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Background To determine, in a general population, how much rates of stress reactions (SR), major depression (MD), alcohol-use disorder (AUD) and drug-use disorder (DUD) increase after the death of close relatives. Methods SR, MD, AUD, and DUD registrations were assessed from national Swedish registries. From the population followed from 2000 to 2018, those exposed to death of a close relative in 2002–2016 were matched to unexposed controls and analyzed in males and females by a controlled pre-post design using a difference-in-difference method. Results Substantial, brief increases in risk for SR and more modest prolonged increases in MD were observed after death of relatives in both men and women greatest with children, followed by spouses, parents, and siblings. Relatively long-lasting modest increases in AUD but not DUD were also observed following death of relatives. The absolute increases for SR and MD were greater in females than males and for AUD greater in males than females. However, logistic regression analyses showed most effects did not differ significantly by sex. Consistently larger increases in disorder risk were seen with the death of younger v. older parents, siblings, and spouses and with accidental v. non-accidental death in children. Conclusions Applying a matched cohort design to Swedish population registries, death of close relatives was associated with, and likely caused, substantial increases in rates of SR, MD, and AUD, consistent with smaller prior clinical investigations. Through such registries, we can, in large representative samples, integrate the impact of exposures to selected environmental adversities into disorder risk pathways.

Background To clarify, in a national sample, associations between risk for seven psychiatric and substance use disorders and five key transitions in Sweden's public educational system. Methods Swedish-born individuals (1972–1995, N = 1 997 910) were followed through 12-31-2018, at mean age 34.9. We predicted, from these educational transitions, risk for major depression (MD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), schizophrenia (SZ), anorexia nervosa (AN), alcohol use disorder (AUD), and drug use disorder (DUD), assessed from Swedish national registers, by Cox regression, censoring individuals with onsets ⩽17. We also predicted risk from the deviation of grades from family-genetic expectations (deviation 1) and from changes in grades from ages 16 to 19 (deviation 2). Results We observed four major risk patterns across transitions in our disorders: (i) MD and BD, (ii) OCD and SZ, (iii) AUD and DUD, and (iv) AN. Failing early educational transitions had the greatest impact on risk for OCD and SZ while for other disorders, not progressing from basic to upper high school had the largest effect. Completing vocational v. college-prep upper high school was strongly associated with risk for AUD and DUD, had little relation with MD, OCD, BD, and SZ risk, and was protective for AN. Deviation 1 predicted risk most strongly for SZ, AN, and MD. Deviation 2 predicted risk most strongly for SZ, AUD, and DUD. Conclusions The pattern of educational transitions and within family and within person development deviations are strongly and relatively specifically associated with future risk for seven psychiatric and substance-use disorders.

ImportanceThe nature of the genetic relationship between major depression and bipolar disorder remains unclear and might be clarified by considering disorders outside of the mood spectrum.ObjectiveTo better understand the relationship between genetic liabilities for major depression (MD) and bipolar disorder (BD).Design, Setting, and ParticipantsA cohort study was conducted with data for individuals born in Sweden to Swedish parents from 1960 to 1990, with follow-up through December 31, 2018. The data included family genetic risk scores for MD and BD and International Classification of Diseases codes for a range of disorders as reported in primary care, specialist, and hospital registries. Data analysis was conducted from April 2022 to July 2022.ExposuresHigh and low genetic liability were defined as being in the upper and lower 2 risk deciles. Risk was compared in individuals at high genetic liability to (1) MD only, (2) BD only, and (3) both MD and BD and those at (4) high genetic liability to BD and low genetic liability to MD and (5) high genetic liability to MD and low genetic liability to BD.Main Outcomes and MeasuresRisk for nonpsychotic MD and BD, psychotic MD and BD, anxiety disorders, obsessive-compulsive disorder, schizoaffective disorder (SAD), schizophrenia, and other nonaffective psychosis.ResultsData were included for 2 736 950 individuals with a mean (SD) age at follow-up of 43.9 (9.1) years. High genetic liability to only BD increased risk for nonpsychotic BD, psychotic BD, and SAD. High genetic liability to only MD augmented risk for nonpsychotic MD, anxiety disorders, and nonpsychotic BD. High genetic liability to both BD and MD had the strongest association with risk for nonpsychotic BD, anxiety disorders, and nonpsychotic MD. High genetic liability to BD and low genetic liability to MD increased risk for psychotic BD, nonpsychotic BD, and SAD with no increased risk for nonpsychotic MD or anxiety disorders. High genetic liability to MD and low genetic liability to BD increased risk for nonpsychotic MD, nonpsychotic BD, and anxiety disorders with no increased risk for psychotic BD.Conclusions and RelevanceIn this study, hypotheses that BD and MD are either genetically distinct or genetically closely interrelated were not supported. Both BD and MD were associated with a genetic vulnerability to mood disorders, but even that liability was partially selective. However, compared with individuals at high liability to MD, those at elevated genetic liability for BD had a substantially increased risk for psychosis. Compared with individuals at elevated genetic liability to BD, those at high genetic risk for MD had a considerably augmented risk for anxiety disorders. Clarifying genetic relationships between psychiatric syndromes can be substantially aided by the consideration of profiles of risk for a range of disorders.

We aimed to explore the association between various physiological factors and pyelonephritis in parous women.Swedish nationwide registers were used to identify 1,073,467 parous women aged 15-50 years. The study period began in 1997 and ended in 2018, or at the first incidence of pyelonephritis, death, or emigration. Cox proportional hazards methods were used to determine hazard ratios (HRs) and 95% confidence intervals (CIs) of pyelonephritis in relation to body mass index (BMI) and body height adjusted for age, parity, and individual-level sociodemographic variables.A total of 21,625 women (2.0%) were diagnosed with pyelonephritis during follow-up. In the fully adjusted model, low BMI (18.5) was associated with pyelonephritis (HR 1.13, 95% CI 1.06-1.21). Parity and certain sociodemographic characteristics were also independently associated with pyelonephritis. Body height161 cm was associated with pyelonephritis (HR 1.12, 95% CI 1.09-1.16) in all but the fully adjusted model.Low BMI and body height seem to be associated with uncomplicated pyelonephritis. More research is needed to verify these findings and identify possible mechanisms.

Few, if any, prior studies have considered whether undetermined intent (UDI) deaths and suicide deaths differ with respect to genetic liability for suicidal behavior or psychopathology.The authors used Swedish national registry data to identify suicide deaths (N = 31,835) and UDI deaths (N = 10,623); sociodemographic covariates; and registrations for psychopathology. Family genetic risk scores (FGRS) were derived for each form of psychopathology. The authors used LASSO models to assess genetic and phenotypic differences across outcomes.In the multivariate LASSO regressions, higher FGRS for major depression, bipolar disorder, and suicide death were associated with lower odds of UDI relative to unambiguous suicide (OR = 0.91-0.95), while those for alcohol and drug use disorders, ADHD, and criminal behavior were associated with higher odds of UDI relative to unambiguous suicide (OR = 1.04-1.12). When the corresponding phenotypic registration status for these outcomes was included in a subsequent model, the associations were attenuated and of small magnitude, but many remained different from OR = 1.Aggregate genetic differences between unambiguous suicide decedents and UDI deaths are small, particularly when accounting for psychiatric comorbidity, but in some cases, statistically significant. These findings suggest that different analytic treatment of UDI deaths may be warranted depending on the research question. Replication in other samples, and using molecular genetic data, is necessary.

The purpose of this study was to clarify the clinical heterogeneity of alcohol use disorder (AUD) in a national Swedish sample of affected individuals using latent class analysis.Using a Swedish population-based sample of AUD cases ascertained from medical, criminal, and pharmacy registries (in/i= 217,071), we applied latent class analysis to sex, externalizing and internalizing syndromes before first registration, and age at first registration. The resulting types were evaluated against 15 diverse validators and degree of resemblance in relative pairs concordant for AUD.A three-class solution was preferred by fit indices. The three classes were as follows: type 1 (male preponderant, externalizing; 32%), type 2 (minimal prior psychopathology; 46%), and type 3 (mixed-sex internalizing; 23%). Repeated split-half analyses revealed the statistical stability of these solutions. Meaningful differences emerged between the classes on many validators. Type 1 had the greatest family disruption, lowest educational levels, most AUD registrations, highest rates of criminal registration, and highest genetic risk for externalizing disorders and AUD. Type 2 had the least social dysfunction. Type 3 had the highest educational attainment, genetic liability to internalizing disorders, and proportion of women. All types significantly aggregated in affected pairs of relatives.Meaningful and reproducible subtypes of AUD, consistent with prior typological results, can be obtained from national registry-based samples. Using a range of external validators and patterns of familial aggregation, our results suggest that our three-class solution captured a meaningful proportion of the clinical heterogeneity of AUD.

To clarify, using an extended adoption design, the sources of parent-offspring transmission for anxiety disorder (AD) and its major subforms and their familial cross-generational relationship with major depression (MD).Offspring (born 1960-1992) and their parents, from six family types (intact, not-lived-with biological father or mother, lived-with step-father or step-mother, and adoptive), were ascertained from Swedish national samples. Diagnoses were obtained from national medical registers. We assessed three sources of parent-child resemblance: genes plus rearing, genes only, and rearing only. To test comorbidity effects, single diagnoses were assigned in comorbid cases based on frequency and recency.For AD to AD parent-child transmission, best-estimate tetrachoric correlations for the three types of parent-offspring relationships genes plus rearing, genes only, and rearing only-equaled +0.16 (95% CI=0.16, 0.16), +0.12 (95% CI=0.10, 0.13), and +0.06 (95% CI=0.04, 0.07), respectively, with broadly similar results for MD to MD transmission. Cross-disorder cross-generation correlations were modestly lower, with genetic and rearing correlations for AD and MD estimated at +0.83 (95% CI=0.76, 0.90) and +0.83 (95% CI=0.69, 0.96), respectively. Analyses for panic disorder and generalized anxiety disorder (GAD) produced comparable findings, with the genetic correlation with MD modestly higher for generalized anxiety disorder than panic disorder. Applying a diagnostic hierarchy to comorbid cases resulted in a decline in cross-disorder cross-generation transmission with the estimated genetic correlation equaling +0.46 (95% CI=0.30, 0.62).For AD and its major subforms, cross-generational transmission includes both genetic and rearing effects. In traditional analyses, AD and MD demonstrate highly correlated genetic and rearing effects. The genetic correlation weakened when applying a diagnostic hierarchy.

Background Among individuals with alcohol use disorder (AUD) and drug use disorder (DUD), is their genetic liability and its specificity moderated by substance availability? Methods Offspring (born 1960–1995) and their biological parents from three family types [not-lived-with (NLW) biological father, mother and adoptive] and their AUD and DUD diagnoses were ascertained from Swedish national registers. Parent–offspring resemblance was calculated by tetrachoric correlation. Results In Swedes born from 1960 to 1995, prevalence rates of AUD were stable while DUD rates increased substantially. Best-estimate tetrachoric correlations (±95% confidence intervals) between AUD in biological parents and AUD and DUD in their offspring were, respectively, +0.19 (0.18–0.20) and +0.18 (0.17–0.20). Parallel results from DUD in parents to AUD and DUD in children were +0.12 (0.10–0.13) and +0.27 (0.26–0.28). When divided into older and younger cohorts, the specificity of DUD transmission increased substantially over time, while the genetic correlation between AUD and DUD significantly decreased. Conclusions Raised when alcohol was the preferred substance of abuse and illicit drugs highly stigmatized, AUD in parents reflected a general liability to substance use disorders, as they transmitted similar genetic risk for AUD and DUD to their children raised when both substances were widely available and relatively acceptable. DUD in parents, by contrast, reflected a more specific liability to DUD and, when transmitted to offspring, produced a considerably stronger risk for DUD than for AUD that increased over time. The magnitude and specificity of the genetic liability to psychoactive substances can be influenced by the availability of that substance.

Background: We aim to estimate population-attributable fractions (PAF) for 13 comorbidities potentially predisposing to hepatobiliary cancer of hepatocellular carcinoma (HCC), gallbladder cancer (GBC), cancers of the intrahepatic and extrahepatic bile ducts (ICC and ECC), and ampullary cancer. Methods: Patients were identified from the Swedish Inpatient Register from 1987 to 2018 and cancers from the Swedish Cancer Registry from 1997 through 2018. PAFs were calculated for each comorbidity-associated cancer using a cohort study design. Results: For male HCC, the major individual comorbidities (PAF > 10) were diabetes, alcohol-related liver disease, and hepatitis C virus infection. For female HCC, diabetes and autoimmune diseases were important contributors. For female GBC, gallstone disease was an overwhelming contributor, with a PAF of 30.57%, which was also important for men. The overall PAF for male ICC was almost two times higher than the female one. For ECC and ampullary cancer, infection of bile ducts was associated with the highest PAF. Conclusions: The 13 comorbidities accounted for 50% or more of the potential etiological pathways of each hepatobiliary cancer except female ICC. The underlying convergent mechanism for these cancers may be chronic inflammation lasting for decades and thus offering possibilities for intervention and disease monitoring.

Background The experiences of art and music are an essential part of human life and this study aimed to examine the longitudinal association between cultural participation and coronary heart disease. Methods This was a longitudinal study on a randomly selected representative adult cohort (n = 3296) of the Swedish population. The study period was over 36 years (1982–2017) with three separate eight-year interval measurements of cultural exposure (for example, visiting theatres and museums) starting in 1982/83. The outcome was coronary heart disease during the study period. Marginal structural Cox models with inverse probability weighting were used to account for time-varying weights of the exposure and potential confounders during the follow-up. The associations were also examined through a time-varying Cox proportional hazard regression model. Results Cultural participation shows a graded association, the higher the exposure the lower the risk of coronary heart disease; the hazard ratio was 0.66 (95% confidence interval, 0.50 to 0.86) for coronary heart disease in participants with the highest level of cultural exposure compared with the lowest level. Conclusion Although causality cannot be determined due to the remaining risk of residual confounding and bias, the use of marginal structural Cox models with inverse probability weighting strengthens the evidence for a potentially causal association with cardiovascular health, which warrants further studies.

Background Abdominal aortic aneurysm (AAA) is a vascular disease with a mortality rate of >80% if ruptured. Mitochondrial dysfunction has been previously implicated in AAA pathogenesis. In this study, we aimed to characterize the mitochondrial genetic landscape in AAA. Methods and Results Whole mitochondrial genome sequencing and bioinformatics analysis were performed in comorbidity matched 48 cases without AAA and 48 cases with AAA, objectively diagnosed, and selected from a cohort of 65‐year‐old men recruited for a screening program. We identified differential mutational landscapes in men with and without AAA, with errors in mitochondrial DNA replication or repair as potential sources. Heteroplasmic insertions and overall heteroplasmy of structural rearrangements were significantly elevated in AAA cases. Three heteroplasmic variants were associated with risk factors of AAA: leukocyte concentration, plasma glucose, and cholesterol levels, respectively. Interestingly, mutations were more prevalent in regulatory part of the mitochondria, the displacement loop region, in AAA as compared with controls ( P value Conclusions This is the first study investigating the mitochondrial genome in AAA, where important genetic alterations and haplogroups associated with AAA and clinical risk factors were identified. Our findings have the potential to fill in gaps in the missing genetic information on AAA.

To examine the risk of post-polio syndrome (PPS) in immigrant groups using native Swedish-born individuals as referents. This is a retrospective study. The study population included all individuals aged 18 years and older registered in Sweden. PPS was defined as having at least one registered diagnosis in the Swedish National Patient Register. The incidence of post-polio in different immigrant groups, using Swedish-born individuals as referents, was assessed by Cox regression, with hazard ratios (HRs) and 99% confidence intervals (CI). The models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, co-morbidities, and neighbourhood socioeconomic status. In total 5300 post-polio cases were registered, 2413 males and 2887 females. Fully adjusted HRs (99% CI) in immigrants versus Swedish-born were 1.77 in men (1.52–2.07) and 1.39 (1.19–1.62) in women. Statistically significant excess risks of post-polio were found in the following subgroups: men and women from Africa, HRs (with 99% CI) 7.40 (5.17–10.59) and 8.39 (5.44–12.95), respectively, and Asia, HRs 6.32 (5.11–7.81) and 4.36 (3.38–5.62) respectively, and in men from Latin America, HR 3.66 (2.17–6.18). It is of importance to be aware of risks of PPS in immigrants settled in Western countries, and that it is more common in immigrants from regions of the world where polio is still prevalent. Patients with PPS need treatment and proper follow-up until polio has been eradicated through global vaccination programs.

Background: Complete atrioventricular block (CAVB) is a major reason for implantation of permanent pacemakers, but knowledge of CAVB inheritance is sparse. This nationwide study aimed to determine the occurrence of CAVB in first-, second-, and third-degree relatives (full siblings, half-siblings, and cousins). Methods: The Swedish multigeneration register was linked to the Swedish nationwide patient register for the period 1997 to 2012. All Swedish full sibling, half-sibling, and cousin pairs born to Swedish parents between 1932 and 2012 were included. Competing risks and time-to-event, subdistributional hazard ratios (SHRs) according to Fine and Gray and hazard ratios using Cox proportional hazards model were estimated using robust SEs and considering the relatedness of relatives (full siblings, half-siblings, cousins). Additionally, odds ratios (ORs) for CAVB were calculated for traditional cardiovascular comorbidities. Results: The study population (N=6 113 761) consisted of 5 382 928 full siblings, 1 266 391 half-siblings, and 3 750 913 cousins. In total, 6442 (0.11%) unique individuals were diagnosed with CAVB. Of these, 4200 (65.2%) were males. SHRs for CAVB were 2.91 for full siblings (95% CI, 2.43–3.49), 1.51 for half-siblings (0.56–4.10), and 3.54 for cousins (1.73–7.26) of affected individuals. Age-stratified analysis showed higher risk in young individuals born from 1947 to 1986: SHR, 5.30 (3.78–7.43) for full siblings, SHR, 3.30 (1.06–10.31) for half-siblings, and SHR, 3.15 (1.39–7.17) for cousins. Similar familial HRs according to Cox proportional hazard model and ORs were obtained without any major differences. Apart from familial relationship, CAVB was associated with hypertension (OR, 1.83), diabetes (OR, 1.41), coronary heart disease (OR, 2.08), heart failure (OR, 5.01), and structural heart disease (OR, 4.59). Conclusions: Risk of CAVB among relatives of affected individuals depends on relationship degree, being strongest in young siblings. The familial association extending to third-degree relatives indicates presence of genetic components in the cause of CAVB.

Substance use disorder (SUD) is related to widespread adverse consequences, including higher suicidality. Shared genetic liability has been demonstrated between SUD and suicidality. Here, we measured the factors that contribute to increased risk of non-fatal suicide attempt among individuals with SUD by focusing upon aggregate genetic risks and both childhood and past-year environmental factors.Longitudinal study. Family genetic risk scores and environmental factors (childhood, aged from 0 to 15 years, and the year preceding SUD registration) were used to predict the relative risk of non-fatal suicide attempt using Cox proportional hazards models. Additional analyses employed a co-relative design, accounting for genetic factors and shared familial environment, to test for potential causality.Based on longitudinal Swedish registry data, 228 617 individuals with SUD registrations from 1991 to 2015 were included.SUD and suicide attempts were identified using medical records (International Classification of Diseases codes). SUD was also identified using pharmacy and criminal registries.In multivariable analyses that jointly accounted for all the selected potential predictors, individuals with SUD were at higher risk for non-fatal suicide attempt if they had experienced a parental death [hazard ratio (HR) = 1.58; 95% confidence interval (CI) = 1.30, 1.93], were female (HR = 1.53, 95% CI = 1.49, 1.57), had low educational attainment (HR = 1.50, 95% CI = 1.46, 1.55), received social welfare (HR = 1.21, 95% CI = 1.17, 1.25) or had lived in a non-intact family (HR = 1.11, 95% CI = 1.08, 1.14). In co-relative analyses, low education was supported as a possible causal factor for suicide attempt. Aggregate genetic risks interacted with low education and being raised in a non-intact family, with increased prevalence of suicide attempt in people with high genetic risks and unfavorable environmental exposures.Aggregate genetic liability, childhood environmental experiences and specific socio-economic indicators are important risk factors for non-fatal suicide attempt among individuals with substance use disorder.

Background Despite a large descriptive literature linking creativity and risk for psychiatric illness, the magnitude and specificity of this relationship remain controversial. Methods We examined, in 1 137 354 native Swedes with one of 59 3-digit official and objective occupational codes in managerial and educated classes, their familial genetic risk score (FGRS) for ten major disorders, calculated from 1st through 5th degree relatives. Mean FGRS across disorders were calculated, in 3- and 4-digit occupational groups, and then controlled for those whose disorder onset preceded occupational choice. Using sequential analyses, p values were evaluated using Bonferroni correction. Results 3-digit professions considered to reflect creativity (e.g. ‘artists’ and ‘authors’) were among those with statistically significant elevations of FGRS. Among more specific 4-digit codes, visual artists, actors, and authors stood out with elevated genetic risks, highest for major depression (MD), anxiety disorders (AD) and OCD, more modest for bipolar disorders (BD) and schizophrenia and, for authors, for drug and alcohol use disorders. However, equal or greater elevations in FGRS across disorders were seen for religious (e.g. ministers), helping (e.g. psychologists, social workers), and teaching/academic occupations (e.g. professors). The potential pathway from FGRS → Disorder → Occupation accounts for a modest proportion of the signal, largely for MD and AD risk. Conclusions While traditional creative occupations were associated with elevated genetic risk for a range of psychiatric disorders, this association was not unique, as similar, or greater elevations were seen for religious, helping and teaching professions and was stronger for internalizing than psychotic disorders.

To study incident narcolepsy in first- and second-generation immigrant groups using Swedish-born individuals and native Swedes as referents.The study population included all individuals registered and alive in Sweden at baseline. Narcolepsy was defined as having at least one registered diagnosis of narcolepsy in the Swedish National Patient Register. The incidence of narcolepsy in different immigrant groups was assessed by Cox regression, with 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, co-morbidities, and neighbourhood socioeconomic status.In the first-generation study, 1225 narcolepsy cases were found; 465 males and 760 females, and in the second-generation study, 1710 cases, 702 males and 1008 females. Fully adjusted HRs (95% CI) in the first-generation study was for males 0.83 (0.61-1.13) and females 0.83 (0.64-1.07), and in the second-generation study for males 0.76 (0.60-0.95) and females 0.91 (95% CI 0.76-1.09). Statistically significant excess risks of narcolepsy were found in first-generation males from North America, and second-generation males with parents from North America, and second-generation females with parents from Latin America.There were only significant differences in incident narcolepsy between native Swedes and second-generation male immigrants. The observed differences can partly be explained by differences in Pandemrix® vaccinations and are probably not attributable to genetic differences between immigrants and natives.

OBJECTIVE: Given the public health importance of opioid use disorder (OUD), we sought to understand better its risk predictors in the Swedish general population. METHOD: We examined the Swedish population, born 1950–1970 (n = 2,092,359), and followed through 2018. Using Cox, logistic, and co-sibling models, we explored associations between a wide range of putative risk factors and a first onset of OUD—assessed through medical, criminal, and pharmacy registers—in the entire cohort and in the cohort wherein prior cases of drug use disorder (DUD) were censored. RESULTS: OUD was predicted by the following four risk factor domains: (a) externalizing syndromes, especially prior non-opioid DUD; (b) psychopathology; (c) psychosocial factors, including social class and immigrant and marital status; and (d) serious injuries and pain diagnoses. When predicting OUD as the first form of DUD, the importance of pain diagnoses as a predictor increased. Co-sibling analyses suggested that the association of some of these risk factors with OUD onset was likely largely causal, whereas others were a mixture of causal effects and familial confounding. An aggregate risk score from these individual risk factors had reasonable receiver operating characteristic (ROC) curve performance. CONCLUSIONS: OUD is a multifactorial syndrome for which risk can be meaningfully predicted by prior externalizing syndromes, internalizing and psychotic psychopathology, indicators of psychosocial status, and predictors of pain diagnoses. Some important differences were seen in the prediction of any OUD onset versus OUD onset as the first form of DUD. Much of the effect of these predictors appear, in co-sibling analyses, to likely reflect causal influences.

Summary: Background: Peripheral arterial disease (PAD) is a common atherosclerotic disease with severity ranging from asymptomatic to chronic limb threatening ischemia. The aim of the present cross-sectional study was to identify novel biomarkers associated with PAD. Patients and methods: Levels of 91 cardiovascular specific proteins in plasma samples were measured by the Proseek Multiplex CVD III96x96 panel from a cohort consisting of 267 65-year-old men recruited from a screening program for abdominal aortic aneurysm (AAA) Levels of protein biomarkers were compared in men with and without PAD (defined as an ankle brachial index of

Background: The influence of familial factors on the prognosis of ischemic stroke (IS) is unknown. This nationwide follow-up study evaluated familial mortality risks of IS among Swedish sibling pairs hospitalized for IS. Methods: We linked Swedish nationwide registers for the identification of 1380 Swedish born sibling pairs (2760 cases), where both siblings were hospitalized for first-time IS between 1991 and 2010. Median age was 62 years (range, 26–78 years). Sibling pairs with cancer were excluded. Familial hazard ratios (FHRs) for mortality after first IS hospitalization were determined with Cox regression. The influence of proband survival after IS was categorized as short sibling survival ( Results: Short sibling survival (ie, Conclusions: Our results suggest that family history of short survival in siblings after IS is associated with mortality after IS for younger male subjects. Additional studies are needed to characterize possible genetic and nongenetic familial environmental causes of this association.

Incidence rates for brain tumor subtypes by age and sex (1973-2010).

Perinatal factors, including high birth weight, have been associated with childhood brain tumors in case–control studies. However, the specific contributions of gestational age and fetal growth remain unknown, and these issues have never been examined in large cohort studies with follow-up into adulthood. We conducted a national cohort study of 3,571,574 persons born in Sweden in 1973–2008, followed up for brain tumor incidence through 2010 (maximum age 38 years) to examine perinatal and familial risk factors. There were 2,809 brain tumors in 69.7 million person-years of follow-up. After adjusting for potential confounders, significant risk factors for brain tumors included high fetal growth [incidence rate ratio (IRR) per additional 1 SD, 1.04; 95% confidence interval (CI), 1.01–1.08, P = 0.02], first-degree family history of a brain tumor (IRR, 2.43; 95% CI, 1.86–3.18, P < 0.001), parental country of birth (IRR for both parents born in Sweden vs. other countries, 1.21; 95% CI, 1.09–1.35, P < 0.001), and high maternal education level (Ptrend = 0.01). These risk factors did not vary by age at diagnosis. The association with high fetal growth appeared to involve pilocytic astrocytomas, but not other astrocytomas, medulloblastomas, or ependymomas. Gestational age at birth, birth order, multiple birth, and parental age were not associated with brain tumors. In this large cohort study, high fetal growth was associated with an increased risk of brain tumors (particularly pilocytic astrocytomas) independently of gestational age, not only in childhood but also into young adulthood, suggesting that growth factor pathways may play an important long-term role in the etiology of certain brain tumor subtypes. Cancer Res; 75(3); 576–83. ©2014 AACR.

Adjusted incidence rate ratios for associations between perinatal or familial characteristics and primitive neuroectodermal tumors in 1973-2010.

Background Drug Use Disorder (DUD) is a major contributor to world-wide morbidity and mortality. The extensive national registers in Sweden provide the basis for a study of spatial and temporal patterns of DUD onset and recurrence in Sweden from 2001–2015. Methods To identify patterns of DUD over space, time and gender for Swedish individuals aged 15–35, space–time clustering using SaTScan was applied. We used yearly information on residential locations in Demographic Statistical Areas (DeSO) for all of Sweden. The clustering analysis used a Poisson probability model and a null hypothesis that the expected number of cases in each DeSO was proportional to the population size of DeSOs. As SaTScan results can be unstable, steps were taken to determine stable clusters and to refine and optimize cluster size. Results for each gender-register combination were compared to the results of spatial clustering using Gi* statistics. The space–time scanning model was also run with an adjustment for neighborhood socioeconomic status to determine DUD prevalence as it relates to education, income, unemployment and receipt of social welfare. Results DUD prevalence increased over time. Males yielded more significant clusters than females for both criminal and medical registers. Female DUD prevalence rates increased over time, especially after 2012. Higher correlations in DUD rates existed across the two registers than across gender. Male clusters were present from 2004 onwards while female–criminal clusters appeared after 2007, and female–medical clusters not until 2010. By 2013, clusters existed for all gender–register combinations. Male–criminal clusters were concentrated in Stockholm, Göteborg and Malmö as were male and female-medical clusters. Neighborhood SES was more highly related to the distribution of criminal than medical DUD clusters. A persistent gap in core clusters was identified in Stockholm in an area with notably high SES. Conclusions Persistent hotspots of DUD in Sweden were confirmed as well as new and emerging hotspots, especially in Stockholm, Göteborg and Malmö. Higher correlations existed in DUD rates across registers than across gender. The findings are useful for monitoring the current drug problem and for identifying drivers underlying patterns of spread and important causal pathways to DUD.

Background The ability of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to decrease certain microvascular events has called for the investigation of GLP-1 RAs against diabetic retinopathy (DR), but the evidence is limited. By combining data from observational and Mendelian randomization (MR) studies, we aimed to investigate whether GLP-1 RAs decrease the risk of DR. Methods We combined data from several Swedish Registers and identified patients with incident type 2 diabetes being treated with GLP-1 RAs between 2006 and 2015, and matched them to diabetic patients who did not use GLP-1 RAs as the comparisons. The Cox proportional hazards models were applied to assess the risk of DR. We further performed the summary-data-based MR (SMR) analyses based on the Genotype-Tissue Expression databases and the Genome-Wide Association Study of DR from the FinnGen consortium. Results A total of 2390 diabetic patients were treated with GLP-1 RAs and the incidence of DR was 5.97 per 1000 person-years. Compared with diabetic patients who did not use GLP-1 RAs having an incidence of 12.85 per 1000 person-years, the adjusted hazard ratio (HR) of DR was 0.42 [95% confidence interval (CI), 0.29–0.61]. Genetically-predicted GLP1R expression (the target of GLP-1 RAs) showed an inverse association with background [odds ratio (OR)=0.83, 95% CI, 0.71–0.97] and severe nonproliferative DR (OR=0.72, 95% CI, 0.53–0.98), and a non-significant association with overall (OR=0.97, 95% CI, 0.92–1.03) and proliferative DR (OR=0.98, 95% CI, 0.91–1.05). Conclusions Both observational and mendelian randomization analyses showed a significantly lower risk of DR for patients treated with GLP-1 RAs, which calls for further studies to validate these findings.

Background Functional somatic disorders (FSD) feature medical symptoms of unclear etiology. Attempts to clarify their origin have been hampered by a lack of rigorous research designs. We sought to clarify the etiology of the FSD by examining the genetic risk patterns for FSD and other related disorders. Methods This study was performed in 5 829 186 individuals from Swedish national registers. We quantified familial genetic risk for FSD, internalizing disorders, and somatic disorders in cases of chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS), using a novel method based on aggregate risk in first to fifth degree relatives, adjusting for cohabitation. We compared these profiles with those of a prototypic internalizing psychiatric – major depression (MD) – and a somatic/autoimmune disorder: rheumatoid arthritis (RA). Results Patients with FM carry substantial genetic risks not only for FM, but also for pain syndromes and internalizing, autoimmune and sleep disorders. The genetic risk profiles for IBS and CFS are also widely distributed although with lower average risks. By contrast, genetic risk profiles of MD and RA are much more restricted to related conditions. Conclusion Patients with FM have a relatively unique family genetic risk score profile with elevated genetic risk across a range of disorders that differs markedly from the profiles of a classic autoimmune disorder (RA) and internalizing disorder (MD). A similar less marked pattern of genetic risks was seen for IBS and CFS. FSD arise from a distinctive pattern of genetic liability for a diversity of psychiatric, autoimmune, pain, sleep, and functional somatic disorders.

Purpose To analyse risk of vision impairment (VI) and blindness in adult foreign-born individuals and Swedish-born individuals. Methods A nationwide study of individuals 18 years of age and older (N = 6,042,891; 2,902,918 men and 3,139,973 women) in Sweden. VI (in general) and blindness was defined as at least one registered diagnosis in the 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 VI in foreign-born compared to Swedish-born individuals. The Cox regression models were stratified by sex and adjusted for age, co-morbidities, and for sociodemographic status. Results A total of 14,597 cases (6433 men and 8164 women) of VI were registered, with an age-standardized incidence per 100,000 person-years of 10.37 in men and 11.03 in women. VI (in general) was more common in immigrants, fully adjusted HRs (95% CI) were for immigrant men 1.38 (95% CI, 1.29–1.48) and women 1.24 (95% CI, 1.16–1.32), with significantly higher HRs among men and women from Eastern Europe, Africa, Latin America and Asia. Higher risks of blindness were also seen for immigrant men, HR 1.75 (95% CI 1.36–2.25), as well as for the other degrees of VI among immigrant men, HR 1.36 (95% CI 1.26–1.47), and immigrant women, HR 1.26 (95% CI 1.18–1.35). Conclusions We observed a generally higher risk of VI among foreign-born men and women, especially from some regions.

Objective: This study aimed to estimate the association between potential risk factors and common vaginal infections using nationwide primary health care and other national registers. Methods: An open cohort study consisting of 2,357,711 women aged 15 years to 50 years (2001 to 2018) was conducted in Sweden. The outcomes were first event of vulvovaginal candidiasis (VVC) and bacterial vaginosis (BV) in relation to sociodemographic factors. Cox regression models were used. Sensitivity analyses including diabetes mellitus, contraceptive use, and cervical cancer were conducted. Results: The incidence rates per 1,000 person-years for VVC and BV were 3.3 (95% confidence interval [CI] 3.2-3.3) and 3.4 (95% CI 3.4-3.4), respectively. In the fully adjusted model, sociodemographic factors were significantly associated with both outcomes. Compared with Swedish-born women, women from Middle East/North Africa had the highest risk of VVC (hazard ratio [HR] 2.77, 95% CI, 2.72-2.83), followed by Africa (excluding North Africa) (HR 2.53, 95% CI, 2.45-2.61), and Latin America and the Caribbean (HR 2.18, 95% CI, 2.09-2.27). For BV, women from Latin America and the Caribbean had the highest risk (HR 1.83, 95% CI, 1.75-1.92). Conclusion: This study presents novel risk factors associated with medically attended vaginal infections. Women from non-Western countries seem to develop these conditions disproportionately.

Mitochondrial DNA copy number (mtDNA-CN) is a surrogate biomarker of mitochondrial dysfunction and is associated with type 2 diabetes (T2D) and cardiovascular disease (CVD). However, despite being associated with both CVD and T2D, it is not known what role mtDNA-CN has in the association between T2D and CVD. Our aims were to investigate whether, (1) baseline mtDNA-CN is associated with CVD incidence and (2) mtDNA-CN has a role as a mediator between T2D and CVD.We quantified absolute mtDNA-CN by droplet digital PCR method in a population-based follow-up study of middle aged (52-65 years) women (n = 3062). The median follow-up period was 17 years.Our results show that low baseline levels of mtDNA-CN (111 copies/μL) were associated with an increased risk of CVD (HR = 1.32, 95% CI = 1.08; 1.63) as well as with specific CVDs: coronary heart disease (HR = 1.28, 95% CI = 0.99; 1.66), stroke (HR = 1.26, 95% CI = 0.87; 1.84) and abdominal aortic aneurysm (HR = 2.61, 95% CI = 1.03; 6.62). The associations decreased but persisted even after adjustment for potential confounders. Furthermore, our results show that the total effect of T2D on future risk of CVD was reduced after controlling for mtDNA-CN and the proportion mediated by mtDNA-CN was estimated to be 4.9%.Lower baseline mtDNA-CN is associated with incident CVD and may have a mediating effect on the association between T2D and CVD; however, this novel observation needs to be confirmed in future studies.

Background Does the genetic aptitude for educational attainment (GAEA) moderate the genetic risk for alcohol use disorder (AUD) and drug use disorder (DUD)? Methods In the native Swedish population, born 1960–1980 and followed through 2017 (n = 1 862 435), the family genetic risk score (FGRS) for AUD and DUD and GAEA were calculated from, respectively, the educational attainment and risk for AUD and DUD, of 1st through 5th degree relatives from Swedish national registers. Analyses utilized Aalen's linear hazards models. Results Risk for AUD was robustly predicted by the main effects of FGRSAUD [b = 6.32 (95% CI 6.21–6.43), z = 64.9, p < 0.001) and GAEA [b = −2.90 (2.83–2.97), z = 44.1, p < 0.001] and their interaction [b = −1.93 (1.83–2.03), z = 32.9, p < 0.001]. Results were similar for the prediction of DUD by the main effects of FGRSDUD [b = 4.65 (CI 4.56–4.74), z = 59.4, p < 0.001] and GAEA [−2.08 (2.03–2.13), z = 46.4, p < 0.001] and their interaction [b = −1.58 (1.50–1.66)), z = 30.2, p < 0.001]. The magnitude of the interactions between GAEA and FGRSAUD and FGRSDUD in the prediction of, respectively, AUD and DUD was attenuated only slightly by the addition of educational attainment to the model. Conclusions and relevance The genetic propensity to high educational attainment robustly moderates the genetic risk for both AUD and DUD such that the impact of the genetic liability to AUD and DUD on the risk of illness is substantially attenuated in those with high v. low GAEA. This effect is not appreciably mediated by the actual level of educational attainment. These naturalistic findings could form the basis of prevention efforts in high-risk youth.

Background– Comorbidity between psychiatric disorders is extensive but, from a genetic perspective, still poorly understood. Modern molecular genetic approaches to this problem are limited by a reliance on case–control designs.Methods– In 5 828 760 individuals born in Sweden from 1932–1995 with a mean (s.d.) age at follow-up of 54.4 (18.1), we examined family genetic risk score (FGRS) profiles including internalizing, psychotic, substance use and developmental disorders in 10 pairs of psychiatric and substance use disorders diagnosed from population registries. We examined these profiles in three groups of patients: disorder A only, disorder B only and comorbid cases with both disorders.Results– The most common pattern of findings, seen in five pairings, was simple and quantitative. Comorbid cases had higher FGRS than both non-comorbid cases for all (or nearly all) disorders. However, the pattern was more complex in the remaining five pairings and included qualitative changes where the comorbid cases showed no increases in FGRS for certain disorders and in a few cases significant decreases. Several comparisons showed an asymmetric pattern of findings with increases, in comorbidity compared to single disorder cases, of the FGRS for only one of the two disorders.Conclusions– The examination of FGRS profiles in general population samples where all disorders are assessed in all subjects provides a fruitful line of inquiry to understand the origins of psychiatric comorbidity. Further work will be needed, with an expansion of analytic approaches, to gain deeper insights into the complex mechanisms likely involved.

BackgroundPrevious studies have demonstrated substantial associations between substance use disorders (SUD) and suicidal behavior. The current study empirically assesses the extent to which shared genetic and/or environmental factors contribute to associations between alcohol use disorders (AUD) or drug use disorders (DUD) and suicidal behavior, including attempts and death.MethodsThe authors used Swedish national registry data, including medical, pharmacy, criminal, and death registrations, for a large cohort of twins, full siblings, and half siblings (N = 1 314 990) born 1960–1980 and followed through 2017. They conducted twin-sibling modeling of suicide attempt (SA) or suicide death (SD) with AUD and DUD to estimate genetic and environmental correlations between outcomes. Analyses were stratified by sex.ResultsGenetic correlations between SA and SUD ranged from rA = 0.60–0.88; corresponding shared environmental correlations were rC = 0.42–0.89 but accounted for little overall variance; and unique environmental correlations were rE = 0.42–0.57. When replacing attempt with SD, genetic and shared environmental correlations with AUD and DUD were comparable (rA = 0.48–0.72, rC = 0.92–1.00), but were attenuated for unique environmental factors (rE = −0.01 to 0.31).ConclusionsThese findings indicate that shared genetic and unique environmental factors contribute to comorbidity of suicidal behavior and SUD, in conjunction with previously reported causal associations. Thus, each outcome should be considered an indicator of risk for the others. Opportunities for joint prevention and intervention, while limited by the polygenic nature of these outcomes, may be feasible considering moderate environmental correlations between SA and SUD.

Purpose Prostate cancer is the second most common cancer in men and a leading cause of cancer mortality worldwide. Men with drug use disorders (DUD) may potentially be at high risk for prostate cancer mortality because of delayed diagnosis and/or undertreatment. In this study, we aimed to investigate prostate cancer incidence, mortality, and stage at time of diagnosis among men with DUD compared to the general male population in Sweden. Methods We performed a follow-up study based on Swedish national register data for the period January 1997–December 2016. The study was based on 1,361,532 men aged 50–75 years at inclusion, of whom 9,259 were registered with DUD. Cox regression analysis was used to compute adjusted hazard ratios (HRs) for incident and fatal prostate cancer, and cancer stage at time of diagnosis, associated with DUD. Results DUD was associated with a slightly increased risk of incident prostate cancer (HR: 1.07, 95% confidence interval [CI] 1.00–1.14, p = 0.048) and substantially higher risk of fatal prostate cancer (HR: 1.59, 95% CI 1.40–1.82, p Conclusions Men with DUD have an increased risk of fatal prostate cancer, possibly related to undertreatment in this patient population. Our findings should raise attention among medical staff and decision-makers towards a disadvantaged group of men in need of easily accessible prostate cancer evaluation and treatment.

Background: The aim of this study was to explore the risk of invasive colorectal cancer (CRC) in relatives of patients with colorectal carcinoma in situ (CCIS), which is lacking in the literature. Patients and Methods: We collected data from Swedish family-cancer datasets and calculated standardized incidence ratio (SIR) and cumulative risk of CRC in family histories of CCIS in first- and second-degree relatives. Family history was defined as a dynamic (time-dependent) variable allowing for changes during the follow-up period from 1958 to 2015. Of 12,829,251 individuals with available genealogical data, 173,796 were diagnosed with CRC and 40,558 with CCIS. Results: The lifetime (0–79 years) cumulative risk of CRC in first-degree relatives of patients with CCIS was 6.5%, which represents a 1.6-fold (95% CI, 1.5–1.7; n=752) increased risk. A similarly increased lifetime cumulative risk (6.7%) was found among first-degree relatives of patients with CRC (SIR, 1.6; 95% CI, 1.6–1.7; n=6,965). An increased risk of CRC was also found in half-siblings of patients with CCIS (SIR, 1.9; 95% CI, 1.1–3.0; n=18) and also in half-siblings of patients with CRC (SIR, 1.7; 95% CI, 1.3–2.1; n=78). Moreover, the increased risk of CRC was higher for younger age at diagnosis of CCIS in the affected first-degree relative and for younger age at diagnosis of CRC in the index person. Conclusions: Results of this study show that first-degree relatives and half-siblings of patients with CCIS have an increased risk of CRC, which is comparable in magnitude to the risk of those with a family history of invasive CRC. These findings extend available evidence on familial risk of CRC and may help to refine guidelines and recommendations for CRC screening.

BackgroundAlcohol use disorder (AUD) is clinically heterogeneous. We examine its potential genetic heterogeneity as a function of sex, age, clinical features and mode of ascertainment.MethodsIn the Swedish population born 1932–1995 (n = 5 829 952), we examined the genetic risk profiles for AUD, major depression (MD), anxiety disorders, bipolar disorder, drug use disorder (DUD), attention deficit-hyperactivity disorder (ADHD) and criminal behavior (CB) in 361 124 cases of AUD subdivided by sex, age at onset (AAO), recurrence, mode of ascertainment and medical complications. Family genetic risk scores (FGRS), calculated from 1st to 5th-degree relatives controlling of cohabitation, assesses genetic risk from phenotypes in the family, not from DNA variants.ResultsFGRS profiles differed modestly across sex with all scores higher in females. Differences were more pronounced for AAO and recurrence with the FGRS for AUD, DUD, ADHD and CB substantially higher in cases with early AAO or high recurrence rates. Genetic profiles differed considerably by mode of ascertainment, with higher FGRS for AUD and most other disorders in patients seen in hospital v. primary care settings. Cases of AUD with medical complications had higher FGRS for AUD. AUD cases comorbid with MD and DUD had higher FGRS risk for AUD, but this genetic may be less specific given increases in FGRS for multiple other disorders.ConclusionsFrom a genetic perspective, AUD differs substantially as a function of AAO, recurrence, mode of ascertainment and patterns of comorbidity, suggesting caution in cross-sample comparisons of AUD cohorts that differ in these features.

Objective: To study the relationship between sociodemographic factors and pyelonephritis. Methods: A nationwide open cohort study consisting of 2,052,873 women (76.2% Swedish-born) aged 15-50 years was conducted (1997-2018). The outcome was the first event of acute uncomplicated pyelonephritis diagnosed in primary healthcare settings in relation to the sociodemographic factors. Cox regression models were used in the analyses. Results: The study identified 40,724 cases. In the fully adjusted model, women from non-Western countries had a higher risk of pyelonephritis compared to Swedish-born women. Women from Latin America/the Caribbean had the highest risk (Hazard ratio = 1.60; 95% CI 1.49-1.72), followed by Eastern Europe (HR = 1.26; 95% CI 1.21-1.32) and the Middle East/North Africa (HR = 1.25; 95% CI 1.19-1.30). Low education, low income, urban living, and young age were also associated with higher risks of pyelonephritis. Conclusion: This study presents novel risk factors associated with pyelonephritis. Women from non-Western countries and with low socioeconomic status might disproportionately suffer from this serious infection. This might be due to biological predispositions and the fact that immigrant women do not acquire the same level of health or might receive less healthcare compared to native women, even in the presence of universal healthcare. (Less)