twins were included in this study and were found to have a lower prevalence of hyperlipidemia than in the general population study, with population and regional differences. Genetic factors influence hyperlipidemia, but the genetic effect may vary with gender and area.

A population-based twin study of the symptomatic diagnostic criteria for major depression that occur within versus outside of major depressive episodes.

BACKGROUND: Are genetic risk factors for current depressive symptoms good proxies for genetic risk factors for syndromal major depression (MD)? METHODS: In over 9000 twins from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, the occurrence of all nine DSM symptomatic criteria for MD in the last year was assessed at personal interview and then grouped by their temporal co-occurrence. The DSM criteria which occurred outside (OUT) v. inside of (IN) MD episodes were then separated. We calculated tetrachoric correlations for OUT and IN depressive criteria in monozygotic (MZ) and dizygotic (DZ) pairs and fitted univariate and bivariate ACE twin models using OpenMx. RESULTS: The mean twin correlations (±95% CIs) for IN depressive criteria were substantially higher than for OUT depressive criteria in both MZ [+0.35 (0.32-0.38) v. 0.20 (0.17-0.24)] and DZ pairs [0.20 (0.17-0.24) v. 0.10 (0.04-0.16]. The mean IN-OUT cross-correlation in MZ and DZ pairs was modest [+0.15 (0.07-0.24) and +0.07 (0.03-0.12)]. The mean heritability estimates for the nine In v. Out depressive criteria was 0.31 (0.22-0.41) and 0.15 (0.08-0.21), in MZ and DZ pairs, respectively. The mean genetic correlation between the nine IN and OUT depressive criteria was +0.07 (-0.07 to 0.21). CONCLUSIONS: Depressive criteria occurring outside depressive episodes are less heritable than those occurring within. These two ways criteria can manifest are not closely genetically related. Current depressive symptoms - most of which are occurring outside of depressive episodes - are not, for genetic studies, good proxies for MD.

Long-term adverse neurodevelopmental outcomes of discordant twins delivered at term: A nationwide population-based study.

OBJECTIVE: To evaluate long-term adverse neurodevelopmental outcomes of discordant twins delivered at term. DESIGN: Retrospective cohort study. SETTING: Nationwide (Republic of Korea). POPULATION: All twin children delivered at term between 2007 and 2010. METHODS: The study population was divided into two groups according to inter-twin birthweight discordancy: the 'concordant twin group', twin pairs with inter-twin birthweight discordancy less than 20%; and the 'discordant twin group', twin pairs with inter-twin birthweight discordancy of 20% or more. The risk of long-term adverse neurodevelopmental outcomes was compared between the concordant twin group and the discordant twin group. Long-term adverse neurodevelopmental outcomes between smaller and larger twin children within twin pairs were further analysed. The composite adverse neurodevelopmental outcome was defined as the presence of at least one of the following: motor developmental delay, cognitive developmental delay, autism spectrum disorders/attention deficit hyperactivity disorders, tics/stereotypical behaviour or epileptic/febrile seizure. MAIN OUTCOME MEASURES: Long-term adverse neurodevelopmental outcome. RESULTS: Of 22 468 twin children (11 234 pairs) included, 3412 (15.19%) twin children were discordant. The risk of composite adverse neurodevelopmental outcome was higher in the discordant twin group than in the concordant twin group (adjusted hazard ratio [HR] 1.13, 95% CI 1.03-1.24). The long-term adverse neurodevelopmental outcomes were not significantly different between smaller and larger twin children in discordant twin pairs (adjusted HR 1.01, 95% CI 0.81-1.28). CONCLUSION: In twin pairs delivered at term, an inter-twin birthweight discordancy of 20% or greater was associated with long-term adverse neurodevelopmental outcomes; and long-term adverse neurodevelopmental outcomes were not significantly different in smaller or larger twin children in discordant twin pairs.

First report of surgery for anencephaly in twin pregnancies: Technical notes and postoperative management.

Anencephaly, the most severe form of neural tube defect, has no known cure, and in most cases, patients die before or shortly after birth. To date, no surgical intervention has been reported in the management of anencephaly. This study presents a case of dichorionic-diamniotic twin pregnancy in which 1 twin was anencephalic and describes the surgical management of this complex case. We aimed to share the problems experienced during the follow up of a patient who survived for a long time after surgery. We also aimed to highlight several clinical issues, including the challenges of managing anencephaly in twin pregnancies, problems experienced during the follow up process in our case, diagnosis of brain death in anencephaly cases, and ethical dilemmas related to organ donation. This case is notable because of the challenging nature of the surgical procedure and complexity of postoperative care. By highlighting the difficulties encountered during the follow up period, we hope to provide insights to health professionals that can inform the management of similar cases in the future.

The Concept of Resistance to Substance Use and a Research Approach: The Resist! Project.

Illicit substance use is dangerous in both acute and chronic forms, frequently resulting in lethal poisoning, addiction, and other negative consequences. Similar to research in other psychiatric conditions, whose ultimate goal is to enable effective prevention and treatment, studies in substance use are focused on factors elevating the risk for the disorder. The rapid growth of the substance use problem despite the effort invested in fighting it, however, suggests the need in changing the research approach. Instead of attempting to identify risk factors, whose neutralization is often infeasible if not impossible, it may be more promising to systematically reverse the perspective to the factors enhancing the aspect of liability to disorder that shares the same dimension but is opposite to risk, that is, resistance to substance use. Resistance factors, which enable the majority of the population to remain unaffected despite the ubiquity of psychoactive substances, may be more amenable to translation. While the resistance aspect of liability is symmetric to risk, the resistance approach requires substantial changes in sampling (high-resistance rather than high-risk) and using quantitative indices of liability. This article provides an overview and a practical approach to research in resistance to substance use/addiction, currently implemented in a NIH-funded project. The project benefits from unique opportunities afforded by the data originating from two longitudinal twin studies, the Virginia Twin Study of Adolescent and Behavioral Development and the Minnesota Twin Family Study. The methodology described is also applicable to other psychiatric disorders.

Disadvantage and disordered eating in boys: Examining phenotypic and genotype × environment associations across development.

Socioeconomic disadvantage may be a significant risk factor for disordered eating, particularly for individuals with underlying genetic risk. However, little to nothing is known about the impact of disadvantage on disordered eating in boys during the critical developmental risk period. Crucially, risk models developed for girls may not necessarily apply to boys, as boys show different developmental patterns of disordered eating risk (i.e., earlier activation of genetic influences during adrenarche, an early stage of puberty). This is the first study to examine phenotypic and Genotype × Environment (G × E) effects of disadvantage in boys. Analyses examined 3,484 male twins ages 8-17 (Mage = 12.27, SD = 2.96) from the Michigan State University Twin Registry. Disordered eating (e.g., body dissatisfaction, binge eating) was measured using the parent-report Michigan Twins Project Eating Disorder Survey. Neighborhood disadvantage was measured using a census-tract level Area Deprivation Index, and family socioeconomic status was determined from parental income and education. Adrenarche status was determined using multiple indicators, including age and Pubertal Development Scale scores. G × E models suggested that genetic influences on disordered eating were activated earlier for boys experiencing familial or neighborhood disadvantage, with substantial genetic influences in early adrenarche, when genetic influences were low in more advantaged boys. Phenotypically, both neighborhood and familial disadvantage were associated with greater disordered eating for boys in late adrenarche, which could indicate a lasting impact of earlier activation of genetic influences on later risk. Results highlight disadvantage as a novel risk factor for disordered eating in boys, particularly those with genetic vulnerabilities. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Inference on the Genetic Architecture of Breast Cancer Risk.

BACKGROUND: What are the major determinants of women's breast cancer risk? Rare mutations such as those in the BRCA1/2 genes, polygenic scores of common alleles identified by genome-wide association studies, or nongenetic factors? METHODS: The population-based Nordic Twin Study of Cancer, with 3,933 breast cancer cases among 21,054 monozygotic (MZ) and 30,939 dizygotic (DZ) female twin pairs, provides three key clues to this question: (i) the average lifetime risk, approximately 8%, does not differ by twin zygosity; (ii) the mean time interval between diagnoses when both twins develop disease (i.e., disease concordance) also does not differ by zygosity; but, (iii) conditioning on one twin having developed disease, the incidence rate in the co-twin is approximately 1% per year if the pair is MZ and 0.5% per year if DZ. RESULTS: Assuming that nongenetic risk factors are shared similarly between twins regardless of zygosity, we can draw two conclusions from (i) to (iii). CONCLUSIONS: First, (i) and (iii) imply that the chief determinant of risk is in the germline DNA, because the conditional incidence rate is several-fold higher than the average risk (8% lifetime) in MZ twins but only half as much in DZ twins. Second, the seeming inconsistency between the two-fold conditional incidence rate (iii) and the equality of the mean inter-twin disease intervals in disease concordance (ii) can be resolved if the risk factors in the germline DNA are rare variants, not common variants. IMPACT: This paper details simple deductive reasoning for these conclusions and draws a critical inference regarding breast cancer etiology. See related In the Spotlight, p. 1477.

Stressful life events increase the risk of major depressive episodes: A population-based twin study.

BACKGROUND: Previous studies have found that stressful life events (SLEs) are associated with an increased risk of adult depression. However, many studies are observational in nature and limited by methodological issues, such as potential confounding by genetic factors. Genetically informative research, such as the co-twin control design, can strengthen causal inference in observational studies. Discrete-time survival analysis has several benefits and multilevel survival analysis can incorporate frailty terms (random effects) to estimate the components of the biometric model. In the current study, we investigated associations between SLEs and depression risk in a population-based twin sample (N = 2299). METHODS: A co-twin control design was used to investigate the influence of the occurrence of SLEs on depression risk. The co-twin control design involves comparing patterns of associations in the full sample and within dizygotic (DZ) and monozygotic twins (MZ). Associations were modelled using discrete-time survival analysis with biometric frailty terms. Data from two time points were used in the analyses. Mean age at Wave 1 was 28 years and mean age at Wave 2 was 38 years. RESULTS: SLE occurrence was associated with increased depression risk. Co-twin control analyses indicated that this association was at least in part due to the causal influence of SLE exposure on depression risk for event occurrence across all SLEs and for violent SLEs. A minor proportion of the total genetic risk of depression reflected genetic effects related to SLEs. CONCLUSIONS: The results support previous research in implicating SLEs as important risk factors with probable causal influence on depression risk.