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The Swedish Twin Registry functions as research infrastructure containing information on 216,258 twins born between 1886 and 2015, of whom 86,199 pairs have zygosity determined by DNA, an intrapair similarity algorithm, or being of opposite sex. In essence, practically all twins alive and currently 9 years or older have been invited for participation and donation of DNA on which genomewide single nucleotide polymorphisms array genotyping has been performed. Content, management and alternatives for future improvements are discussed.
The Interplay of Genes and Environment across Multiple Studies (IGEMS) is a consortium of 18 twin studies from 5 different countries (Sweden, Denmark, Finland, United States, and Australia) established to explore the nature of gene–environment (GE) interplay in functioning across the adult lifespan. Fifteen of the studies are longitudinal, with follow-up as long as 59 years after baseline. The combined data from over 76,000 participants aged 14–103 at intake (including over 10,000 monozygotic and over 17,000 dizygotic twin pairs) support two primary research emphases: (1) investigation of models of GE interplay of early life adversity, and social factors at micro and macro environmental levels and with diverse outcomes, including mortality, physical functioning and psychological functioning; and (2) improved understanding of risk and protective factors for dementia by incorporating unmeasured and measured genetic factors with a wide range of exposures measured in young adulthood, midlife and later life.
Existing evidence for gene × environment interaction (G × E) in neuroticism largely relies on candidate gene studies, although neuroticism is highly polygenic. This study aimed to investigate the long-term associations between polygenic risk scores for neuroticism (PRSN), objective childhood adversity and their interplay on emotional health aspects such as neuroticism itself, depressive symptoms, anxiety symptoms, loneliness and life satisfaction.
The sample consisted of reared-apart (TRA) and reared-together (TRT) middle- and old age twins (N = 699; median age at separation = 2). PRSN were created under nine p value cut-off thresholds (pT-s) and the pT with the highest degree of neuroticism variance explained was chosen for subsequent analyses. Linear regressions were used to assess the associations between PRSN, childhood adversity (being reared apart) and emotional health. G × E was further investigated using a discordant twin design.
PRSN explained up to 1.7% (pT < 0.01) of phenotypic neuroticism in the total sample. Analyses across two separation groups revealed substantial heterogeneity in the variance explained by PRSN; 4.3% was explained in TRT, but almost no effect was observed in TRA. Similarly, PRSN explained 4% and 1.7% of the variance in depressive symptoms and loneliness, respectively, only in TRT. A significant G × E interaction was identified for depressive symptoms.
By taking advantage of a unique sample of adopted twins, we demonstrated the presence of G × E in neuroticism and emotional health using PRSN and childhood adversity. Our results may indicate that genome-wide association studies are detecting genetic main effects associated with neuroticism, but not those susceptible to early environmental influences.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
Genetic and environmental factors contribute to the etiology of anorexia nervosa (AN). The co-twin control design is one of the most powerful methods available to evaluate environmental factors that could contribute to differences between monozygotic (MZ) twins who are discordant for AN. Using available data from a unique and rare sample of 22 Swedish female MZ pairs discordant for AN, we compared personality, life events, comorbidity, and health factors. Twins with AN had significantly higher perfectionism scores than unaffected co-twins and reported younger ages at first diet than unaffected co-twins who had dieted. Consistent with previous literature, more twins with AN reported gastrointestinal problems than unaffected co-twins. Although not significant due to low statistical power, more unaffected co-twins reported experiencing emotional neglect than twins with AN. Early dieting may be a harbinger of the development of AN or an early symptom. Higher perfectionism may represent a risk factor, sequela, or both. Sibling perception of neglect is noteworthy given the impact of an ill child with AN on family function and wellbeing. The health and wellbeing of siblings should be addressed clinically when one child in the family suffers from AN.
Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.
We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.
Twin pairs discordant for disease may help elucidate the epigenetic mechanisms and causal environmental factors in disease development and progression. To obtain the numbers of pairs, especially monozygotic (MZ) twin pairs, necessary for in-depth studies while also allowing for replication, twin studies worldwide need to pool their resources. The Discordant Twin (DISCOTWIN) consortium was established for this goal. Here, we describe the DISCOTWIN Consortium and present an analysis of type 2 diabetes (T2D) data in nearly 35,000 twin pairs. Seven twin cohorts from Europe (Denmark, Finland, Norway, the Netherlands, Spain, Sweden, and the United Kingdom) and one from Australia investigated the rate of discordance for T2D in same-sex twin pairs aged 45 years and older. Data were available for 34,166 same-sex twin pairs, of which 13,970 were MZ, with T2D diagnosis based on self-reported diagnosis and medication use, fasting glucose and insulin measures, or medical records. The prevalence of T2D ranged from 2.6% to 12.3% across the cohorts depending on age, body mass index (BMI), and national diabetes prevalence. T2D discordance rate was lower for MZ (5.1%, range 2.9–11.2%) than for same-sex dizygotic (DZ) (8.0%, range 4.9–13.5%) pairs. Across DISCOTWIN, 720 discordant MZ pairs were identified. Except for the oldest of the Danish cohorts (mean age 79), heritability estimates based on contingency tables were moderate to high (0.47–0.77). From a meta-analysis of all data, the heritability was estimated at 72% (95% confidence interval 61–78%). This study demonstrated high T2D prevalence and high heritability for T2D liability across twin cohorts. Therefore, the number of discordant MZ pairs for T2D is limited. By combining national resources, the DISCOTWIN Consortium maximizes the number of discordant MZ pairs needed for in-depth genotyping, multi-omics, and phenotyping studies, which may provide unique insights into the pathways linking genes to the development of many diseases.
A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m2 in childhood and adolescence and up to 0.2 kg/m2 in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes.
For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m2) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes.
Previous studies have found that major depression and neuroticism are positively associated with urinary incontinence (UI). However, the genetic contribution to these associations has never been investigated. In 2005, a total of 14,094 female twins born 1959–1985 in the Swedish Twin Registry participated in a comprehensive survey on common exposures and complex diseases. Structured questions provided information on UI, depressive symptoms, major depression, and neuroticism. A logistic regression model based on generalized estimating equations (GEE) was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Environmental and genetic influences were assessed in co-twin control analyses and quantitative genetic analyses, which were also used to determine the proportion of the phenotypic correlation explained by familial factors. Major depression, depressive symptoms, and neuroticism were positively associated with all UI subtypes (overall, stress, urge, and mixed UI). In a trivariate Cholesky model with neuroticism, depressive symptoms (or depression), and UI a modest genetic correlation was found between indicators of depression and overall, or stress, UI. The majority of this correlation was independent from neuroticism. In contrast, the genetic factors shared between indicators of depression and urge or mixed UI were entirely in common with neuroticism. In conclusion, depression and neuroticism are associated with UI among premenopausal women: the associations are in part determined by genetic factors in common to the disorders.
The Interplay of Genes and Environment across Multiple Studies (IGEMS) group is a consortium of eight longitudinal twin studies established to explore the nature of social context effects and gene-environment interplay in late-life functioning. The resulting analysis of the combined data from over 17,500 participants aged 25–102 at baseline (including nearly 2,600 monogygotic and 4,300 dizygotic twin pairs and over 1,700 family members) aims to understand why early life adversity, and social factors such as isolation and loneliness, are associated with diverse outcomes including mortality, physical functioning (health, functional ability), and psychological functioning (well-being, cognition), particularly in later life.
The Swedish Twin Registry (STR) today contains more than 194,000 twins and more than 75,000 pairs have zygosity determined by an intra-pair similarity algorithm, DNA, or by being of opposite sex. Of these, approximately 20,000, 25,000, and 30,000 pairs are monozygotic, same-sex dizygotic, and opposite-sex dizygotic pairs, respectively. Since its establishment in the late 1950s, the STR has been an important epidemiological resource for the study of genetic and environmental influences on a multitude of traits, behaviors, and diseases. Following large investments in the collection of biological specimens in the past 10 years we have now established a Swedish twin biobank with DNA from 45,000 twins and blood serum from 15,000 twins, which effectively has also transformed the registry into a powerful resource for molecular studies. We here describe the main projects within which the new collections of both biological samples as well as phenotypic measures have been collected. Coverage by year of birth, zygosity determination, ethnic heterogeneity, and influences of in vitro fertilization are also described.
Studies suggest a role for cardiovascular fitness in the prevention of
To determine whether cardiovascular fitness at age 18 is associated with
future risk of serious affective illness.
Population-based Swedish cohort study of male conscripts
(n = 1 117 292) born in 1950–1987 with no history of
mental illness who were followed for 3–40 years. Data on cardiovascular
fitness at conscription were linked with national hospital registers to
calculate future risk of depression (requiring in-patient care) and
In fully adjusted models low cardiovascular fitness was associated with
increased risk for serious depression (hazard ratios (HR)=1.96, 95%, CI
1.71–2.23). No such association could be shown for bipolar disorder
(HR=1.11, 95% CI 0.84–1.47).
Lower cardiovascular fitness at age 18 was associated with increased risk
of serious depression in adulthood. These results strengthen the theory
of a cardiovascular contribution to the aetiology of depression.
The Study of Dementia in Swedish Twins is a study of dementia in a defined population of twins. The goals included estimating heritability of Alzheimer's disease and identifying risk and protective factors in twin pairs discordant for the disease. The data, including not only diagnoses and age of onset but also extensive information about potential environmental risk factors, are now archived as Study ICPSR 25963 at National Archive for Computerized Data on Aging, Inter-university Consortium for Political and Social Research, at the University of Michigan, and available for researchers to use. Up to the time of archiving, 215 cases of dementia have been identified from a base sample of 2,394 individuals.
Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene–environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (P = 3.98 × 10−8). We followed up the association in further genotyped monozygotic twins (N = 1,261), which showed a moderate association for the variant (P = 0.200, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (P = 4.03 × 10−8).
Since the Swedish Twin Registry was first established in the late 1950s to study the importance of smoking and alcohol consumption on cancer and cardiovascular diseases, it has been expanded and updated on several occasions. The focus has similarly broadened to most common complex diseases. The content of the database is described, ongoing projects based on the registry are summarized, and we review some of the principal findings on aging, cancer and cardiovascular disease that have come from the registry. Ongoing efforts and future plans for the STR are discussed. Among others, we plan blood collection and genotyping to study the genetic bases of complex diseases, a first contact ever with the cohorts born after 1958, and in-depth studies of selected diseases, such as Parkinson’s disease and chronic fatigue syndrome.
Database infrastructure has become a critical component for competitive life sciences research and discovery. The explosion of data requires that the data are properly loaded, accessed, managed, queried, analyzed, and shared with others. The key purpose of the population-based twin cohorts housed at different institutions in Europe is to gather an extremely large quantity of information from their twin populations, and share it. Longitudinal research over a long period of time, hopefully generations, demands completely new methods and systems to handle the gathering of information and storing. These cohorts bring to the fore problems concerning the need for a standardization of research data and a computer and storage strategy. In the following we describe the preliminary strategy being implemented in the Database Core of GenomEUtwin.