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STUDY QUESTION Is there a relation between ART and DNA methylation (DNAm) patterns in cord blood, including any differences between IVF and ICSI? SUMMARY ANSWER DNAm at 19 CpGs was associated with conception via ART, with no difference found between IVF and ICSI. WHAT IS KNOWN ALREADY Prior studies on either IVF or ICSI show conflicting outcomes, as both widespread effects on DNAm and highly localized associations have been reported. No study on both IVF and ICSI and genome-wide neonatal DNAm has been performed. STUDY DESIGN, SIZE, DURATION This was a cross-sectional study comprising 87 infants conceived with IVF or ICSI and 70 conceived following medically unassisted conception. The requirement for inclusion in the study was an understanding of the Swedish language and exclusion was the use of donor gametes. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were from the UppstART study, which was recruited from fertility and reproductive health clinics, and the Born into Life cohort, which is recruited from the larger LifeGene study. We measured DNAm from DNA extracted from cord blood collected at birth using a micro-array (450k array). Group differences in DNAm at individual CpG dinucleotides (CpGs) were determined using robust linear models and post-hoc Tukey’s tests. MAIN RESULTS AND THE ROLE OF CHANCE We found no association of ART conception with global methylation levels, imprinted loci and meta-stable epialleles. In contrast, we identify 19 CpGs at which DNAm was associated with being conceived via ART (effect estimates: 0.5–4.9%, PFDR < 0.05), but no difference was found between IVF and ICSI. The associated CpGs map to genes related to brain function/development or genes connected to the plethora of conditions linked to subfertility, but functional annotation did not point to any likely functional consequences. LIMITATIONS, REASONS FOR CAUTION We measured DNAm in cord blood and not at later ages or in other tissues. Given the number of tests performed, our study power is limited and the findings need to be replicated in an independent study. WIDER IMPLICATIONS OF THE FINDINGS We find that ART is associated with DNAm differences in cord blood when compared to non-ART samples, but these differences are limited in number and effect size and have unknown functional consequences in adult blood. We did not find indications of differences between IVF and ICSI. STUDY FUNDING/COMPETING INTEREST(S) E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128) and JPI-H2020 Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI HDHL) under proposal number 655 (PREcisE Project) through ZonMw (529051023). Financial support was provided from the European Union’s Seventh Framework Program IDEAL (259679), the Swedish Research Council (K2011-69X-21871-01-6, 2011-3060, 2015-02434 and 2018-02640) and the Strategic Research Program in Epidemiology Young Scholar Awards, Karolinska Institute (to A.N.I.) and through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Strategic Research Program in Epidemiology at Karolinska Institutet and the Swedish Heart-Lung Foundation and Danderyd University Hospital (Stockholm, Sweden). The funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript. The authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.

The study aimed to investigate if assisted reproductive technology (ART) treatment or a diagnosis of infertility were associated with the risk of ovarian cancer or borderline ovarian tumors (BOT) in parous women. In a population-based register study of 1,340,097 women with a first live birth in Sweden 1982–2012, the relationship between ART treatments, infertility and incidence of ovarian cancer or BOT were investigated using Cox regression analysis. In the cohort, 38,025 women gave birth following ART, 49,208 following an infertility diagnosis but no ART and 1,252,864 without infertility diagnosis or ART. During follow-up, 991 women were diagnosed with ovarian cancer and 747 with BOT. Women who gave birth following ART had higher incidence of both ovarian cancer (adjusted hazard ratio [aHR] 2.43, 95% confidence interval [CI] 1.73–3.42) and BOT (aHR 1.91, 95% CI 1.27–2.86), compared to women without infertility. Compared to women with infertility diagnoses and non-ART births, women with ART births also had a higher incidence of ovarian cancer (aHR 1.79, 95% CI 1.18–2.71) and BOT (aHR 1.48, 95% CI 0.90–2.44). Our results suggest that women who have gone through ART have a higher risk of ovarian cancer and BOT. At least part of that risk seems to be due to the underlying infertility and not the treatment per se, since the increased risk was smaller when comparing to other infertile women. As ART treatments are becoming more common and ovarian cancer usually occur in women of advanced age, larger studies with longer follow-up are needed in order to confirm or refute our findings. Electronic supplementary material The online version of this article (10.1007/s10654-019-00540-3) contains supplementary material, which is available to authorized users.

Some studies have suggested that infertility is a risk factor for endometrial, ovarian and breast cancer. The study aimed to create a comprehensive picture of the association between infertility and the risk of ovarian, endometrial and breast cancer, and whether any association could be explained by ovulatory disturbances, endometriosis or nulliparity. In a population-based cohort of 2,882,847 women, cox regression analysis was used to investigate cancer incidence among infertile women. Overall, infertility was associated with a higher incidence rate of ovarian (adjusted hazard ratio [aHR] 1.53, 95% confidence interval [CI] 1.38–1.71) and endometrial cancer (aHR 1.25, 95% CI 1.11–1.40), but not of breast cancer (aHR 0.96, 95% CI 0.92–1.01). Ovarian cancer incidence was higher in women diagnosed with endometriosis, and in nulliparous women with ovulatory disturbances, compared to women with none of the diagnoses. Endometrial cancer incidence was higher in women with ovulatory disturbances, but not in women with endometriosis. These findings suggest that infertility could have long-term consequences of importance to physicians and public health workers. Electronic supplementary material The online version of this article (10.1007/s10654-018-0474-9) contains supplementary material, which is available to authorized users.

Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting 5-15% of reproductive-aged women and characterized by high levels of circulating androgens. Given that androgens have been implicated in the aetiology of several psychiatric disorders, it was hypothesized that women with PCOS have high risk for psychiatric comorbidity. We aimed to investigate this risk amongst women with PCOS, as well as in their siblings, to elucidate if familial factors underlie any potential associations. Using the Swedish national registers, we identified all women diagnosed with PCOS between 1990 and 2013 (n=24,385), their full-siblings (n=25,921), plus matched individuals (1:10/100) from the general population and their full-siblings. Psychiatric disorder diagnoses were identified including schizophrenia, bipolar disorder, depressive and anxiety disorders, eating disorders, personality and gender identity disorder, autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), tics, attempted and completed suicide. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression and adjusted ORs (AOR) were determined by adjustment for comorbid psychiatric disorders. Overall, women with PCOS had an increased odds of having at least one psychiatric disorder (OR=1.56 [95CI%, 1.51-1.61]). Crude ORs showed associations with nearly all psychiatric disorders included in this study. Following adjustment for comorbid psychiatric disorders, women with PCOS were still at a significantly increased risk for bulimia, schizophrenia, bipolar disorder, depressive and anxiety disorders, personality disorders, with the highest AORs for ASD (AOR=1.55 [95%CI, 1.32-1.81]) and tics (AOR=1.65 [95%CI, 1.10-2.47]). Significantly higher AORs were found for ASD in both brothers and sisters of women with PCOS, and for depressive, anxiety, and schizophrenia spectrum disorders in the sisters only. Notably, the crude ORs for attempted suicide were 40% higher in women with PCOS and 16% higher in their unaffected sisters. However, the AORs were greatly attenuated indicating that underlying psychiatric comorbidity is important for this association. Women with PCOS had higher risks for a range of psychiatric disorders not shown before. Elevated risk in their siblings suggests shared familial factors between PCOS and psychiatric disorders. This study is an important first step towards identifying the underlying mechanisms for risk of psychiatric disorders in women with PCOS. Health professionals treating women with PCOS should be aware that these patients - as well as their family members - are important targets for mental health care.

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

Background Women with polycystic ovary syndrome (PCOS) are at elevated risk for suffering from depression. Neuroticism is a personality trait that has been associated with an increased risk for developing major depressive disorder (MDD). The aim of the present study was to quantify and decompose the correlation between neuroticism, PCOS, and MDD into shared and unique genetic and environmental etiologies, by using quantitative genetic methods. Methods In a cohort of 12,628 Swedish female twins born from 1959 to 1985, neuroticism, PCOS identified by symptoms of hyperandrogenemia (i.e., hirsutism) and oligo- and/or anovulation, and lifetime MDD status were determined through questionnaire responses. Structural equation modeling was used to study the genetic and environmental sources of the variation within, and covariation between neuroticism, PCOS, and MDD. Results Female twins with PCOS (n = 752) had significantly higher levels of neuroticism than women without PCOS, and a 2-fold increase in odds for a lifetime prevalence of MDD. The phenotypic correlation between PCOS and MDD was 0.19, with 63% of the correlation attributable to common genetic factors between the two traits. When taking into account neuroticism, 41% was attributable to common genetic factors and 9% attributable to common environmental factors shared between all three traits, with the remainder attributable to components unique to PCOS and MDD. Conclusion There are common genetic factors between neuroticism, PCOS, and MDD; however, neuroticism shares approximately half of the genetic and environmental components behind the phenotypic correlation between PCOS and MDD, providing some etiological evidence behind the comorbidity between PCOS and depression.

PurposeThe Uppsala–Stockholm Assisted Reproductive Techniques (UppStART) study is a prospectively recruited sample of couples undergoing assisted reproduction in Stockholm and Uppsala county in Sweden. The study was initiated to (1) investigate possible changes in the epigenetic profile of infants inferred through the ART procedures and their consequence and (2) to assess the impact of lifestyle and health exposures on treatment outcome.ParticipantsRecruitment took place between September 2011 and December 2013, and in vitro fertilisation (IVF) cycles initiated and pregnancies conceived during this time were followed until December 2014. The cohort includes 971 participants (n= 514 women; n= 457 men), and 129 pregnancies were achieved from the first IVF cycle included in the study.Findings to dateSelf-reported demographic, health and lifestyle data were collected from a baseline questionnaire, and to assess changes to lifestyle, a follow-up questionnaire was issued at the time of oocyte retrieval, and at subsequent IVF cycles. Questionnaire data were linked to data extracted from medical records. Biological samples were collected at baseline: blood for extraction of serum, plasma and DNA, morning and evening saliva samples for cortisol measurement and at delivery including samples of maternal blood, placenta and amniotic fluid, and cord blood for epigenetic analysis.Future plansThrough the unique identification number assigned to each Swedish citizen at birth or immigration, UppStART study participants will be linked to the Swedish population-based national and quality registers to provide data from prenatal, obstetrical, neonatal and infant care, and subsequent updates will provide data on childhood health and educational outcomes. Collaboration and use of UppStART data is encouraged, and more information about access can be found at www.ki.se/meb/uppstart

Objective To investigate the association between a history of gestational diabetes mellitus (GDM) and overactive bladder (OAB) in women of premenopausal age. Design Population-based study. Setting The Swedish Twin Register. Population In 2005, a total of 14 094 female twins born between 1959 and 1985 in the Swedish Twin Registry participated in a comprehensive survey on common exposures and complex diseases. Structured questions provided information on GDM and OAB. The present study was designed as a cross-sectional analysis including all women in the cohort having given birth before 2005 (n = 7855). Methods A logistic regression model based on generalised estimating equations was used to derive odds ratios (ORs). Main outcome measure The association between a history of GDM and OAB was estimated using ORs with 95% confidence intervals (CIs). Results The prevalence of OAB in women with a history of GDM was 19.1% compared with 10.7% in women without GDM. This corresponded to a two-fold increased odds of OAB in women with a history of gestational diabetes (OR 2.13, 95% CI 1.48–3.05). After adjusting the analysis for age, body mass index, parity, smoking, and diabetes mellitus, having had GDM was associated with doubled odds of OAB (OR 1.88, 95% CI 1.26–2.80). Conclusions A history of GDM was positively associated with OAB among women of premenopausal age. The association does not seem to be mediated by body mass index or type-I or type-II diabetes mellitus.

Does the intergenerational influence on birthweight and birth length remain within female dizygotic and monozygotic twin pairs?The intergenerational influence on birthweight and birth length remained within dizygotic but not within monozygotic twin pairs.Low birthweight is associated with increased morbidity and mortality in both the short and long term; therefore it is important to understand determinants of fetal growth. There is a known intergenerational association between parents' and offspring's size at birth.This is a register-based cohort study with a nested within-twin-pair comparison. The study is retrospective, but based on prospectively collected information. The study population included 8685 monozygotic and like-sexed dizygotic female twins born in Sweden from 1926 to 1985, who had given birth to their first infant between 1973 and 2009.This study is set in Sweden and used data from the Swedish Twin Register and the Swedish Medical Birth Register. We used generalized estimating equations to obtain regression coefficients with 95% confidence intervals (CI) for the outcomes: offspring birthweight and birth length. To control for genetic and shared environmental factors, we performed within-twin-pair analyses in 1479 dizygotic and 1526 monozygotic twin pairs.In the cohort of both dizygotic and monozygotic twins, there was an association between mother's and offspring's size at birth. Within-dizygotic twin pairs, a 500-g increase from the twin pair's mean birthweight was associated with increased offspring birthweight [70 g (95% CI: 35-106)] and birth length [0.22 cm (95% CI: 0.07-0.38)]. The corresponding increase in birth length of 1 cm was estimated to increase offspring's birthweight by 26 g (95% CI: 12-40) and birth length by 0.11 cm (95% CI: 0.04-0.17). Within-monozygotic twin pairs there were no such associations.This study is limited to twins who themselves or whose co-twin voluntarily responded to questionnaires.The intergenerational influence on size at birth is suggested to be due to direct or indirect genetic factors.

OBJECTIVES Previous studies suggest that maternal smoking during pregnancy is associated with elevated offspring blood pressure during childhood. We aimed to investigate whether this association remained in late adolescence and, if so, whether it could be attributed to an intrauterine effect or to familial confounding. METHODS We used a national cohort of 87,223 young Swedish men born between 1983 and 1988 with information on both maternal smoking during pregnancy and blood pressure at military conscription. The cohort included 780 full brothers discordant for maternal smoking. Generalized estimation equations were used to estimate regression coefficients (β) with 95% confidence intervals (95% CIs). RESULTS We found a small but significant increase in both SBP and DBP for young men whose mothers had been daily smokers during pregnancy compared with sons of nonsmoking mothers: 0.26 (95% CI 0.09 to 0.44) and 0.45 mmHg (95% CI 0.31 to 0.59) for SBP and DBP, respectively. In a within-sibling analysis comparing full brothers discordant for maternal smoking exposure, point estimates were similar but not statistically significant: 0.85 (95% CI -0.19 to 1.90) for DBP and 0.81 (-0.56 to 2.19) for SBP. CONCLUSION Maternal smoking during pregnancy is associated with a small but statistically significant increase in offspring blood pressure in late adolescence. Because the association does not appear to be explained by familial confounding, our results support an intrauterine effect of prenatal smoking exposure on blood pressure in late adolescence.

Background— The widely reported inverse association between birth weight and risk of cardiovascular disease (CVD) has sparked theories about early life determinants of adult disease. Within-twin-pair analysis provides a unique opportunity to investigate whether factors shared within twin pairs influence the association. Methods and Results— In a population-based cohort of like-sexed twins with known zygosity born in Sweden from 1926 to 1958, disease-discordant twin pairs were identified through linkage to the National Inpatient and Cause of Death registers between 1973 and 2006. Co-twin–control analyses were performed on twins discordant for cardiovascular disease (n=3884), coronary heart disease (n=2668), and stroke (n=1372). Overall, inverse associations between birth weight and risk of cardiovascular diseases were seen within dizygotic but not monozygotic twin pairs. In dizygotic twins, the odds ratios for a 1-kg within-pair increase in birth weight were 0.74 (95% confidence interval, 0.56 to 0.98) for coronary heart disease and 0.57 (95% confidence interval, 0.37 to 0.88) for stroke. Conversely, no statistically significant associations were found within monozygotic twins (for coronary heart disease: odds ratio, 1.10; 95% confidence interval, 0.73 to 1.68; for stroke: odds ratio, 0.92; 95% confidence interval, 0.48 to 1.80). Conclusions— We found an association between birth weight and risk of cardiovascular disease within disease-discordant dizygotic but not monozygotic twin pairs. This indicates that the association between birth weight and cardiovascular disease could be a result of common causes, and that factors that vary within dizygotic but not monozygotic twin pairs may help identify them.

The relative importance of genetic and environmental factors for the occurrence of lower urinary tract symptoms (LUTS) is poorly understood.To (1) estimate the prevalence of urinary incontinence (UI), overactive bladder (OAB), and other LUTS and (2) to assess the heritability of these symptoms.Cross-sectional survey of LUTS in a national population-based cohort of Swedish twins 20-46 yr of age (n=42 582) from the Swedish Twin Registry.Prevalence rates were determined and heritability of LUTS (in female twins) was assessed using indicators of twin similarity.A total of 25 364 twins completed the questionnaire (response rate: 59.6%). LUTS were more common in women (UI: 7%; OAB: 9%; nocturia: 61%; micturition frequency: 18%) than in men (UI: 1%; OAB: 5%; nocturia: 40%; micturition frequency: 11%), and prevalence increased with age. The strongest genetic effects were observed for UI, frequency, and nocturia. The lowest estimate for genetic effects was observed for OAB where environmental effects dominated, and more specifically shared family environment accounted for a third or more of the total variation. For stress UI, a fifth of the total variation in susceptibility to the disorder could be attributed to shared environment. Nonshared environmental effects were seen in the range of 45-65% for the various LUTS. The prevalence of LUTS was low in the men, and there were too few male cases to compute measures of similarity or heritability estimates.This study provides robust evidence of a genetic influence for susceptibility to UI, frequency, and nocturia in women. In contrast, shared environmental factors seem more important for the predisposition to develop OAB, which may reflect familial patterns such as learning from parental behaviours.

Background In utero exposure to tobacco smoking has been suggested to cause persistent alterations in cognitive functioning. We examined if mothers’ smoking during pregnancy (SDP) is associated with long-term impairment in offspring stress coping and the causal mechanism behind a possible link. Methods We used a large cohort (n = 187 106) of young males in Sweden (mean age = 18.2 years), who underwent a semi-structured psychological assessment in 1997–2006, including an evaluation of stress coping ability, as part of the compulsory military conscript examination. We compared differentially exposed siblings within nuclear families and cousins in extended families and used multilevel structural equation models to disentangle genetic from environmental contributions to the association between SDP and stress coping. Results SDP and offspring stress coping was moderately strongly associated when comparing unrelated individuals [regression coefficient (b) = −0.38 on a nine-point scale; 95% confidence interval (CI) −0.40 to −0.36, P

We examined the risk of tuberculosis in relation to birth weight and ponderal index among 21,596 Swedish twins born from 1926 through 1958. Using a cohort design, tuberculosis risk was 11% lower for every 500 g of birth weight (P = .05) and 8% lower for every 0.2 of ponderal index, calculated as birth weight in grams multiplied by 100 and divided by the cube of birth length in centimeters (P = .08). The association between birth weight and tuberculosis was stronger in male individuals than in female individuals. In co-twin control analyses among disease-discordant monozygotic twins, tuberculosis risk was 46% lower for every 500 g of birth weight (P = .05). The association was stronger in male individuals (87% risk reduction; P = .02) than it was in female individuals (16% reduction; P = .62). A similarly stronger relation with male sex, compared with female sex, was found for ponderal index. Because associations among monozygotic twins are largely independent of shared genetic or environmental factors, we postulate that fetal growth may play a causal role in susceptibility to tuberculosis, possibly through early programming of immunity.

Maternal smoking during pregnancy (SDP) is associated with lower academic achievement in offspring. The current study, which was based on all births in Sweden from 1983 through 1991, explored the possible causal processes underlying the association between SDP and offspring school grades and a standardized assessment of mathematic proficiency at age 15. The analyses compared relatives who varied in their exposure to SDP and who varied in their genetic relatedness. Although SDP was statistically associated with academic achievement when comparing unrelated individuals, the results suggest that SDP does not cause poorer academic performance, as full siblings differentially exposed to SDP did not differ in their academic scores. The pattern of results suggests that genetic factors shared by parents and their offspring explain significant variance in why offspring opposed to SDP have lower levels of academic achievement. Nevertheless, SDP impacts pregnancy-related outcomes. Reducing SDP, therefore, remains a major public health issue.

Objective To assess the impact of oral contraceptives on lower urinary tract dysfunction in premenopausal women. Design Nationwide cohort study. Setting National registry. Patient(s) A total of 10,791 women (born 1959–1985) from the population- based Swedish Twin Registry who participated in a web-based survey of common diseases. Intervention(s) None. Main Outcome Measure(s) Symptoms of urinary incontinence. Result(s) For users of oral contraception there was a significantly reduced risk for symptoms of stress urinary incontinence, mixed urinary incontinence, and urgency urinary incontinence. The reduction remained significant when adjusting for age, body mass index, and pregnancy history. A reduced prevalence of symptoms of overactive bladder in oral contraceptive users was also observed although the association was nonsignificant. There were no significant associations between lower urinary tract symptoms and women using a levonorgestrel-releasing intrauterine device compared with noncontraceptive users, with the exception of nocturia. Conclusion(s) Oral contraceptive use reduces the overall risk for symptoms of urinary incontinence.

Type-2 diabetes increases the risk of colorectal cancer, and is also associated with low birth weight. However, we found no evidence of associations between birth characteristics and risk of colorectal cancer (m=248) among Swedish twins.

Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, with a correlation between RA disease severity and lymphoma risk, most pronounced for diffuse large B cell lymphomas (DLBCLs), which also constitute the majority of RA-associated lymphomas. DLBCLs can be further subdivided into germinal center (GC)-like and non-GC-like subtypes, with different cellular origins and prognoses. This study was undertaken to investigate whether RA displays a specific association with any of the DLBCL subtypes.We identified 139 patients with DLBCLs within a population-based case-control study of 378 RA patients with lymphoma. The DLBCLs were examined for CD10, Bcl-6, and interferon regulatory factor 4 expression patterns, subclassified into GC and non-GC subtypes, and then correlated with clinical parameters.We found a statistically significant predominance of the non-GC subtype (97 patients; 70% of all DLBCLs). These patients more often had an advanced stage of lymphoma at diagnosis and had a worse 5-year overall survival rate (16% versus 33%) compared with patients with the GC subtype. There was a strong association with RA disease activity in both subtypes, with70% of the GC and non-GC cases occurring in RA patients with the highest overall disease activity scores.These findings suggest that severe RA is particularly associated with the non-GC subtype of DLBCL, and indicate a critical role of activated peripheral B cells as the cells of origin in these lymphomas.

The aim of the current study was to investigate the importance of genetic and environmental effects in the variation of body mass index, and to investigate linkage for obesity to previously reported candidate regions on chromosome 2 and 10. A sample of 1422 twin pairs from the population based Swedish Twin Registry was used in order to estimate the genetic and environmental effects in the variation of body mass index by means of structural equation modeling. A selection of those, 51 concordant and 155 discordant for obesity, was used for the linkage analysis by implementing the "combined" Haseman-Elston approach. Heritability of body mass index ranged from 59-70%, implying that genetic effects were of importance for the variation of obesity, and there were significant sex and age differences. Linkage could not be verified in candidate regions of chromosomes 2 and 10, indicating that these genetic variants have a significant effect in extreme obese populations rather than in moderately obese Caucasians. However, the results were sensitive to issues related to power, minor effects of the genes, ethnic differences and the complex mechanism underlying obesity.

The contribution of genetic and environmental factors to variation in lipids and apolipoproteins has been estimated in previous twin and family studies. However, it is unclear whether there are sex and/or age differences in parameter estimates. We investigated a sample selected from the population-based Swedish Twin Registry of 725 like- and unlike-sex twin pairs, ages 17-85. Quantitative genetic methods were used to evaluate sex and age differences in genetic and environmental variation in lipid and apolipoprotein levels in three age groups, 17-49, 50-69, and 70-85. Heritabilities for lipids and apolipoproteins ranged from 35%-74%. Consistent sex differences were found in triglycerides. Females had higher heritabilities (56%) than males (35%) across the age groups. Total phenotypic variation increased across the age groups for cholesterol and apolipoprotein B due to an increase in unique environmental variance components. In contrast, in apolipoprotein A1 variance was highest in the middle age group and no differences were found in the phenotypic variance between age groups for triglycerides. We concluded that differences in phenotypic variation for cholesterol and apolipoprotein B were almost entirely due to the accumulation of environmental experiences throughout life, whereas there were no consistent patterns of differences in phenotypic variance for apolipoprotein A1 and triglycerides.

Most, but not all, studies report a positive association between birth weight, as an indirect marker of prenatal hormone exposure, and offspring breast cancer risk, particularly premenopausal breast cancer. Females from opposite-sexed twin pairs may also be prenatally exposed to androgens from their twin brothers. A Swedish study of opposite-sexed twins with a small sample size found a very strong positive association between female birth weight and breast cancer risk. In this case-control study, nested within a cohort of female opposite-sexed twins, we included 543 breast cancer case subjects diagnosed in the period from 1972 to 2008 and 2715 matched control subjects. Conditional logistic regression estimated the breast cancer risk associated with birth weight and other birth characteristics, including gestational age and co-twin birth weight. All statistical tests were two-sided. There was no association between birth weight (odds ratio = 1.01; 95% confidence interval = 0.70 to 1.46) or twin brother's birth weight and risk of breast cancer, which suggests the previously reported strong positive association may have been a chance finding.

OBJECTIVE—To determine the diabetes- and obesity-related risks for surgically managed stress urinary incontinence and pelvic organ prolapse. RESEARCH DESIGN AND METHODS—This twin cohort study used the Swedish Twin Register to identify 8,443 female twin pairs born from 1926 through 1958. The association between diabetes and pelvic floor surgery was estimated while taking into account the correlated (twin) structure of the data. RESULTS—For type 1 and type 2 diabetes, no significant associations were observed for stress urinary incontinence (odds ratio [OR] 1.0 [95% CI 0.1–9.2] and 2.0 [1.0–4.0], respectively). There were no cases of prolapse surgery in type 1 diabetic subjects, and for type 2 diabetes the risk estimate was nonsignificant (1.6 [1.0–2.7]). BMI >25 kg/m2, age ≥60 years, and childbirth were the strongest risk factors for having incontinence surgery. CONCLUSIONS—Our data suggest that diabetes is not associated with stress urinary incontinence or pelvic organ prolapse surgery.

Importance Between 1978 and 2010, approximately 5 million infants were born after in vitro fertilization (IVF) treatments. Yet limited information on neurodevelopment after IVF exists, especially after the first year of life. Objective To examine the association between use of any IVF and different IVF procedures and the risk of autistic disorder and mental retardation in the offspring. Design, Setting, and Participants A population-based, prospective cohort study using Swedish national health registers. Offspring born between 1982 and 2007 were followed up for a clinical diagnosis of autistic disorder or mental retardation until December 31, 2009. The exposure of interest was IVF, categorized according to whether intracytoplasmic sperm injection (ICSI) for male infertility was used and whether embryos were fresh or frozen. For ICSI, whether sperm were ejaculated or surgically extracted was also considered. Main Outcomes and Measures Relative risks (RRs) for autistic disorder and mental retardation and rates per 100 000 person-years, comparing spontaneously conceived offspring with those born after an IVF procedure and comparing 5 IVF procedures used in Sweden vs IVF without ICSI with fresh embryo transfer, the most common treatment. We also analyzed the subgroup restricted to singletons. Results Of the more than 2.5 million infants born, 30 959 (1.2%) were conceived by IVF and were followed up for a mean 10 (SD, 6) years. Overall, 103 of 6959 children (1.5%) with autistic disorder and 180 of 15 830 (1.1%) with mental retardation were conceived by IVF. The RR for autistic disorder after any procedure compared with spontaneous conception was 1.14 (95% CI, 0.94-1.39; 19.0 vs 15.6 per 100 000 person-years). The RR for mental retardation was 1.18 (95% CI, 1.01-1.36; 46.3 vs 39.8 per 100 000 person-years). For both outcomes, there was no statistically significant association when restricting analysis to singletons. Compared with IVF without ICSI with fresh embryo transfer, there were statistically significantly increased risks of autistic disorder following ICSI using surgically extracted sperm and fresh embryos (RR, 4.60 [95% CI, 2.14-9.88]; 135.7 vs 29.3 per 100 000 person-years); for mental retardation following ICSI using surgically extracted sperm and fresh embryos (RR, 2.35 [95% CI, 1.01-5.45]; 144.1 vs 60.8 per 100 000 person-years); and following ICSI using ejaculated sperm and fresh embryos (RR, 1.47 [95% CI, 1.03-2.09]; 90.6 vs 60.8 per 100 000 person-years). When restricting the analysis to singletons, the risks of autistic disorder associated with ICSI using surgically extracted sperm were not statistically significant, but the risks associated with ICSI using frozen embryos were significant for mental retardation (with frozen embryos, RR, 2.36 [95% CI, 1.04-5.36], 118.4 vs 50.6 per 100 000 person-years]; with fresh embryos, RR, 1.60 [95% CI, 1.00-2.57], 80.0 vs 50.6 per 100 000 person-years). Conclusions and Relevance Compared with spontaneous conception, IVF treatment overall was not associated with autistic disorder but was associated with a small but statistically significantly increased risk of mental retardation. For specific procedures, IVF with ICSI for paternal infertility was associated with a small increase in the RR for autistic disorder and mental retardation compared with IVF without ICSI. The prevalence of these disorders was low, and the increase in absolute risk associated with IVF was small.

This study examines the familial clustering and relative influence of genetic and environmental effects on postterm birth in the Swedish population by considering all full- and half-siblings born in Sweden between 1992 and 2004. Of the eligible 475,429 births, 21% occurred after 41 completed weeks and 5.5% occurred after 42 completed weeks of gestation. Odds of postterm birth increased if mothers were older, heavier, more educated, primiparous, or carrying a male fetus. The highest odds increase was seen in women with a previous postterm birth, both with the same partner (odds ratio = 4.4, 95% confidence interval: 4.0, 4.6) and after a partner change (odds ratio = 3.4, 95% confidence interval: 2.9, 3.9). Sisters of women with a postterm birth were also at increased odds of postterm birth (odds ratio = 1.8, 95% confidence interval: 1.6, 2.0) while brothers' partners were not. Half of the variation in postterm birth could not be explained by factors shared in families, and the remaining half was explained by genetic factors, namely fetal (26%) and maternal (21%) genetic factors. Familial clustering of postterm birth is attributed to genetic effects, and fetal genetic effects have a considerable influence on the liability of postterm birth.

Objective To investigate associations between depression, anxiety, and antidepressants before in vitro fertilization (IVF) and IVF cycle outcomes, including pregnancy, live birth, and miscarriage. Design Nationwide register-based cohort study. Setting Not applicable. Patient(s) Nulliparous women undergoing their first IVF cycle recorded in the Swedish Quality Register of Assisted Reproduction, January 2007 to December 2012 (n = 23,557). Intervention(s) Not applicable. Main Outcome Measure(s) Associations between diagnoses of depression/anxiety, antidepressants, and IVF cycle outcome evaluated using logistic regression to produce adjusted odds ratios (AOR) and 95% confidence intervals (CI). Result(s) In total, 4.4% of women had been diagnosed with depression/anxiety and/or dispensed antidepressants before their IVF first cycle. The odds for pregnancy and live birth were decreased (n = 1,044; AOR=0.86; 95% CI, 0.75–0.98; and AOR=0.83; 95% CI, 0.72–0.96, respectively). For women with a prescription for a selective serotonin reuptake inhibitor (SSRI) only (n = 829), no statistically significant associations were found. Women with non-SSRI antidepressants (n = 52) were at reduced odds of pregnancy (AOR = 0.41; 95% CI, 0.21–0.80) and live birth (AOR = 0.27; 95% CI, 0.11–0.68). Women with a depression/anxiety diagnosis with no antidepressant (n = 164) also had reduced odds of pregnancy (AOR = 0.58; 95% CI, 0.41–0.82) and live birth (AOR = 0.60; 95% CI, 0.41–0.89). Among the women who became pregnant (39.7%), there were no statistically significant associations between exposure and miscarriage except for the women taking non-SSRI antidepressants (AOR = 3.56; 95% CI, 1.06–11.9). Conclusion(s) A diagnosis of depression/anxiety and/or treatment with antidepressants before IVF was associated with slightly reduced odds of pregnancy and live birth. Women with the presence of depression/anxiety without antidepressants had a more pronounced reduction in odds, implying that the underlying disorder is important for the observed association.

Prenatal exposure to adverse environmental conditions is related to increased adult mortality in regions where infections are highly prevalent, yet there is little evidence of the impact of perinatal conditions on the risk of severe infections throughout life. Using prospectively collected data from 21 604 like-sexed Swedish twins of known zygosity born in 1926-1958, we examined the risk of polio in relation to perinatal characteristics using cohort and nested co-twin case-control analyses. Polio incidence was determined through an interview in 1998, and linkage with the Swedish national inpatient and death registries. There were 133 cases of polio. In the cohort analysis, birth length, birthweight and head circumference were positively associated with polio risk. After adjustment for sex, birth year, gestational age at birth and within-twin pair correlations, twins of shortest length (44 cm) had a 67% ([95% CI: 6%, 88%]; P=0.04) lower risk of polio compared with the reference group (47-49 cm). After additional adjustment for birth length, every 100-g increase in birthweight was related to a 34% increased risk of polio ([95% CI: -1%, 82%]; P=0.06), and every 10-mm increase in head circumference was related to a 17% greater risk of polio ([95% CI: 5%, 31%]; P=0.004). In co-twin control analyses among 226 disease-discordant twins, birth length, birthweight and head circumference were 0.3 cm (P=0.19), 84 g (P=0.07) and 3 mm (P=0.08) higher in cases than controls, respectively. Similar associations were observed among monozygotic (n=84) and dizygotic (n=142) twins. These findings suggest that early intrauterine growth restriction may be inversely related to the incidence of polio.

STUDY DESIGN A cross-sectional study on 21,225 twins based on a Web-based questionnaire was performed in 2005-2006 and administered by the Swedish Twin Registry. OBJECTIVE To investigate the importance of genetic factors for the occurrence of "Concurrent low back (LBP) and neck-shoulder pain (NSP)" as well as of "Solely LBP," and "Solely NSP" in an adult population of women and men. SUMMARY OF BACKGROUND DATA Many individuals suffering from LBP also have concurrent NSP, and little is known about the factors influencing the occurrence of this spinal comorbidity. METHODS Heritability of Concurrent LBP and NSP, solely LBP, and solely NSP was analyzed in 2934 monozygotic twin pairs, 2009 same-sex dizygotic (DZ) twin pairs, and 1960 opposite-sex DZ twin pairs without any known rheumatic disorders using structural equation modeling (SEM). RESULTS The SEM showed that 60% of the total variance for concurrent LBP and NSP can be explained by additive genetic effects, which was twice as large as for solely LBP (30%) and more than twice as large as for solely NSP (24%). CONCLUSION Genetic factors had a considerably greater importance for the occurrence of concurrent LBP and NSP compared with solely LBP or solely NSP. The influence of genetic factors was similar for solely LBP and solely NSP.

The aetiology of bladder pain syndrome (BPS) remains poorly understood, and a number of pathogenic mechanisms have been proposed. The importance of genetic factors for BPS is receiving growing attention, but data so far are of a preliminary nature.To empirically assess the genetic and environmental contribution to BPS in a population-based sample of twins.The study included25,000 twins born between 1959 and 1985. Individuals with BPS were identified using latent class cluster analysis (LCCA) based on self-reported symptoms from a nationwide screening for complex diseases in the Swedish Twin Registry. By comparing monozygotic and dizygotic twins, we estimated twin similarity and the relative proportions of phenotypic variance resulting from genetic and environmental factors.Twin similarity was measured.The LCCA yielded an overall BPS prevalence of 1.1% and 2.4% for males and females, respectively. In males, the contribution of genetic effects to BPS could not be assessed because of the small number of concordant twin pairs. In women, twin similarity estimates indicated a genetic component for the aetiology of BPS, but genetic factors contributed less than one-third of the total variation in susceptibility to BPS. Nonshared environmental factors accounted for more than two-thirds of the variance, whereas early nongenetic factors shared within the family were of little or no consequence to the risk of developing BPS later in life. Use of self-reported symptoms to define the disease phenotype is a limitation of the study.The influence of environmental factors in the development of BPS in women is substantial, whereas genetic influences are of only modest importance for the possibility of developing the disease.

Obstetric and neonatal complications have been associated with completed and attempted suicide (suicidal acts) in young offspring. Maternal smoking is one of the most important risk factors for obstetric complications, but the association between prenatal smoking exposure and offspring risk of suicidal acts is unknown. We performed a population-based study of 1,449,333 single births born in Sweden between 1983 and 1996, derived from linked registry data. Maternal smoking and risks of suicidal acts in offspring were estimated using hazard ratios, derived from proportional-hazard models, controlling for potential confounding of parental socio-demographic factors and psychiatric care in first degree relatives. To control for unmeasured familial confounding, a matched case–control analysis of suicidal acts was performed within sibling pairs discordant for prenatal smoking exposure. In the cohort analysis, the adjusted hazard ratio for completed suicide among offspring to women smoking 1–9 cigarettes and at least 10 cigarettes per day were 1.67, 95% confidence interval (CI), 1.29–2.16, and 1.54, 95% CI, 1.12–2.10. For suicidal acts, corresponding hazard ratios were 1.28, 95% CI 1.21–1.35 and 1.48, 95% CI 1.39–1.57, respectively. However, in sibling pairs discordant for suicidal acts and prenatal smoking exposure, we found no evidence that prenatal smoking exposure increased the risk of suicidal acts. We conclude that the association between prenatal smoking exposure and offspring risk of suicidal acts is probably confounded by unmeasured familial factors.

Background The understanding of the influence of smoking and sex on lung function and symptoms is important for understanding diseases such as COPD. The influence of both genes and environment on lung function, smoking behaviour and the presence of respiratory symptoms has previously been demonstrated for each of these separately. Hence, smoking can influence lung function by co-varying not only as an environmental factor, but also by shared genetic pathways. Therefore, the objective was to evaluate heritability for different aspects of lung function, and to investigate how the estimates are affected by adjustments for smoking and respiratory symptoms. Methods The current study is based on a selected sample of adult twins from the Swedish Twin Registry. Pairs were selected based on background data on smoking and respiratory symptoms collected by telephone interview. Lung function was measured as FEV1, VC and DLco. Pack years were quantified, and quantitative genetic analysis was performed on lung function data adjusting stepwise for sex, pack years and respiratory symptoms. Results Fully adjusted heritability for VC was 59% and did not differ by sex, with smoking and symptoms explaining only a small part of the total variance. Heritabilities for FEV1 and DLco were sex specific. Fully adjusted estimates were10 and 15% in men and 46% and 39% in women, respectively. Adjustment for smoking and respiratory symptoms altered the estimates differently in men and women. For FEV1 and DLco, the variance explained by smoking and symptoms was larger in men. Further, smoking and symptoms explained genetic variance in women, but was primarily associated with shared environmental effects in men. Conclusion Differences between men and women were found in how smoking and symptoms influence the variation in lung function. Pulmonary gas transfer variation related to the menstrual cycle has been shown before, and the findings regarding DLco in the present study indicates gender specific environmental susceptibility not shown before. As a consequence the results suggest that patients with lung diseases such as COPD could benefit from interventions that are sex specific.

Purpose: The study aimed to investigate whether the association between birth weight and the risk of breast cancer can be confounded by familial factors, such as shared environment and common genes. Materials and Methods: Eligible were all female like-sexed twins of the Swedish Twin Registry, born during the period 1926-1958 and alive in 1973. Data were obtained from birth records, and the final study population with reliable birth weight data was made up of 11,923 twins. Hazard ratios (HR) for breast cancer according to birth weight were estimated through Cox regression, using robust SE to account for the dependence within twin pairs. Paired analysis was done to account for potential confounding by familial factors. Results: In the cohort analysis, a birth weight ≥3,000 g was associated with an increased risk of breast cancer diagnosed at or before 50 years [adjusted HR, 1.57; 95% confidence interval (95% CI), 1.03-2.42] but not with breast cancer with a later onset (adjusted HR, 0.80; 95% CI, 0.57-1.12). From ≥2,500 g, a 500-g increase in birth weight conferred a HR of 1.62 (95% CI, 1.16-2.27) for breast cancer diagnosed at or before 50 years. This risk remained in analysis within twin pairs (HR, 1.57; 95% CI, 1.00-2.48). Conclusion: In the present study, findings indicate that the association between birth weight and breast cancer risk, seen only in women diagnosed early (≤50 years), is not confounded by familial factors. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2447–52)

Background: Prostate cancer has a strong hereditary component, but it has been proposed that hormonal influences in utero may contribute to offspring risk. We investigated the associations between birth characteristics and the risk of prostate cancer in twins, and whether possible associations could be confounded by familial factors, such as shared environment and common genes. Methods: All like-sexed male twins in the Swedish Twin Registry, born from 1926 to 1958 and alive in 1973, were eligible. Data were obtained from birth records, and 11,420 male twins with reliable birth weight data were included in the final study population. Hazard ratios with 95% confidence intervals (CI) from Cox regression models were used to estimate associations between birth characteristics and risk of prostate cancer. Paired analysis was done to account for potential confounding by familial factors. Results: Compared with twins with a birth weight of 2,500 to 2,999 g, the hazard ratio (95% CI) for twins with a higher birth weight (≥3,000 g) corresponded to 1.22 (0.94-1.57). In analyses within twin pairs, in which both twins had a birth weight of ≥2,500 g, a 500 g increase in birth weight was associated with an increased risk of prostate cancer within dizygotic twin pairs (odds ratio, 1.41; 95% CI, 1.02-1.57), but not within monozygotic twin pairs (odds ratio, 1.06; 95% CI, 0.61-1.84). Conclusions: High birth weight is associated with an increased risk of prostate cancer. The difference in risk within dizygotic and monozygotic twin pairs may be due to genetic factors playing an important role in this association. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2422–6)

Benefits and risks of corticosteroid treatment in rheumatoid arthritis (RA) are debated. Patients with RA are at increased risk of malignant lymphomas. In a large case-control study of risk factors for lymphoma in RA, it was recently reported that steroid treatment was associated with decreased lymphoma risk.To further assess the nature of the association between steroid treatment in RA and the risk of lymphoma.In a cohort of 74 651 patients with RA, 378 patients with lymphoma and 378 matched RA controls were identified, and information on inflammatory activity and different aspects of steroid treatment (duration, therapeutic strategy and mode of administration) abstracted from their medical records. Lymphomas were reclassified (WHO classification) and examined for Epstein-Barr virus. Relative risks were assessed as adjusted odds ratios (ORs) through conditional logistic regression.A total duration of oral steroid treatment of2 years was not associated with lymphoma risk (OR=0.87; 95% CI 0.51 to 1.5), whereas total treatment2 years was associated with a lower lymphoma risk (OR=0.43; 95% CI 0.26 to 0.72). RA duration at the initiation of oral steroids did not affect lymphoma risk. Intra-articular steroids were associated with a reduced lymphoma risk, but only when used as swift flare treatment (OR=0.22; 95% CI 0.13 to 0.37). Analyses by lymphoma subtype showed a reduced risk of diffuse large B-cell lymphoma (crude OR=0.59; 95% CI 0.37 to 0.94).In this RA population, use of steroids was associated with reduced lymphoma risk. Whether this association is a generic effect of steroids or specific to the studied population remains unknown.

Epidemiologic evidence linking birth weight and asthma is inconsistent. The authors examined the association between birth weight and asthma during childhood and adult life in twins. Using prospectively collected data on 21,588 like-sexed Swedish twins of known zygosity born in 1928-1952, they first conducted a cohort study to examine the risk of asthma in relation to birth weight. Next, they conducted nested co-twin control analyses among 643 dizygotic and 365 monozygotic twin pairs discordant for asthma to ascertain whether the association between birth weight and asthma could be confounded by genetic and shared environmental exposures. In the cohort analysis, birth weight of

Objectives: To investigate if high physical workload is associated with low back pain (LBP) and/or neck–shoulder pain (NSP) when taking into account the influence of genetic and shared environmental factors. Further, the study aims to explore the potential influence of genetic and shared environmental factors in the associations between high physical workload and the three disorder subgroups: solely LBP, solely NSP, and concurrent LBP and NSP. Methods: Data on 16 107 monozygotic and dizygotic twins, born during 1959–1985, were obtained from a cross-sectional study, performed in 2005–2006 by the Swedish Twin Registry. Odds ratios (ORs) calculated in cohort analyses and co-twin control analyses were used to assess the associations between high physical workload and LBP and NSP when controlling for genetic and shared environmental factors. Results: In the cohort analysis, the association between high physical workload and the group with any one symptom (LBP and/or NSP) was OR 1.47 (95% CI 1.37 to 1.57). The co-twin control analyses indicated that the association was not confounded by genetic and shared environmental factors with OR 1.34 (95% CI 1.02 to 1.75) for dizygotic twins and OR 1.44 (95% CI 1.06 to 1.95) for monozygotic twins. In the cohort analyses the association with high physical workload was higher for concurrent LBP and NSP (OR 1.80 (95% CI 1.62 to 1.99)) than for solely LBP (OR 1.41 (95% CI 1.27 to 1.57)) and solely NSP (OR 1.31 (95% CI 1.20 to 1.43)). Concurrent LBP and NSP was the only group that showed a stepwise decrease of the point estimates between the cohort analysis and the co-twin control analyses, OR 1.71 (95% CI 1.00 to 2.94) for dizygotic twins, and OR 1.29 (95% CI 0.64 to 2.59) for monozygotic twins indicating confounding by genetic and shared environmental factors. Conclusions: High physical workload was associated with LBP and/or NSP even after adjusting for genetic or shared environmental factors. Only for concurrent LBP and NSP, genetic and shared environmental factors seemed to have an influence on the association with high physical workload.

Background It is hypothesized that associations found between birth weight and subsequent risk of type-2 diabetes are due to inherited genes affecting both fetal growth and metabolism of insulin. Methods To study whether there is a familial (shared environmental and genetic) link between birth weight and type-2 diabetes, the authors used a sample of 11,411 Swedish like-sexed twins born from 1926 to 1958 with at least one offspring, to study the association between offspring birth weight for gestational age and parental risk of type-2 diabetes. Results Decreasing offspring birth weight for gestational age (with 1 SD) was associated with an increased risk of type-2 diabetes among father's [odds ratio (OR)=1.72, 95% confidence interval (CI): 1.33-2.23] and decreased risk among mothers (OR=0.43, 95% CI: 0.30-0.62), independent of grand parental and parental socio-economic status and parental smoking. In paired twin analysis, the association between offspring birth weight and mothers with risk of type-2 diabetes was similar within- and between-twin pairs, whereas father's risk was slightly smaller within than between pairs (OR(Between)=1.90, 95% CI: 1.10-3.28, and OR(Within)=1.71, 95% CI: 1.10-2.67, respectively). Conclusions The well-established association between paternal type-2 diabetes and offspring birth weight seems to primarily be due to as yet unidentified non-shared environmental factors. However, familial factors shared within twin pairs may contribute to the association.

Background— Studies have found associations between low birth weight and increased risks of cardiovascular diseases in adulthood. However, these associations could be due to confounding by genetic or socioeconomic factors. Methods and Results— We performed a study on Swedish like-sexed twins with known zygosity who were born from 1926 to 1958. First, to obtain an overall effect of birth weight on risk of hypertension, we performed cohort analyses on all twins (n=16 265). Second, to address genetic and shared environmental confounding, we performed a nested co-twin control analysis within 594 dizygotic and 250 monozygotic twin pairs discordant for hypertension. Birth characteristics, including birth weight, were obtained from original birth records. Information from adulthood was collected from a postal questionnaire in 1973 (body mass index, height, smoking, and alcohol use) and from a telephone interview conducted from 1998 to 2002 (hypertension and socioeconomic status). Hypertension was defined as reporting both high blood pressure and treatment with antihypertensive medication. In the cohort analysis, the adjusted odds ratio for hypertension in relation to a 500-g decrease in birth weight was 1.42 (95% confidence interval, 1.25 to 1.61). In the co-twin control analyses, the corresponding odds ratios were 1.34 (95% confidence interval, 1.07 to 1.69) for dizygotic and 1.74 (95% confidence interval, 1.13 to 2.70) for monozygotic twins. Conclusions— In the largest twin study on the fetal origins of hypertension, we found that decreased birth weight is associated with increased risk of hypertension independently of genetic factors, shared familial environment, and risk factors for hypertension in adulthood, including body mass index.

Background— Survivors of preterm birth constitute a new generation of young adults, but little is known about their long-term health. We investigated the association between gestational age (GA) and risk of high blood pressure (HBP) in young Swedish men and whether GA modified the risk of HBP; ie, whether HBP was related to being born small for gestational age (SGA). Methods and Results— This population-based cohort study included 329 495 Swedish men born in 1973 to 1981 who were conscripted for military service in 1993 to 2001. Multivariate linear- and logistic-regression analyses were performed. Main outcome measures were systolic and diastolic BPs at conscription. Linear-regression analyses showed that systolic BP increased with decreasing GA (regression coefficient −0.31 mm Hg/wk, P P Conclusions— Preterm birth, a common pregnancy complication, is a risk factor for HBP in young men. The risk of high systolic BP associated with birth weight for GA is modified by GA, suggesting that perinatal contributions to BP elevation later in life may be induced by different biological pathways.

Although an inverse association between size at birth and blood pressure has been found in several studies, few studies have adjusted for the influence of socioeconomic and familial effects.We investigated whether the association between birth weight and systolic blood pressure in young men is confounded by socioeconomic factors in adolescence or familial factors (ie, common genes and shared environment). Our population-based cohort study comprised 330,768 Swedish men born between 1973 and 1981, and conscripted for military service between 1991 and 2000. The analyses of family effects were restricted to 89,856 siblings from the initial cohort. A high systolic blood pressure at conscription was defined as a systolic blood pressure/=140 mm Hg. Birth weight for gestational age-2 standard deviation scores was considered "light for gestational age."Compared with men who had normal birth weight for gestational age, men who had been born light for gestational age were at increased risk of high systolic blood pressure (odds ratio = 1.14; 95% confidence interval = 1.07-1.22), even after adjustment for important confounders such as socioeconomic status. The increase in risk of high systolic blood pressure related to 1 standard deviation score decrease in birth weight for gestational age was similar within families (1.08; 1.04-1.12) and between families (1.05; 1.03-1.08).This study suggests that low birth weight for gestational age slightly increases the risk of high systolic blood pressure, and that the association appears not to be confounded by socioeconomic or familial effects.

BACKGROUND To investigate the association between low birthweight and diabetes in a population-based Swedish twin sample. Method A cohort of 11 162 same-sexed Swedish twins born between 1906 and 1958 was used in order to investigate the risk of developing Type 2 diabetes between and within twin pairs by utilizing random effects linear models. RESULTS Between pairs there was a significant increase in risk of developing Type 2 diabetes for a 1-kg increase in their mean birthweight (odds ratio [OR] = 2.13; P < 0.01), adjusted for age, sex, body mass index (BMI), and smoking status. The corresponding risk within pair was 2.03 (P = 0.07) for monozygotic twins and 1.15 (P = 0.71) for dizygotic twins. The test of the heterogeneity of the within and between effects showed no significant difference between the estimates. CONCLUSIONS The study suggests that reduced fetal growth increase the risk of Type 2 diabetes due to an in utero programming effect possibly caused by intrauterine malnutrition. However, it does not exclude the possibility of a common genetic mechanism.

Background Twin and family studies have shown that genetic effects explain a relatively high amount of the phenotypic variation in blood pressure. However, many studies have not been able to replicate findings of association between specific polymorphisms and diastolic and systolic blood pressure. Methods In a structural equation-modelling framework the authors investigated longitudinal changes in repeated measures of blood pressures in a sample of 298 like-sexed twin pairs from the population-based Swedish Twin Registry. Also examined was the association between blood pressure and polymorphisms in the angiotensin-I converting enzyme and the angiotensin 11 receptor type 1 with the 'Fulker' test Both linkage and association were tested simultaneously revealing whether the polymorphism is a Quantitative Trait Locus (QTL) or in linkage disequilibrium with the QTL. Results Genetic influences explained up to 46% of the phenotypic variance in diastolic and 63% of the phenotypic variance in systolic blood pressure. Genetic influences were stable over time and contributed up to 78% of the phenotypic correlation in both diastolic and systolic blood pressure. Non-shared environmental effects were characterised by time specific influences and little transmission from one time point to the next. There was no significant linkage and association between the polymorphisms and blood pressure. Conclusions There is a considerable genetic stability in both diastolic and systolic blood pressure for a 6-year period of time in adult life. Non-shared environmental influences have a small long-term effect Although associations with the polymorphisms could not be replicated, results should be interpreted with caution due to power considerations. (C) 2002 Lippincott Williams Wilkins.

The contribution of hereditary factors to the causation of sporadic cancer is unclear. Studies of twins make it possible to estimate the overall contribution of inherited genes to the development of malignant diseases.We combined data on 44,788 pairs of twins listed in the Swedish, Danish, and Finnish twin registries in order to assess the risks of cancer at 28 anatomical sites for the twins of persons with cancer. Statistical modeling was used to estimate the relative importance of heritable and environmental factors in causing cancer at 11 of those sites.At least one cancer occurred in 10,803 persons among 9512 pairs of twins. An increased risk was found among the twins of affected persons for stomach, colorectal, lung, breast, and prostate cancer. Statistically significant effects of heritable factors were observed for prostate cancer (42 percent; 95 percent confidence interval, 29 to 50 percent), colorectal cancer (35 percent; 95 percent confidence interval, 10 to 48 percent), and breast cancer (27 percent; 95 percent confidence interval, 4 to 41 percent).Inherited genetic factors make a minor contribution to susceptibility to most types of neoplasms. This finding indicates that the environment has the principal role in causing sporadic cancer. The relatively large effect of heritability in cancer at a few sites suggests major gaps in our knowledge of the genetics of cancer.

Background Low socioeconomic status (SES) has been linked to increased risk of hypertension, a known risk factor for cardiovascular disease. How the risk is altered by intergenerational social mobility is not well known. The aim of this study is to investigate parental SES, adult SES and the intergenerational social mobility in relation to hypertension risk. Methods By using data from the Swedish Twin Registry, the authors obtained information about both parental and adult SES and hypertension in 12 030 individuals born from 1926 to 1958. Generalised estimating equations were used to estimate ORs with 95% CIs. Results Low parental SES was associated with increased odds of hypertension (OR 1.42, 95% CI 1.14 to 1.76). Low SES in adulthood was associated with increased odds for women but not for men (OR 1.40, 95% CI 1.15 to 1.70 and OR 1.01, 95% CI 0.83 to 1.24, respectively). Compared with the stable low social status group, the upward mobile group had lower odds of hypertension (OR 0.82, 95% CI 0.70 to 0.97). Compared with the stable high social status group, the results for the downward mobile group indicated an increased risk. A co-twin case-control analysis indicated that the results were independent of familial factors. Conclusions These findings suggest that the risk of hypertension associated with low parental social status can be modified by social status later in life. Possibly, this could be targeted by public health or political interventions. As parental social status has an impact on later health, such interventions should be introduced early.

Low birth weight has been associated with an increased risk of type 2 diabetes in adulthood. Poor fetal nutrition has been suggested to explain this association. Our objective was to determine whether genetic factors contribute to the association between low birth weight and subsequent risk of type 2 diabetes.We retrieved information from original birth records on same-sex Swedish twins with known zygosity, born from 1926 to 1958. We used regression models to investigate whether birth weight was associated with risk of type 2 diabetes in the cohort of twins overall, and in case-control analyses within disease-discordant dizygotic and monozygotic twin pairs.Of 18,230 twins, 592 (3.2%) had type 2 diabetes. The rate of type 2 diabetes consistently increased with decreasing birth weight, from 2.4% among twins with birth weights of 3500 g or more to 5.3% among those with birth weights less than 2000 g. In the cohort analysis, in which twins are analyzed as independent individuals, the adjusted odds ratio (95% confidence interval) of type 2 diabetes per 500-g decrease in birth weight was 1.44 (1.28-1.63). When we compared the diseased twin with the healthy cotwin, the corresponding odds ratios were 1.38 (1.02-1.85), among dizygotic twins, and 1.02 (0.63-1.64), among monozygotic twins.Low birth weight is associated with type 2 diabetes in adulthood. The difference in this association between monozygotic and dizygotic twin pairs suggests that genetic mechanisms play an important role in this association.

CONTEXT: The association between maternal smoking during pregnancy (SDP) and offspring disruptive behaviors has been well documented, but it is unclear whether exposure to SDP or the effects of factors correlated with SDP account for the increased risk. OBJECTIVE: To test whether the association between SDP and offspring criminal convictions was consistent with a causal connection or due to familial background factors by controlling for measured covariates and using a quasi-experimental approach. DESIGN: We used a population-based study of children born in Sweden from 1983 to 1989 (N = 609,372) to examine the association between SDP and offspring criminal convictions while controlling for measured traits of both parents. We also compared siblings differentially exposed to SDP (n = 50,339) to account for unmeasured familial factors that could account for the association. SETTING: Population-based study of all children born in Sweden from 1983 to 1989 with information on maternal SDP and offspring criminal convictions based on national registries collected by the Swedish government. PATIENTS OR OTHER PARTICIPANTS: Children born in Sweden from 1983 to 1989 (N = 609,372) and siblings differentially exposed to SDP (n = 50,339). MAIN OUTCOME MEASURES: Violent and nonviolent convictions, based on the Swedish National Crime Register, a register with detailed information on all convictions in the country. RESULTS: Moderate (hazard rate [HR], 2.47; 95% confidence interval [CI], 2.34-2.60) and high (HR, 3.43; 95% CI, 3.25-3.63) levels of maternal SDP were associated with an increased risk for offspring violent convictions, even when controlling for maternal and paternal traits. There was no association between SDP and violent convictions, however, when comparing differentially exposed siblings (HR(moderate), 1.02; 95% CI, 0.79-1.30; HR(high), 1.03; 95% CI, 0.78-1.37). Smoking during pregnancy also was associated with nonviolent convictions in the entire population (HR(moderate), 1.62; 95% CI, 1.58-1.66; HR(high), 1.87; 95% CI, 1.82-1.92) and when controlling for covariates. But, there was no association when comparing siblings who were differentially exposed (HR(moderate), 0.89; 95% CI, 0.78-1.01; HR(high), 0.89; 95% CI, 0.78-1.02). CONCLUSION: The results suggest that familial background factors account for the association between maternal SDP and criminal convictions, not the specific exposure to SDP. Language: en