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BACKGROUND AND AIM: Having a family member with an alcohol use disorder (AUD) may negatively affect a person's health. Our aim was to study the long-term risk of coronary heart disease (CHD) in parents who have an offspring with AUD. DESIGN: Cohort study. Cox regression models and co-sibling analyses. PARTICIPANTS: From population registers, we selected all parent-offspring pairs in which the parent was born in Sweden between 1945 and 1965. MEASUREMENTS: Baseline was set when the offspring was 15 years old and AUD was assessed from medical and criminal registers. The parents were followed for CHD during a mean follow-up of 18 years. Hazard ratios (HRs) in mothers and fathers were calculated and adjusted for potential confounders (year of birth, age at childbirth, sex of the child, parent's AUD, educational level and marital status). FINDINGS: In mothers, the adjusted HR for CHD was 1.24 (95% confidence interval [CI]: 1.19-1.28) in relation to having a child with AUD. In fathers, the HR for CHD was lower than in mothers but still increased; the adjusted HR was 1.08 (95% CI: 1.05-1.12). In the co-sibling analyses, the HRs for mothers were similar to the HRs estimated from the population-based sample, but in fathers the association did not remain significant (HR 0.98 [0.90-1.06]). CONCLUSIONS: In Sweden there appears to be an association between having an offspring with alcohol use disorder and increased risk of developing coronary heart disease. For fathers, the association did not remain in co-sibling analyses.

Aims Certain autoimmune diseases (ADs), such as Crohn’s disease and celiac diseases, have been linked to acute cardiovascular disorders. We examined whether there is an association between 43 different ADs and risk of subsequent hospitalization and mortality of cardiomyopathy in a nationwide follow-up study in Sweden. Methods and results All individuals in Sweden hospitalized with a main diagnosis of an AD (n = 955 410) without previous or coexisting cardiomyopathy, between 1 January 1987 and 31 December 2018, were followed for hospitalization or mortality of cardiomyopathy. The reference population was the total population of Sweden. Standardized incidence ratios (SIRs) for cardiomyopathy were calculated. Overall risk of cardiomyopathy during the first year after hospitalization for an AD was 3.63 [99% confidence interval (CI) 3.29–4.00]. A total of 21 of the 43 ADs studied were associated with an increased risk of cardiomyopathy during the first year after hospitalization. The overall risk of cardiomyopathy decreased over time, from 1.18 (99% CI 1.12–1.25) after 1+ year to 1.07 (99% CI 0.96–1.19) after 5+ years. Females generally had higher SIRs than males. The ADs for which the SIRs of cardiomyopathy were highest after 1 year of hospitalization included Crohn’s disease (1.92), rheumatoid arthritis (1.57), sarcoidosis (1.48), and psoriasis (1.31). Conclusion Most ADs are associated with an increased risk of cardiomyopathy, particularly in the first year after hospital admission. Our findings show that many hospitalized ADs are tightly linked to cardiomyopathy but the mechanisms need to be further evaluated.

Objectives. The aim of this study was to analyse the risk of valvular heart diseases among foreign-born individuals in Sweden. Design. This was a nationwide study of individuals aged 18 years of age and older (N = 6,118,649; 2,970,055 men and 3,148,594 women). Valvular heart diseases were defined as at least one registered diagnosis in the National Patient Register between 1 January 1998 and 31 December 2012. Cox regression analysis was used to estimate hazard ratios (HR) with 99% confidence intervals (CI) of incident valvular heart diseases in foreign-born individuals compared to Swedish natives. The Cox regression models were adjusted for age, co-morbidities, and sociodemographic factors. Sub-categories were chronic rheumatic valvular heart diseases and non-rheumatic valvular heart diseases. Results. There were 64,979 male cases and 59,075 female cases. Fully adjusted HRs (99% CI) were among immigrant men 0.86 (0.82–0.89) and immigrant women 0.96 (0.92–1.00). For chronic rheumatic valvular disease among immigrant men and women, the HRs were 1.62 (1.37–1.92) and 1.75 (1.52–2.00), respectively, and, for non-rheumatic valvular disease among immigrant men 0.83 (0.80–0.87) and immigrant women 0.92 (0.88–0.96). Increased risks for chronic rheumatic valvular disease were found among men from Southern, Eastern and Central Europe, Africa and Asia and among women from Western, Eastern and Central Europe and Africa, Latin America and Asia. Conclusions. We observed lower risks in general of valvular heart disease, but higher risks of chronic rheumatic valvular heart disease in immigrants, which is important in the clinical situation.

Background The authors sought to clarify the impact of spousal psychiatric disorders of differing severity [major depression or anxiety disorders (DAD) v. bipolar disorder or nonaffective psychosis (BPN)] on proband risk for alcohol use disorder (AUD) during marriage. Methods In a Swedish cohort (N = 744 628), associations between spousal DAD and BPN and proband AUD were estimated with Cox proportional hazards; associations between parental AUD, proband premarital AUD, and spousal lifetime DAD and BPN were estimated with logistic regression; and whether spousal DAD or BPN causally increased risk for AUD was evaluated with frailty models. Results Spousal premarital DAD, spousal marital-onset DAD, and spousal BPN (premarital or marital-onset) were associated with proband AUD during marriage [hazard ratios (HR) range 1.44–3.72]. Those with a parental or premarital history of AUD (v. without) were more likely to marry a spouse with DAD or BPN (odds ratios 1.22–2.77). Moving from an unaffected first spouse to a DAD-affected second spouse increased AUD risk in males (HR 2.90). Moving from an unaffected first spouse to a BPN-affected second spouse increased AUD risk (HRmales 3.96; HRfemales 5.64). Moving to an unaffected second spouse from a DAD-affected first spouse decreased AUD risk, with stronger evidence in females compared to males (HRmales 0.59; HRfemales 0.28). Conclusions Associations between spousal DAD or BPN and proband AUD reflect both selection and causal effects. Marriage to a BPN-affected spouse has a particularly strong effect on AUD risk, with more modest effects for spousal DAD.

Background: Stroke has a high burden of disease in women, and adverse pregnancy outcomes have been identified as important risk factors for stroke later in life. However, long-term risks of stroke associated with preterm delivery and whether such risks are attributable to familial confounding are unclear. Such knowledge is needed to improve long-term risk assessment and stroke prevention in women. Methods: A national cohort study was conducted of all 2 188 043 women with a singleton delivery in Sweden in 1973 through 2015 who were followed up for stroke identified from nationwide diagnoses through 2015. Cox regression was used to compute adjusted hazard ratios (aHRs) for stroke associated with pregnancy duration, and cosibling analyses assessed for confounding by shared familial (genetic or environmental) factors. Results: In 48.0 million person-years of follow-up, 36 372 (1.7%) women were diagnosed with stroke. In the 10 years after delivery, the aHR for stroke associated with preterm delivery (gestational age Conclusions: In this large national cohort, preterm delivery was associated with higher future risks of both hemorrhagic and ischemic stroke. These associations remained substantially elevated at least 40 years later, and were largely independent of covariates and shared familial factors. Preterm delivery should be recognized as a risk factor for stroke in women across the life course.

There is a growing interest in the contextual effect of neighborhood linking social capital on different health outcomes, including cancer. To examine associations between neighborhood linking social capital and incidence and mortality of prostate cancer. This cohort study was based on national registers. Between 2002 and 2015, we included 1,196,563 men aged 50 years and above in the analyses. Multilevel logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the association between exposure and outcome, adjusting for potential confounding factors. The total incidence of prostate cancer and mortality in patients with prostate cancer were 8.22 (per 100) and 1.80 (per 100), respectively, during the follow-up period. Individuals living in neighborhoods with low (OR 0.90; 95% CI 0.88–0.93) and intermediate (OR 0.94; 95% CI 0.92–0.96) linking social capital were less likely to be diagnosed with prostate cancer than those living in neighborhoods with high linking social capital. Opposite effects were observed for mortality; prostate cancer patients living in neighborhoods with low (OR 1.15; 95% CI 1.08–1.23) and intermediate (OR 1.09; 95% CI 1.03–1.14) linking social capital were more likely to die from prostate cancer than those in neighborhoods with high linking social capital. Lower neighborhood linking social capital was associated with lower incidence but higher mortality in patients with prostate cancer. These findings suggest that men living in neighborhoods with low linking social capital may need additional surveillance for prostate cancer.

Sweden has witnessed an increase in the rates of sexual crimes including rape. Knowledge of who the offenders of these crimes are is therefore of importance for prevention. We aimed to study characteristics of individuals convicted of rape, aggravated rape, attempted rape or attempted aggravated rape (abbreviated rape+), against a woman ≥18 years of age, in Sweden. By using information from the Swedish Crime Register, offenders between 15 and 60 years old convicted of rape+ between 2000 and 2015 were included. Information on substance use disorders, previous criminality and psychiatric disorders were retrieved from Swedish population-based registers, and Latent Class Analysis (LCA) was used to identify classes of rape+ offenders. A total of 3 039 offenders were included in the analysis. A majority of them were immigrants (n = 1 800; 59.2%) of which a majority (n = 1 451; 47.7%) were born outside of Sweden. The LCA identified two classes: Class A — low offending class (LOC), and Class B — high offending class (HOC). While offenders in the LOC had low rates of previous criminality, psychiatric disorders and substance use disorders, those included in the HOC had high rates of previous criminality, psychiatric disorders and substance use disorders. While HOC may be composed by more “traditional” criminals probably known by the police, the LOC may represent individuals not previously known by the police. These two separated classes, as well as our finding in regard to a majority of the offenders being immigrants, warrants further studies that take into account the contextual characteristics among these offenders. Key points Rape, aggravated rape, attempted rape or attempted aggravated rape (rape+) are increasing in Sweden. The majority of those convicted of rape+ are immigrants. LCA identifies two classes of rape+ offenders: LOC and HOC.

Background/Aim Cervical cancer incidence and mortality has decreased after introduction of national screening in Sweden, but women with drug use disorders (DUD) are less likely to participate in screening programs. We aimed to investigate cervical cancer incidence and mortality among women with DUD compared to the general female population in Sweden. Methods We conducted a cohort study based on Swedish national register data for the period January 1997–December 2015. Data was collected for 3,838,248 women aged 15–75 years of whom 50,858 had DUD. Adjusted hazard ratios (HRs) for incident and fatal cervical cancer were calculated for women with and without DUD using Cox regression analysis. Results DUD was significantly associated with incident cervical cancer (HR = 1.39, 95% confidence interval [CI] 1.39–1.61), but not fatal cervical cancer (HR = 1.25, 95% CI: 0.91–1.71), after adjusting for age, educational attainment, social welfare, region of residence, marital status and HIV infection. Conclusion Women with DUD were thus identified as a risk group for incident cervical cancer, which calls for attention from clinicians and policy makers. It is possible that non-attendance in cancer screening and other healthcare seeking barriers may affect the risk of incident cervical cancer among women with DUD but more research on this topic is needed.

ImportanceWe know little about the transmission of obsessive-compulsive disorder (OCD) across generations.ObjectiveTo evaluate the sources of parent-offspring transmission of OCD and familial cross-generational association with more typical anxiety disorders.Design, Setting, and ParticipantsThis Swedish population register–based study analyzed data for offspring born in Sweden from 1960 to 1995 from the following 4 family types: intact, not-lived-with biological father, lived-with stepfather, and adoptive. Follow-up occurred on December 31, 2018, and data were analyzed from April 6, 2022, to September 26, 2022.ExposuresThree sources of parent-offspring resemblance: genes plus rearing, genes only, and rearing only.Main Outcomes and MeasuresDiagnoses of OCD, all anxiety disorders, generalized anxiety disorder (GAD), social phobia, and panic disorder were obtained from national inpatient, outpatient, and primary care medical registers. Parent-child resemblance was assessed by tetrachoric correlation (r).ResultsThe offspring population consisted of 2 413 128 individuals; mean (SD) age at follow-up was 40.2 (10.7) years, 1 258 670 individuals (52.2%) were male, and 1 154 458 individuals (47.8%) were female. For each type of parent-child relationship, the best-estimate correlation for OCD for genes plus rearing was 0.19 (95% CI, 0.17 to 0.20); genes only, 0.18 (95% CI, 0.11 to 0.24); and rearing only, 0.04 (95% CI, −0.10 to 0.19). From bivariate adoption analyses, the cross-generational genetic correlations between OCD with anxiety disorder diagnostic categories were estimated as follows: for all anxiety disorders, 0.62 (95% CI, 0.46 to 0.77); GAD, 0.87 (95% CI, 0.53 to 1.00); social phobia, 0.70 (95% CI, 0.31 to 1.00); and panic disorder, 0.47 (95% CI, 0.20 to 0.73).Conclusions and RelevanceThis Swedish population register–based study found that OCD was transmitted from parents to children largely through a genetic relationship, with rearing playing a minor role. Viewed cross-generationally, OCD and anxiety disorders were moderately genetically correlated, with the genetic correlations strongest between OCD and GAD, intermediate for OCD and social phobia, and weakest between OCD and panic disorder. These genetic correlations were modestly attenuated when diagnostic hierarchies were imposed before analysis.

ImportanceSince its inception under Kraepelin in the modern era, diagnostic stability and familial/genetic risk have been among the most important psychiatric nosologic validators.ObjectiveTo assess the interrelationships of family genetic risk score (FGRS) with diagnostic stability or diagnostic change in major depression (MD), bipolar disorder (BD), other nonaffective psychosis (ONAP), and schizophrenia.Design, Setting, and ParticipantsThis longitudinal population-based cohort (N = 4 171 120) included individuals with incident cases of MD (n = 235 095), BD (n = 11 681), ONAP (n = 16 009), and schizophrenia (n = 6312) who had at least 1 further diagnosis of the 4 disorders during follow-up, as assessed from Swedish national medical registries, observed over a mean (SD) of 13.1 (5.9) years until a mean (SD) age of 48.4 (12.3) years. Data were collected from January 1973 to December 2018, and data were analyzed from August to September 2022.ExposuresFGRS for MD, BD, ONAP, and schizophrenia, calculated from morbidity risks for disorders in first-degree through fifth-degree relatives, controlling for cohabitation effects.Main Outcomes and MeasuresFinal diagnostic outcome of MD, BD, ONAP, or schizophrenia.ResultsOf 269 097 included individuals, 173 061 (64.3%) were female, and the mean (SD) age at first registration was 35.1 (11.9) years. Diagnostic stability was highest for MD (214 794 [91.4%]), followed by schizophrenia (4621 [73.2%]), BD (7428 [63.6%]), and ONAP (6738 [42.1%]). The second most common final diagnosis for each of these MD, schizophrenia, BD, and ONAP were BD (15 506 [6.6%]), ONAP (1110 [17.6%]), MD (2681 [23.0%]), and schizophrenia (4401 [27.5%]), respectively. A high FGRS for the incident diagnosis was consistently associated with diagnostic stability, while a high FGRS for the final diagnosis and a low FGRS for the incident diagnosis was associated with diagnostic change. In multivariate models, those in the upper 5% of genetic risk had an odds ratio (OR) of 1.75 or greater for the following diagnostic transition: for MD FGRS, ONAP to MD (OR, 1.91; 95% CI, 1.59-2.29) and schizophrenia to MD (OR, 2.45; 95% CI, 1.64-3.68); for BD FGRS, MD to BD (OR, 2.60; 95% CI, 2.47-2.73), ONAP to BD (OR, 2.16; 95% CI, 1.85-2.52), and schizophrenia to BD (OR, 2.20; 95% CI, 1.39-3.49); for ONAP FGRS, MD to ONAP (OR, 1.80; 95% CI, 1.62-2.02), MD to schizophrenia (OR, 1.95; 95% CI, 1.58-2.41), and BD to schizophrenia (OR, 1.89; 95% CI, 1.39-2.56); and for schizophrenia FGRS, MD to schizophrenia (OR, 1.80; 95% CI, 1.46-2.23), and BD to schizophrenia (OR, 1.75; 95% CI, 1.25-2.45). FGRS profiles for incident cases confirmed at final diagnosis were more homogenous than genetic profiles for those who changed diagnoses.Conclusions and RelevanceIn a large population-based longitudinal cohort, the genetic risk factors for MD, BD, ONAP, and schizophrenia were meaningfully and systematically associated with the diagnostic trajectories of these 4 disorders. Over time, clinical diagnosis and genetic risk profiles became increasingly consilient, thereby providing genetic validation of these diagnostic constructs. Diagnostically unstable incident cases were more genetically heterogeneous than those who were diagnostically stable over time.

Background There is a lack of evidence-based recommendations for the age at which women with a family history of cancers other than breast cancer should start breast cancer screening. Methods Using Swedish family cancer data sets, the authors conducted a nationwide cohort study including 5,099,172 Swedish women born after 1931 (follow-up, 1958-2015). Accounting for calendar time, they calculated the relative risk of breast cancer for women with a family history of a discordant cancer in 1 first-degree relative. Furthermore, the authors used 10-year cumulative risk to determine the ages at which women with a family history of discordant cancer reached risk thresholds at which women in the general population were recommended to start breast cancer screening. Results A family history of cancer at 15 sites was associated with an increased risk of breast cancer. Among women younger than 50 years, the highest risk of breast cancer was observed for those with a family history of ovarian cancer (standardized incidence ratio, 1.44; 95% confidence interval, 1.26-1.64). In these women, the risk of breast cancer associated with a family history at other cancer sites ranged from 1.08-fold for prostate cancer to 1.18-fold for liver cancer. When breast cancer screening was recommended to be started at the age of 50 years for the general population, women with 1 first-degree relative with ovarian cancer attained the threshold risk for screening at the age of 46 years. Women with a family history of other discordant cancers did not reach the risk thresholds for screening at younger ages. Conclusions Many cancers showed familial associations with breast cancer, but women with a family history of these cancers (except for ovarian cancer) did not reach risk thresholds for screening at younger ages.

Background Second primary cancers (SPCs) are increasing due to improving survival in first primary cancers. Previous studies on SPCs in renal cell carcinoma (RCC) have focused on treatment and other risk factors, but data of RCC as an SPC are scarce. Objective In this study, we want to elucidate the risk for any SPC after RCC, and in reverse order, for RCC as an SPC after any cancer. We additionally consider how family histories influence the risks. Design, setting, and participants Patient data were obtained from the Swedish Cancer Registry from years 1990 through 2015, and family data were obtained from the Multigeneration Register. Outcome measurements and statistical analysis We employed standardized incidence ratios to estimate bidirectional relative risks of subsequent cancer associated with RCC. Results and limitations We identified 17 587 RCCs (60% in male patients). The highest increases for SPCs were observed for nervous system hemangioblastoma (HB; 26.8), adrenal (12.09) tumors, and renal pelvic cancer (6.32). In the reverse order, RCC as an SPC, nervous system HB (17.01), and adrenal tumors (15.34) were associated with the highest risks. Risks for many other sites (12 sites and subsites) were increased bidirectionally. For women, a total of seven sites and subsites were increased bidirectionally, and many were shared with men. The only significant sex difference in SPCs was the higher lung cancer risk in women (2.41) than in men (1.28). Patients with a family history of HBs or of prostate, colorectal and lung cancers showed high risks of these cancers as SPCs after RCC. Family history accounted for 30% of prostate cancers after RCC. Conclusions The bidirectional study design was able to suggest risk factors for SPCs and offered a clinical take-home message urging to consider strategies for early detection and prevention of SPCs. Readily available information on lifestyle (eg, smoking) and family history (eg, prostate cancer) may reveal targets for risk reduction with prognostic benefits. Patient summary Close to 10% of kidney cancer patients develop another cancer. The cause for these other cancers may not depend on kidney cancer., Take Home Message The study results recommend considering strategies for early detection and prevention of second primary cancer. Readily available information on lifestyle (eg, smoking) and family history (eg, prostate cancer) may reveal targets for risk reduction with prognostic benefits.

Background There is a lack of studies of Huntington’s disease (HD) in immigrants. Objective To study the association between country of birth and incident HD in first-generation immigrants versus Swedish-born individuals and in second-generation immigrants versus Swedish-born individuals with Swedish-born parents. Methods Study populations included all adults aged 18 years and older in Sweden, i.e., in the first-generation study 6,042,891 individuals with 1034 HD cases and in the second-generation study 4,860,469 individuals with 1001 cases. HD was defined as having at least one registered diagnosis of HD in the National Patient Register. The incidence of HD in different first-generation immigrant groups versus Swedish-born individuals was assessed by Cox regression, expressed as hazard ratios (HRs) and 95% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, and neighborhood socioeconomic status. Results Mean age-standardized incidence rates per 100,000 person-years were for all Swedish-born 0.82 and for all foreign born 0.53 and for all men 0.73 and for all women 0.81, with the highest incidence rates for the group 80–84 years of age. After adjusting for potential confounders, the HRs were lower in women in the first- and second-generation, i.e., 0.49 (95% CI 0.36–0.67) and 0.63 (95% 0.45–0.87), respectively, and also among women from Finland or with parents from Finland. Significance In general, the risk of HD was lower in first-generation and second-generation immigrant women but not among male immigrants.

Summary In this national study of osteoporotic fractures in second-generation immigrants in Sweden, we found a similar risk of osteoporotic fractures in general compared to Swedish natives, which suggests that environmental factors are important for the high risk of osteoporotic fractures in Nordic countries. Introduction Second generation immigrants may have a similar environment as individuals with two native-born parents. These individuals may be of interest to study concerning whether environmental or hereditary factors could be mostly associated to the risk of osteoporotic fractures. The aim of this study was to analyse the risk of osteoporotic fractures in second-generation immigrants compared to Swedish natives. Methods This was a nationwide study of individuals aged 50 years of age and older (N = 1,377,035; 691,750 men and 685,285 women). Osteoporotic fractures were defined as at least one registered diagnosis of fractures in the hip, humerus, forearm or vertebrae, in the National Patient Register between January 1, 1998, and December 31, 2012. Cox regression analysis was used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of incident osteoporotic fractures in second generation immigrants compared to Swedish natives. The Cox regression models were adjusted for age, comorbidities and for sociodemographic status. Results A total of 114,505 osteoporotic fractures were registered, 109,622 (8.4%) were among individuals with Swedish-born parents and 4883 (7.5%) among those with foreign-born parents, with distal forearm fractures dominating in general (44.9%). Fully adjusted HRs (95% CI) were for all immigrants 0.95 (95% CI, 0.91–0.99), for men 0.96 (95% CI, 0.89–1.04) and for women 0.95 (95% CI, 0.90–1.00). Conclusions We observed a similar risk of osteoporotic fractures among second-generation immigrants as in Swedish natives, which suggests that environmental factors are important for osteoporotic fractures. Supplementary Information The online version contains supplementary material available at 10.1007/s00198-020-05776-4.

Design Addison’s disease (AD) is a rare autoimmune disease (AID) of the adrenal cortex, present as an isolated AD or part of autoimmune polyendocrine syndromes (APSs) 1 and 2. Although AD patients present with a number of AID co-morbidities, population-based family studies are scarce, and we aimed to carry out an unbiased study on AD and related AIDs. Methods We collected data on patients diagnosed with AIDs in Swedish hospitals and calculated standardized incidence ratios (SIRs) in families for concordant AD and for other AIDs, the latter as discordant relative risks. Results The number of AD patients was 2852, which accounted for 0.4% of all hospitalized AIDs. A total of 62 persons (3.6%) were diagnosed with familial AD. The SIR for siblings was remarkably high, reaching 909 for singleton siblings diagnosed before age 10 years. It was 32 in those diagnosed past age 29 years and the risk for twins was 323. SIR was 9.44 for offspring of affected parents. AD was associated with 11 other AIDs, including thyroid AIDs and type 1 diabetes and some rarer AIDs such as Guillain–Barre syndrome, myasthenia gravis, polymyalgia rheumatica and Sjögren’s syndrome. Conclusions The familial risk for AD was very high implicating genetic etiology, which for juvenile siblings may be ascribed to APS-1. The adult part of sibling risk was probably contributed by recessive polygenic inheritance. AD was associated with many common AIDs; some of these were known co-morbidities in AD patients while some other appeared to more specific for a familial setting.

Abdominal aortic aneurysm (AAA) is a life-threatening condition with a mortality rate of over 80%. Persistent smoking, which is a risk factor for AAA, has lasting effects on DNA methylation. Moreover, a plasma-amino acid, homocysteine, previously implicated in vascular diseases, including aneurysms, has well-established biological association with methylation. In the present study, we aimed to determine the global DNA methylation, homocysteine levels and their association with AAA and its growth. Enzyme-linked immunosorbent assay (ELISA) was used to quantify global DNA methylation in whole blood-DNA samples and diagnostic enzymatic assay quantified plasma homocysteine, from 65-year old men with (n = 116) and without AAA (n = 230) diagnosed at ultrasound screening. We found significantly higher global DNA methylation (p .001) and homocysteine levels (p .001) in men with AAA compared to those without AAA, and direct linear associations with baseline aortic diameter. On multivariable regression analysis, global DNA methylation (odds ratio [OR]: 1.8; 95% confidence interval [CI]: 1.1-2.9) and homocysteine levels (OR: 1.1; 95% CI:1.0-1.1) were positively associated with AAA, independent of smoking, medication use, and major co-morbidities. However, we did not find any significant association between DNA methylation or homocysteine levels with AAA growth during follow-up. We found that global DNA methylation and homocysteine levels are higher in men with AAA but are not associated with AAA growth. This indicates that different pathways and mechanisms may be involved in initiation and progression of AAA. More studies are needed to understand the precise role of DNA methylation, homocysteine and their interplay in AAA pathophysiology.

As the number of rapes is increasing in Sweden, and the number of individuals convicted of these crimes is decreasing, it is of importance to study offender characteristics of those committing these crimes and the circumstances in which these crimes are conducted, such as indoors or outdoors. Data from Swedish population-based registers were used to identify individuals suspected of rape, aggravated rape, attempted rape or attempted aggravated rape (in short: rape+) against females ≥18 years old between 2007-2017. Latent Class Analysis was then used to identify classes of rape+ suspects with respect to the location of the rape+ and then compare the two groups. A total of 19,723 individuals were included of which the majority (n = 17,520; 88.8%) were suspected of indoor rape+. In both groups, we identified a low offenders' class and a high offenders' class. In addition, first-generation immigrants had a higher odds of being suspected of outdoor rape+ than Swedish-born suspects, and a previous conviction of violent crime was a risk factor for committing outdoor rape+.

BackgroundObservational studies regarding the correlation between the use of antihypertensive medication and the risk of breast cancer (BC) reported inconsistent findings. We performed a two-sample Mendelian randomization using instrumental variables to proxy changes in gene expressions of antihypertensive medication targets to interrogate this.MethodsWe assessed the association between single-nucleotide polymorphisms (SNPs) and drug targetable gene expression with expression quantitative trait loci in blood. Further, we investigated association between the SNPs and BC risk with genome-wide association study summary statistics. We then confirmed the hits from Mendelian randomization with tissue-specific analyses along with additional sensitivity assessments (horizontal pleiotropy, colocalization, multiple tissue enrichment etc.).ResultsThe overall BC risk was decreased 16% with one standard deviation (SD) increase of SLC12A2 gene expression in blood (odds ratio, 0.86, 95% confidential interval, 0.78-0.94). This signal was further confirmed in estrogen receptor positive (ER+) BC (0.85, 0.78-0.94). In addition, one SD increase in expression of PDE1B in blood was associated with 7% increased risk of ER+ BC (1.07, 1.03-1.11). We detected no evidence of horizontal pleiotropy for these associations and the probability of the causal variants being shared between the gene expression and BC risk was 81.5%, 40.5% and 66.8%, respectively. We failed to observe any significant association between other targeted genes and BC risk.ConclusionsUse of antihypertensive medications that target SLC12A2 and PDE1B is associated with increased and decreased BC risk, respectively.FundingThis work was supported by the Swedish Research Council [2018-02400 to K.S., 2020-01175 to J.S., 2021-01187 to J.J.], Cancerfonden [2017 CAN2017/340 to J.J.], Crafoordska Stiftelsen [to J.J.], MAS Cancer [to J.J.], ALF funding from Region Skåne [to J.J. and K.S.]. The funding body was not involved in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

The association between neighbourhood crime and major depression (MD) has been described before but previous studies may be limited by biases in self-reported data and the use of homogenous study populations. Our study aimed to examine the association between neighbourhood crime and clinically diagnosed MD among the immigrant and non-immigrant populations in Sweden.A retrospective cohort study was performed, which included non-immigrants and first- and second-generation immigrants residing in Sweden, who were born between 1960 and 1996. We used linked Swedish national registers, geospatial analysis and multilevel logistic regression models to examine the potential effect of neighbourhood crime on the odds of major depression between January 1, 2012, and December 31, 2015.Overall, individuals living in neighbourhoods with high levels of neighbourhood crime had higher odds of MD than those who did not. There was a significant interaction by immigrant status; the odds of MD among those with non-immigrant backgrounds were more strongly associated with increases in neighbourhood crime, after adjusting for potential confounders. Male and female immigrants born outside Sweden did not seem to be affected by increases in neighbourhood crime.The apparent effect of increases in neighbourhood crime on the odds of MD seemed to differ between those of different immigrant statuses. Future research should aim to explore the possible mechanisms behind the differences in the rates of MD among the non-immigrant and immigrant populations in neighbourhoods with high crime.

Preclinical and human studies suggest that a social partner's genotype may be associated with addiction-related outcomes. This study measured whether spousal genetic makeup is associated with risk of developing drug use disorder (DUD) during marriage, and whether the risk associated with a spouse's genotype could be disentangled from potentially confounding rearing environmental effects.Univariable and multivariable logistic regression analyses.Sweden.Men and women born 1960-1990 and in opposite-sex first marriages before age 35 (N = 294,748 couples).Outcome was DUD diagnosis (inclusive of opioids, sedatives/hypnotics/anxiolytics, cocaine, cannabis, amphetamine and other psychostimulants, hallucinogens, other drugs of abuse, and combinations thereof) obtained from legal, medical, and pharmacy registries. The focal predictor was family genetic risk scores for DUD (FGRS-DUD), which were inferred from diagnoses in first through fifth degree relatives and weighted by degree of genetic sharing. FGRS-DUD were calculated separately for each partner in a couple.Marriage to a spouse with a high FGRS-DUD was associated with increased risk of developing DUD during marriage, odds ratio [OR]There is relatively robust evidence that a person's risk for developing drug use disorder is associated with the genetic makeup of the person's spouse.

We know little about how genetic risk factors for two disorders jointly act and interact in predisposing to illness. Therefore, in the Swedish population, born 1970–1990 (n = 2,116,082) and followed through 2015, we examine, using additive Cox models, the impact of the family genetic risk scores (FGRS) for alcohol use disorder (AUD) and major depression (MD), their interaction with each other and with the relevant comorbid disorder on risk for AUD and MD. FGRS scores are constructed using rates of illness in first-fourth degree relatives. FGRS for AUD and MD interacted in predicting of both disorders and one FRGS (e.g., for AUD) interacted with the phenotype of MD to predict that disorder (e.g., AUD). These FGRS interactions were not substantially attenuated by adding interactions with the disorders. These results replicated across sexes. In predicting risk for a given disorder, we rarely consider genetic liabilities for other disorders. But such effects were here significant and interactive. Furthermore, the primary disorder genetic risk interacts with comorbid disorders. The pathways to risk for disorders from their and other disorders’ genetic liability may be more complex than commonly considered.

Background: Gallstones affect women more frequently than men, and symptomatic gallstones are increasingly treated with surgical removal of the gallbladder (cholecystectomy). Breast, endometrial, and ovarian cancer share several risk factors with gallstones, including overweight, obesity, and exposure to female sex hormones. We intended to assess the association between cholecystectomy and female cancer risk, which has not been comprehensively investigated. Methods: We investigated the risk of female cancers after cholecystectomy leveraging the Swedish Cancer, Population, Patient, and Death registries. Standardized incidence ratios (SIRs) adjusted for age, calendar period, socioeconomic status, and residential area were used to compare cancer risk in cholecystectomized and non-cholecystectomized women. Results: During a median follow-up of 11 years, 325,106 cholecystectomized women developed 10,431 primary breast, 2888 endometrial, 1577 ovarian, and 705 cervical cancers. The risk of ovarian cancer was increased by 35% (95% confidence interval (CI) 2% to 77%) in the first 6 months after cholecystectomy. The exclusion of cancers diagnosed in the first 6 months still resulted in an increased risk of endometrial (19%, 95%CI 14% to 23%) and breast (5%, 95%CI 3% to 7%) cancer, especially in women cholecystectomized after age 50 years. By contrast, cholecystectomized women showed decreased risks of cervical (−13%, 95%CI −20% to −7%) and ovarian (−6%, 95%CI −10% to −1%) cancer. Conclusions: The risk of ovarian cancer increased by 35% in a just short period of time (6 months) following the surgery. Therefore, it is worth ruling out ovarian cancer before cholecystectomy. Women undergoing cholecystectomy showed an increased risk of breast and endometrial cancer up to 30 years after surgery. Further evaluation of the association between gallstones or gallbladder removal on female cancer risk would allow for the assessment of the need to intensify cancer screening in cholecystectomized women.

BackgroundPreterm birth is associated with pulmonary complications early in life; however, long-term risks of asthma into adulthood are unclear.ObjectiveTo determine asthma risks from childhood into adulthood associated with gestational age at birth in a large population-based cohort.MethodsA national cohort study was conducted of all 4 079 878 singletons born in Sweden during 1973–2013, followed up for asthma identified from primary care, specialty outpatient and inpatient diagnoses in nationwide registries through 2018 (up to 46 years). Cox regression was used to adjust for potential confounders, and cosibling analyses assessed the influence of unmeasured shared familial (genetic and/or environmental) factors.ResultsIn 91.9 million person-years of follow-up, 607 760 (14.9%) persons were diagnosed with asthma. Preterm birth was associated with increased risk of asthma at ages ConclusionsIn this large national cohort, preterm and early term birth were associated with increased risks of asthma from childhood into midadulthood. Persons born prematurely need long-term follow-up into adulthood for timely detection and treatment of asthma.

Background Children experience a higher risk of psychiatric problems when their parents are diagnosed with cancer. However, the psychological effect among offspring who are born after parental cancer diagnosed in childhood or adolescence is unknown. We aimed to investigate the risk of psychiatric disorders in children of survivors with childhood or adolescent central nervous system (CNS) tumors. Methods By combining several nationwide Swedish registers, we identified all children who had at least one parent previously diagnosed with CNS tumor below the age of 20. Five children without parental CNS tumor were randomly selected for the matching. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence interval (CI). Results The incidence rate of psychiatric disorders was 8.46 per 1000 person‐years in children of CNS tumor survivors, whereas the rate was 7.47 in the matched comparisons, yielding an adjusted HR of 1.10 (95% CI = 0.94, 1.28). Boys of survivors had a higher risk of psychiatric disorders (adjusted HR = 1.29, 95% CI = 1.04, 1.59). The risk of the specific types of psychiatric disorders in children of tumor survivors was comparable with that in the matched comparisons, except for mental retardation. Children of survivors experienced 2.36 times higher risk of mental retardation (95% CI = 1.21, 4.58), mainly of mild mental retardation (adjusted HR = 2.99, 95% CI = 1.40, 6.38). Conclusion Children of survivors with CNS tumor in early life did not experience a significantly increased risk of overall psychiatric disorders, with the exception of an elevated risk of mental retardation that was mainly mild., Children whose mother or father was ever diagnosed with central nervous system tumor below age of 20 didn't have a higher risk to experience mental diseases, however, they were at an increased risk of mild intellectual disability.

BackgroundOral contraceptive use has been previously associated with an increased risk of suicidal behavior in some, but not all, samples. The use of large, representative, longitudinally-assessed samples may clarify the nature of this potential association.MethodsWe used Swedish national registries to identify women born between 1991 and 1995 (N = 216 702) and determine whether they retrieved prescriptions for oral contraceptives. We used Cox proportional hazards models to test the association between contraceptive use and first observed suicidal event (suicide attempt or death) from age 15 until the end of follow-up in 2014 (maximum age 22.4). We adjusted for covariates, including mental illness and parental history of suicide.ResultsIn a crude model, use of combination or progestin-only oral contraceptives was positively associated with suicidal behavior, with hazard ratios (HRs) of 1.73–2.78 after 1 month of use, and 1.25–1.82 after 1 year of use. Accounting for sociodemographic, parental, and psychiatric variables attenuated these associations, and risks declined with increasing duration of use: adjusted HRs ranged from 1.56 to 2.13 1 month beyond the initiation of use, and from 1.19 to 1.48 1 year after initiation of use. HRs were higher among women who ceased use during the observation period.ConclusionsYoung women using oral contraceptives may be at increased risk of suicidal behavior, but risk declines with increased duration of use. Analysis of former users suggests that women susceptible to depression/anxiety are more likely to cease hormonal contraceptive use. Additional studies are necessary to determine whether the observed association is attributable to a causal mechanism.

Background Expensive cancer treatment calls for alternative ways such as drug repurposing to develop effective drugs. The aim of this study was to analyse the effect of post-diagnostic use of cholera vaccine on survival outcome in breast cancer patients. Methods Cancer diagnosis and cholera vaccination were obtained by linkage of several Swedish national registries. One vaccinated patient was matched with maximum two unvaccinated individuals based on demographic, clinical and socioeconomic factors. We performed proportional Cox regression model to analyse the differences in overall and disease-specific survivals between the matched patients. Results In total, 617 patients received cholera vaccine after breast cancer diagnosis. The median (interquartile range) time from diagnosis to vaccination was 30 (15–51) months and from vaccination to the end of follow-up it was 62 (47–85) months. Among them, 603 patients were matched with 1194 unvaccinated patients. Vaccinated patients showed favourable overall survival (hazard ratio (HR): 0.54, 95% confidence interval (CI): 0.37–0.79) and disease-specific survival (HR: 0.53, 95% CI: 0.33–0.84), compared to their unvaccinated counterpart. The results were still significant in multiple sensitivity analyses. Conclusions Post-diagnostic use of cholera vaccine is associated with a favourable survival rate in breast cancer patients; this provides evidence for repurposing it against breast cancer.

Circulating cell‐free nuclear DNA (nDNA) has been implicated in individual cancer types with a diagnostic value; however, the role of cell‐free mitochondrial DNA (mtDNA) in cancers is controversial. We aimed to investigate and compare the diagnostic potential of both nDNA and mtDNA for multiple cancers and to investigate their ability to distinguish multiple cancers from healthy controls and from nonmalignant diseases. We also investigated the prognostic value of both nDNA and mtDNA. The absolute copy number of circulating DNAs in suspected cancer patients (n = 286) referred to a cancer diagnostic center and healthy controls (n = 109) was quantified by droplet digital polymerase chain reaction. Among the suspected cancer patients, 66 (23%) were diagnosed with various cancers, 193 (67%) with nonmalignant diseases, and 27 (10%) with no active disease. Levels of nDNA were significantly higher in cancers (copies/μl; mean ± SD, 21.0 ± 14.2) as compared with nonmalignant diseases (15.2 ± 10.0) and controls (9.3 ± 4.1). In contrast, levels of mtDNA were significantly lower in cancers (copies/μl; mean ± SD, 68,557 ± 66,663) and nonmalignant diseases (60,174 ± 55,831) as compared with controls (98,714 ± 77,789). Receiver operating curve analysis showed that nDNA not only could distinguish multiple cancers from controls (area under curve [AUC] = 0.78; 95% confidence interval [CI] = 0.70–0.86) but also from nonmalignant diseases (AUC = 0.68; 95% CI = 0.59–0.76). However, mtDNA could only differentiate cancers from controls (AUC = 0.65; 95% CI = 0.56–0.73). Higher levels of nDNA were also associated with increased mortality in the cancer patients (hazard ratio = 2.3; 95% CI = 1.1–4.7). Circulating cell‐free nDNA, but not the mtDNA, could distinguish multiple cancers from nonmalignant diseases and was associated with poor survival of cancer patients.

Background Many cancers are increased in immunosuppressed patients and evidence is accumulating that immune dysfunction may be a contributing risk factor for second primary cancers (SPCs). The aim of this study was to explore the potential influence of immune mechanisms in SPC. Methods We used the Swedish Cancer Registry (1990‐2015) to select 13 male and 14 female first primary cancers (FPCs) that are known to be related to immune suppression. We assessed relative risks (RRs) for any of these as concordant (same first and second cancer) and discordant FPC‐SPC pairs. Hierarchical clustering of significant RRs was performed for cancers as FPC and SPC. Results Concordant risks for SPCs were excessive in men and women for nasal (RRs 59.3 for men and 150.6 for women), tongue/mouth (51.7 and 100.8), and lip (32.4 and 61.2) cancers. Heatmaps showed that some cancers, such as skin cancer, tongue/mouth cancers, and non‐Hodgkin lymphoma had multiple bidirectional associations as FPC and SPC. Nasal cancer and chronic lymphocytic leukemia had associations mainly as FPC while liver and kidney cancers showed most associations as SPC. Conclusions Immune dysfunction may be a plausible contributing factor for most of the associations, which calls for experimental verification., Relative risks for a single second primary cancer after any first primary cancer (top), and RRs for any second primary cancer after a single first primary cancer (bottom). Male data are blue and female data in yellow symbols. The vertical bars show 95%CIs. NHL, non‐Hodgkin lymphoma, CLL, chronic lymphocytic leukemia.

Introduction Academic achievement (AA) is associated with smoking rates. Can we determine the degree to which this relationship is likely a causal one? Methods We predict smoking in male conscripts (mean age 18.2) assessed from 1984 to 1991 (N = 233 248) and pregnant females (mean age 27.7) receiving prenatal care 1972–1990 (N = 494 995) from AA assessed in all students at 16. Instrumental variable (IV) analyses used the instrument month-of-birth as in each school year, older children have high AA. Co-relative analyses used AA-smoking associations in the population, cousins and siblings to predict the AA-smoking relationship in MZ twins, thereby controlling for familial confounding. Results In males, higher AA was associated with a substantial decrease in risk for smoking (odds ratio [OR] [95% confidence intervals [CIs]] per standard deviation [SD] = 0.41 [0.40–0.41]) while the parallel figures obtain from our IV and co-relative analyses were 0.47 (0.39–0.57) and 0.51 (0.43–0.60), respectively. In females, these figures for pre-pregnancy smoking were, respectively, 0.39 (0.39–0.39), 0.50 (0.46–0.54) and 0.54 (0.51–0.58). Results for heavy versus light smoking suggested a causal effect but were inconsistent across methods. However, among females smoking prior to pregnancy, AA predicted a reduced risk for continued smoking with ORs for uncontrolled, IV, and co-relative analyses equaling, respectively, were 0.54 (0.53–0.55) 0.68 (0.56–0.82) and 0.78 (0.66–0.91), respectively. Conclusions Two different methods produced consistent evidence that higher AA has a causal effect on reducing smoking rates and increasing cessation rates in smoking pregnant females. Improving AA may result in meaningful gains in population health through reduced smoking. Implications This study provides consistent evidence across two different methods that high AA is causally related to reduced rates of smoking and increasing rates of smoking cessation among pregnant women. Our results suggest that interventions that improve educational achievement in adolescence would reduce tobacco consumption, thereby improving public health.

Investigations of social-genetic effects, whereby a social partner’s genotype affects another’s outcomes, can be confounded by the influence of the social partner’s rearing environment. We used marital information on more than 300,000 couples from Swedish national data to disentangle social-genetic from rearing-environment effects for alcohol use disorder (AUD). Using observational and extended-family designs, we found that (a) marriage to a spouse with a predisposition toward AUD (as indexed by a parental history of AUD) increased risk for developing AUD; (b) this increased risk was not explained by socioeconomic status, the spouse’s AUD status, or contact with the spouse’s parents; and (c) this increased risk reflected the psychological consequences of the spouse having grown up with an AUD-affected parent (i.e., a rearing-environment effect) rather than a social-genetic effect. Findings illustrate that a spouse’s rearing-environment exposures may confer risk for AUD.

Summary In this national study of osteoporotic fractures in foreign-born individuals, we found a lower risk of osteoporotic fractures in general among foreign-born individuals compared with Swedish-born, especially in immigrants from southern Europe. A higher risk was found among some groups, i.e. men and women from Bosnia and Iraq and men from Lebanon. Introduction The aim of this study was to analyse risk of osteoporotic fractures in foreign-born individuals compared with Swedish-born individuals. Methods This was a nationwide study of individuals 50 years of age and older (N = 2,775,736). Osteoporotic fractures were defined as at least one registered diagnosis of fractures in the hip, humerus, forearm or vertebrae, in the National Patient Register between January 1, 1998, and December 31, 2012. Cox regression analysis was used to estimate the relative risk (hazard ratios (HR) with 99% confidence intervals (CI)) of incident osteoporotic fractures in foreign-born compared with Swedish-born individuals. The Cox regression models were stratified by sex and adjusted for age, comorbidities and sociodemographic status. Results A total of 362,899 osteoporotic fractures were registered (96,847 among men and 266,052 among women), with hip fractures dominating (54.0% among men, 42.6% among women). Fully adjusted HRs (99% CI) were for all immigrant men 0.75 (99% CI, 0.73–0.78) and women 0.83 (99% CI, 0.81–0.84), with significantly lower HRs among most groups but with higher HRs in certain countries. For the specific fractures, higher HRs were found for lower forearm fractures for men from Asia and for vertebral fractures among women from Asia. Conclusions We observed a generally lower risk of osteoporotic fractures among first-generation immigrants, with few exceptions. Electronic supplementary material The online version of this article (10.1007/s00198-020-05597-5) contains supplementary material, which is available to authorized users.

Background: Most literature on second primary cancers (SPCs) focuses on possible factors, which may increase the risk of these cancers, and little attention has been paid for the overall incidence differences between first primary cancers (FPCs) and same SPCs. We wanted to compare the incidence rates for all common cancers when these were diagnosed as FPCs and SPCs after invasive and in situ squamous cell carcinoma (SCC) of the skin, which are usually treated by surgery only. Methods: Cancers were identified from the Swedish Cancer Registry from the years 1990 through to 2015, and they included, in addition to skin cancers, 20 male cancers totaling 484,850 patients and 22 female cancers totaling 452,909 patients. Standardized incidence rates and relative risks (RRs) were calculated for sex-specific common cancers as FPC and as SPC after skin SCC. Spearman rank correlations were used in the analysis of incidence ranking of FPC and SPC. Results: Of total, 29,061 men and 23,533 women developed invasive SCC and 27,842 men and 36,383 women in situ SCC. The total number of 20 other male cancers was 484,850 and of 22 female cancers it was 452,909. Rank correlations ranged from 0.90 to 0.96 (P~5×10−6), indicating that overall skin SCC did not interfere with SPC formation. The exceptions were increased SPC risks for melanoma, sharing risk factors with skin SCC, and non-Hodgkin and Hodgkin lymphoma, and cancers of the upper aerodigestive tract, connective tissue, and male and female genitals suggesting contribution by skin cancer initiated immune dysfunction. Conclusion: The incidence ranking of SPCs after skin cancers largely follows the incidence ranking of FPCs indicating that overall skin SCC does not greatly interfere with the intrinsic carcinogenic process. The main deviations in incidence between FPC and SPC appeared to be due to shared risk factors or immunological processes promoting immune responsive cancer types. (Less)

Congestive heart failure (CHF) is the most important cause of death in patients with atrial fibrillation (AF). We aimed to study the association between cardiovascular drugs in AF patients and incident CHF. The study population included all adults (n = 120 756) aged ≥45 years diagnosed with AF in Sweden diagnosed for the period 1998‐2006. Outcome was incident congestive heart failure (follow‐up 2007‐2015) in AF patients. Associations between treatment with cardiovascular pharmacotherapies and CHF were evaluated using Cox regression to estimate hazard ratios (HRs) with 95% CIs, after adjustment for age, sociodemographic variables, and comorbidities. During a mean 5.3 years (SD 3.0) of follow‐up, there were 28 257 (23.4%) incident cases of CHF. Treatment with beta‐1‐selective and non‐selective beta‐blockers and statins was associated with lower risks of incident CHF in men, HR, (95% CI); 0.90, (0.87‐0.94); 0.90, (0.84‐0.97), and 0.94, (0.90‐0.99), respectively. Only beta‐1‐selective beta‐blockers were protective in women 0.94 (0.91‐0.98). Treatment with loop diuretics, potassium‐saving agents, ACE inhibitors, and angiotensin receptor blockers was associated with a higher risk of CHF. For men, treatment with heart‐active calcium channel blockers also led to a higher risk of CHF. In conclusion, we found that beta‐blockers, in particular, but also statins were associated with lower risk of incident CHF in patients with AF.

OBJECTIVE: We evaluated the claim that interventions to improve academic achievement can reduce the risk for alcohol use disorder (AUD). METHOD: Using nationwide data for individuals born in Sweden from 1972 to 1981 (n = 930,182), we conducted instrumental variable and co-relative analyses of the association between academic achievement and AUD with a mean 21.4-year follow-up. Our instrument, used in the instrumental variable analyses, was month of birth. Co-relative analyses were conducted in cousins, full siblings, and monozygotic twins discordant for AUD, with observed results fitted to a genetic model. The academic achievement–AUD association was modeled in Cox regression. AUD was assessed using national medical, criminal, or pharmacy registries. RESULTS: Later month of birth was significantly associated with poorer academic achievement. Lower standardized academic achievement had a strong relationship with the risk for subsequent AUD registration: hazard ratio (HR) [per SD] = 2.14 [2.11, 2.17]. Instrumental variable analysis produced a substantial but moderately attenuated association: HR = 1.52 [1.28, 1.80]. Controlling for modest associations between month of birth and parental education and AUD risk reduced the association to HR = 1.43 [1.20, 1.69]. Our genetic co-relative model fitted the observed data relatively well and estimated the academic achievement–AUD association in monozygotic twins discordant for academic achievement to equal an HR of 1.44 [1.35, 1.52]. Results were broadly similar when analyzed separately in males and females. CONCLUSIONS: Two distinct methods with different assumptions produced results suggesting that the association observed between academic achievement at age 16 and the risk for AUD into middle adulthood is partly causal, thereby providing support for interventions to improve academic achievement as a means to prevent later AUD risk.

The authors examined the association between alcohol use disorder (AUD) and risk of suicide, before and after accounting for psychiatric comorbidity, and assessed the extent to which the observed association is due to a potentially causal mechanism or genetic and familial environmental confounding factors that increase risk for both.Longitudinal population-wide Swedish medical, criminal, and pharmacy registries were used to evaluate the risk of death by suicide as a function of AUD history. Analyses employed prospective cohort and co-relative designs, including data on 2,229,880 native Swedes born between 1950 and 1970 and observed from age 15 until 2012.The lifetime rate of suicide during the observation period was 3.54% for women and 3.94% for men with AUD, compared with 0.29% and 0.76% of women and men, respectively, without AUD. In adjusted analyses, AUD remained robustly associated with suicide: hazard ratios across observation periods ranged from 2.61 to 128.0 among women and from 2.44 to 28.0 among men. Co-relative analyses indicated that familial confounding accounted for some, but not all, of the observed association. A substantial and potentially causal relationship remained after accounting for a history of other psychiatric diagnoses.AUD is a potent risk factor for suicide, with a substantial association persisting after accounting for confounding factors. These findings underscore the impact of AUD on suicide risk, even in the context of other mental illness, and implicate the time frame shortly after a medical or criminal AUD registration as critical for efforts to reduce alcohol-related suicide.

Women who deliver pre-term have been reported to have increased future risks of cardiometabolic disorders. However, their long-term risks of ischemic heart disease (IHD) and whether such risks are due to shared familial factors are unclear. A better understanding of these risks may help improve long-term clinical follow-up and interventions to prevent IHD in women.The purpose of this study was to determine the long-term risks of IHD in women by pregnancy duration.A national cohort study was conducted of all 2,189,190 women with a singleton delivery in Sweden from 1973 to 2015, who were followed up for IHD through the end of 2015. Cox regression was used to compute adjusted hazard ratios (aHRs) for IHD associated with pregnancy duration, and cosibling analyses assessed the influence of shared familial (genetic and/or environmental) factors.In 47.5 million person-years of follow-up, 49,955 (2.3%) women were diagnosed with IHD. In the 10 years following delivery, the aHR for IHD associated with pre-term delivery (37 weeks) was 2.47 (95% confidence interval [CI]: 2.16 to 2.82), and further stratified was 4.04 (95% CI: 2.69 to 6.08) for extremely pre-term (22 to 27 weeks), 2.62 (95% CI: 2.09 to 3.29) for very pre-term (28 to 33 weeks), 2.30 (95% CI: 1.97 to 2.70) for late pre-term (34 to 36 weeks), and 1.47 (95% CI: 1.30 to 1.65) for early-term (37 to 38 weeks), compared with full-term (39 to 41 weeks). These risks declined but remained significantly elevated after additional follow-up (pre-term vs. full-term, 10 to 19 years: aHR: 1.86; 95% CI: 1.73 to 1.99; 20 to 29 years: aHR: 1.52; 95% CI: 1.45 to 1.59; 30 to 43 years: aHR: 1.38; 95% CI: 1.32 to 1.45). These findings did not appear attributable to shared genetic or environmental factors within families. Additional pre-term deliveries were associated with further increases in risk.In this large national cohort, pre-term delivery was a strong independent risk factor for IHD. This association waned over time but remained substantially elevated up to 40 years later. Pre-term delivery should be recognized as a risk factor for IHD in women across the life course.

BackgroundAlcohol use disorder (AUD) is common and associated with increased risk of suicide.AimsTo examine healthcare utilisation prior to suicide in persons with AUD in a large population-based cohort, which may reveal opportunities for prevention.MethodA national cohort study was conducted of 6 947 191 adults in Sweden in 2002, including 256 647 (3.7%) with AUD, with follow-up for suicide through 2015. A nested case–control design examined healthcare utilisation among people with AUD who died by suicide and 10:1 age- and gender-matched controls.ResultsIn 86.7 million person-years of follow-up, 15 662 (0.2%) persons died by suicide, including 2601 (1.0%) with AUD. Unadjusted and adjusted relative risks for suicide associated with AUD were 8.15 (95% CI 7.86–8.46) and 2.22 (95% CI 2.11–2.34). Of the people with AUD who died by suicide, 39.7% and 75.6% had a healthcare encounter P = 0.01). Of last encounters, 48.1% were in primary care and 28.9% were in specialty out-patient clinics, mostly for non-psychiatric diagnoses.ConclusionsSuicide among persons with AUD is often shortly preceded by healthcare encounters in primary care or specialty out-patient clinics. Encounters in these settings are important opportunities to identify active suicidality and intervene accordingly in patients with AUD.

To determine whether alcohol use disorder (AUD) is transmitted within families as predicted by contagion, we examined parent-offspring, siblings, and cousin pairs ascertained from Swedish registries with a primary case with AUD. Our outcome variable was AUD registration in at-risk secondary cases. In offspring, risks for AUD registration in the 3 years after a parental index registration residing in the same household, neighborhood, or municipality increased by 1.6%, -0.5%, and 0.3%, respectively. For siblings of sibling index cases, parallel results were 3.2%, 1.2%, and 0.3%. For cousins of cousin index cases, no excess risk was seen for those residing in the same neighborhood or municipality. In siblings, AUD transmission was stronger in same versus opposite sex pairs and from older to younger versus younger to older siblings. These results support the hypothesis that AUD is transmitted among close family relationships and over limited geographical distances by a temporally dynamic contagion model.

Introduction Using Swedish nationwide registry data, we investigated the contribution of genetic and environmental risk factors to the etiology of smoking status across stages of pregnancy with increasing degrees of social and psychological pressure to reduce or quit smoking, by twin and sibling modeling. Aims and Methods Smoking status was available before, and during early and late pregnancy from the Medical Birth Register. Twin, full-, and half-sibling pairs, both reared together and apart, born between 1960 and 1990 were obtained from national twin and genealogical registers. Genetic structural equation modeling in OpenMx was applied to the population-based data to estimate shared genetic and/or environmental covariance across stages of pregnancy, accounting for maternal birth cohort and age at pregnancy. Results Analyses of paired data on 258 749 individuals suggested that risk factors for smoking status changed across stages of pregnancy. Results predicted substantial heritability (60–70%) and moderate contributions of shared environmental factors (10–15%) for smoking status. Whilst the same shared environmental factors were amplified from before pregnancy to late pregnancy, new primarily unique environmental factors explained ~10% of the variance during early pregnancy which was carried forward to late pregnancy. Conclusions Using registry data on women across pregnancy, we replicated that smoking status is highly heritable. Furthermore, we found support for increased impact of shared environmental factors during pregnancy of factors already present prior to pregnancy, and an independent set of mostly new unique environmental factors that may be triggered by increased social pressure to reduce or quit smoking during pregnancy. Implications As new factors partially explain smoking status during pregnancy and the effects of familial factors increase across pregnancy, efforts to prevent or reduce smoking during pregnancy should receive continued attention, with a focus on both the individual and the family unit.

The mortality in individuals with a family history of heart failure (HF) has not been determined. This nationwide sib-pair study aimed to determine mortality in individuals with a sibling affected with HF.Sib-pairs were linked using the Swedish Multi-Generation Register, the Hospital Discharge Register and the Cause of Death Register for the period 1987-2012. Families with cardiomyopathy or congenital heart disease were excluded. Mortality hazard ratios (HRs) were calculated for siblings of individuals who had been diagnosed with HF compared with siblings of individuals unaffected by HF as the reference group. Similar analyses were made for spouses. HRs were determined for overall mortality, cardiovascular mortality, and death of unknown cause.Among siblings, the adjusted HR for overall mortality was 1.21 (95% CI 1.18-1.25). This risk remained (HR = 1.19, 95% CI 1.15-1.23) also among subjects without HF themselves. The adjusted HRs for cardiovascular mortality and death of unknown cause were 1.39 (95% CI 1.32-1.45) and 1.58 (95% CI 1.29-1.95), respectively. The mortality risk associations with spousal HF were all minimal, with an overall mortality HR of 1.02 (1.01-1.02). Early sibling age of onset of HF 50 years was associated with higher HRs for overall mortality, cardiovascular mortality, and death of unknown cause, 1.33 (1.27-1.41), 1.54 (1.40-1.68) and 1.84 (1.27-2.67), respectively.Sibling HF, especially early-onset HF, is associated with increased mortality. The low risk in spouses suggests genetic factors might be of importance. Screening for HF, and cardiovascular disease in general, in these individuals may be warranted.

The authors sought to clarify the role of rearing environment in the etiology of major depression.Defining high risk as having at least one biological parent with major depression, the authors identified a Swedish National Sample of 666 high-risk full sibships and 2,596 high-risk half sibships containing at least one home-reared and one adopted-away sibling. Major depression was assessed from national medical registries.Controlling for sex, parental age at birth, and, for half siblings, history of major depression in the nonshared parent, the risk for major depression in the matched adopted compared with home-reared full and half siblings was reduced by 23% (95% CI=7-36) and by 19% (95% CI=10-38), respectively. This protective rearing effect was not influenced by the relative educational status of the biological and adoptive parents. However, in both full and half sibships, the protective effect of adoption disappeared when an adoptive parent or stepsibling had major depression or the adoptive home was disrupted by parental death or divorce.In matched full and half sibships at high risk for major depression, compared with individuals raised in their home environment, those reared in adoptive homes (homes selected in Sweden for their high-quality rearing environment) had a significantly reduced risk for major depression. This protective effect disappeared if an adoptive parent had major depression or if the adoptive home experienced parental death or divorce during childhood/adolescence. The rearing environment has a meaningful impact on risk for major depression, and this effect is likely mediated both by parental depression and the continuity or disruption of the home environment.

BackgroundAlthough alcohol use disorder (AUD) runs strongly within families, studies examining the impact of rearing environment, unconfounded by genetic effects, are rare and, to date, contradictory. We here seek to conduct such a study using an adoptive co-sib control design.MethodsDefining high-risk as having ⩾1 biological parent with an externalizing syndrome (AUD, drug abuse or crime), we identified 1316 high-risk full-sibships and 4623 high-risk half-sibships containing at least one member who was home-reared and one who was adopted-away. Adoptive families are carefully screened in Sweden to provide high-quality rearing environment for adoptees. AUD was assessed from national medical, criminal and pharmacy registries.ResultsControlling for sex, parental age at birth, and, for half-siblings, affection status of the non-shared parent, hazard ratios (±95% CI) for AUD in the matched adopted v. home-reared full- and half-siblings were, respectively, 0.76 (0.65–0.89) and 0.77 (0.70–0.84). The protective effect of adoption on AUD risk was stronger in the full- and half-sibling pairs with very high familial liability (two high-risk parents) and significantly weaker when the adoptive family was broken by death or divorce or contained a high-risk adoptive parent.ConclusionsIn both full- and half-sibling pairs, we found evidence that the rearing environment substantially impacts on the risk for AUD. High-quality rearing environments can meaningfully reduce the risk for AUD, especially in those at high familial risk.

Aim: To compare incidence of urolithiasis in second-generation immigrant children aged 0-17 years to children of Swedish-born parents. Methods: A nationwide study of individuals residing in Sweden. Urolithiasis was defined as having at least one registered diagnosis of urolithiasis in the Swedish National Patient Register between January 1, 1998 and December 31, 2015. Cox regression analysis was used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of incident urolithiasis compared to individuals with Swedish-born parents. The models were stratified by sex and adjusted for age, co-morbidities and sociodemographic status of parents. Results: Totally, 1653 incident cases of urolithiasis were registered, 658 boys and 995 girls, with a mean annual incidence per 100 000 person-years for children with Swedish-born parents of 4.0 (95% CI 3.7-4.3) in boys and 6.7 (95% CI 6.2-7.2) in girls, and for children with foreign-born parents of 5.3 (95% CI 5.1-5.4) in boys and 7.2 (95% CI 6.9-7.4) in girls. The fully adjusted HRs of urolithiasis in second-generation immigrants were non-significant, in boys (1.20, 95% CI 0.99-1.46) and girls (0.95, 95% CI 0.80-1.12). Conclusion: The risk of urolithiasis in second-generation immigrants was not significantly different from that of children with Swedish-born parents. (Less)

Objectives Identification of biological markers that can guide treatment selection is considered to be a viable solution for personalized treatment for patients with psychiatric disorders. This study investigated whether macrophage migration inhibitory factor (MIF) levels at baseline were associated with mindfulness-based group therapy or cognitive behavioral therapy response in patients with mild to moderate symptoms of depression, anxiety, or stress- and adjustment disorders. Methods A total of 168 patients (aged 21–65 years) with psychiatric disorders were included from a randomized controlled trial. Plasma MIF levels in all the patients were analyzed using Luminex assay. Results Higher MIF levels at baseline were significantly associated with better long-term (1-year follow-up) improvement in psychiatric symptoms, as measured by changes in the Montgomery-Åsberg Depression Rating Scale (MADRS-S), compared with lower MIF levels, after adjustment for baseline MADRS-S score, age, sex, BMI, and pharmacotherapy (β = 5.89, p = 0.001). Patients with higher levels of MIF (8235–23,391 pg/ml) had an almost 6 points’ larger decrease in MADRS-S score after 1 year compared with those with lower MIF (727–8223 pg/ml) at baseline. Similar trends were seen after 8 weeks, albeit non-significant (β = 1.99, p = 0.18). Conclusions The findings indicate that higher plasma MIF levels at baseline may predict better long-term outcomes with psychotherapeutic interventions for mild to moderate symptoms of depression, anxiety, or stress and adjustment disorders. MIF levels may serve as a potential biomarker that can guide treatment selection for the personalized treatment for patients with psychiatric disorders.

Background Our aim was to study the potential effect of neighborhood deprivation on incident heart failure (HF) in patients with diabetes mellitus (DM). Methods The study population included adults (n = 434,542) aged 30 years or older with DM followed from 2005 to 2015 in Sweden for incident HF. The association between neighborhood deprivation and the outcome was explored using Cox regression analysis, with hazard ratios (HRs) and 95% confidence intervals (95% CIs). All models were conducted in both men and women and adjusted for age, educational level, family income, employment status, region of residence, immigrant status, marital status, mobility, and comorbidities. DM patients living in neighborhoods with high or moderate levels of deprivation were compared with those living in neighborhoods with low deprivation scores (reference group). Results There was an association between level of neighborhood deprivation and HF in DM patients. The HRs were 1.27, 95% CI 1.21–1.33, for men and 1.30, 95% CI 1.23–1.37, for women) among DM patients living in high deprivation neighborhoods compared with those from low deprivation neighborhoods. After adjustments for potential confounders, the higher HRs of HF remained significant: 1.11, 95% CI 1.06–1.16, in men and 1.15, 95% CI 1.09–1.21, in women living in high deprivation neighborhoods. Conclusions Increased incidence rates of HF among DM patients living in deprived neighborhoods raise important clinical and public health concerns. These findings could serve as an aid to policy-makers when allocating resources in primary health-care settings as well as to clinicians who encounter patients in deprived neighborhoods.

Background: Survival in malignant cutaneous melanoma has improved but increasing survival will result in an increased likelihood of the occurrence of second primary cancers (SPCs). SPCs may adversely interfere with survival. We quantified survival in patients with different types of SPCs, in comparison to known poor prognostic indicators of metastatic disease. Methods: Data for melanoma and any SPCs were obtained from the Swedish Cancer Registry for years 2003 through 2015, including clinical TNM classification. SPCs were grouped into three ‘prognostic groups’ based on 5-year relative survival of these cancers as first primary cancer. Kaplan-Meier survival curves were generated and hazard ratios were estimated using Cox regression, adjusted for a number of variables and treating diagnosis of SPC as a time-dependent variable. Results: The total number of first melanoma patients was 28,716 followed by 3,202 (11.1%) SPCs, 1/3 of which had a second melanoma while 2/3 had other SPCs. Among men diagnosed at age over 70 years, who survived at least 10 years, 31.4% had SPC. HRs (95% CI) for survival increased systematically from the reference rate of 1.00 (no SPC) to 1.59 (1.35–1.87) with SPC of good prognosis (78.6% of SPCs) to 3.49 (2.58–4.72) of moderate prognosis (12.0%) and to 7.93 (5.50–11.44) of poor prognosis (9.4%). In patients without SPC, the HRs increased to 2.62 (2.02–3.39) with any nodal metastases and to 5.88 (4.57–7.57) with any distant metastases compared to patients without local or distant metastases. Conclusion: The data showed that SPCs are an increasingly common negative prognostic factor for melanoma. Future attempts to improve melanoma survival need to target SPCs. (Less)

Purpose: The incidence of colorectal cancer (CRC) varies by age, sex, and anatomical subsite. Few studies have examined the temporal trends of age-specific sex disparity in incidence and survival by age at diagnosis and anatomical site. Patients and Methods: The study was performed on all incident cases of CRC, using data derived from the nationwide Swedish Cancer Register between 1960 and 2014, including right-sided colon cancer (RCC), left-sided colon cancer (LCC), and rectal cancer. Male-to-female age-standardized incidence rate ratio (IRR) and male-to-female five-year survival rate ratio (SRR) were calculated as the main indicators. Furthermore, we performed joinpoint regression analyses to estimate average annual percentage change. Results: The overall male-to-female IRR was 1.05 for RCC, 1.31 for LCC, and 1.66 for rectal cancer. Male-to-female IRR increased steadily for RCC by an average of 0.4% per year until the mid-1990s and then decreased gradually by an average of 1.0% per year. LCC patients showed an increase of 0.6% per year since the mid-1970s. For rectal cancer, a non-significant random fluctuation was noted during the study period. The temporal trends of male-to-female IRR varied by age at diagnosis. The male-to-female SRR was 0.87 for RCC, 0.88 for LCC, and 0.86 for rectal cancer, which remained relatively stable during the study period. Conclusion: Sex disparity of CRC is age-, period-, and anatomical subsite-dependent. Further studies are needed to investigate the underlying contributing factors. (Less)

Background Do genetic risk profiles for drug use disorder (DUD), major depression (MD), and attention-deficit hyperactivity disorder (ADHD) differ substantially as a function of sex, age at onset (AAO), recurrence, mode of ascertainment, and treatment? Methods Family genetic risk scores (FGRS) for MD, anxiety disorders, bipolar disorder, schizophrenia, alcohol use disorder, DUD, ADHD, and autism-spectrum disorder were calculated from 1st–5th degree relatives in the Swedish population born 1932–1995 (n = 5 829 952). Profiles of these FGRS were obtained and compared across various subgroups of DUD, MD, and ADHD cases. Results Differences in FGRS profiles for DUD, MD, and ADHD by sex were modest, but they varied substantially by AAO, recurrence, ascertainment, and treatment with scores typically higher in cases with greater severity (e.g. early AAO, high recurrence, ascertainment in high intensity clinical settings, and treatment). However, severity was not always related to purer genetic profiles, as genetic risk for many disorders often increased together. However, some results, such as by mode of ascertainment from different Swedish registries, produced qualitative differences in FGRS profiles. Conclusions Differences in FGRS profiles for DUD, MD, and ADHD varied substantially by AAO, recurrence, ascertainment, and treatment. Replication of psychiatric studies, particularly those examining genetic factors, may be difficult unless cases are matched not only by diagnosis but by important clinical characteristics. Genetic correlations between psychiatric disorders could arise through one disorder impacting on the patterns of ascertainment for the other, rather than from the direct effects of shared genetic liabilities.

INTRODUCTION: Alcohol use disorder (AUD) has been identified as a strong risk factor for suicide attempt. However, few studies have considered protective factors that may moderate this association, such as resilience. METHODS: We used longitudinal nationwide Swedish data of 903,333 males born 1960–1980 and 48,285 males born 1949–1951. We performed Cox proportional hazards models to test the role of AUD, resilience, and their interaction on risk for suicide attempt. We used co-relative models to account for familial factors. RESULTS: Alcohol use disorder was strongly associated with increased risk of suicide attempt [hazard ratio (HR) = 12.22], while resilience was associated with reduced risk (HR = 0.73). Multiplicative interaction (HR = 1.21) showed that, in the context of AUD, the protective role of resilience on risk of suicide attempt was somewhat attenuated. Co-relative analyses supported both familial liability and a possible causal pathway between AUD, resilience, and suicide attempt. In the cohort born 1949–1951, resilience subcomponents—social maturity, interests, psychological energy, home conditions, and emotional control—were all associated with reduced suicide attempt risk (HRs between 0.63 and 0.74). CONCLUSION: While resilience is associated with reduced risk of suicide attempt, this effect is less pronounced in the context of AUD. These associations are potentially causal.