Search

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.

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.

BackgroundHow does genetic liability to suicide attempt (SA), suicide death (SD), major depression (MD), bipolar disorder (BD), schizophrenia (SZ), alcohol use disorder (AUD), and drug use disorder (DUD) impact on risk for SA and SD?MethodsIn the Swedish general population born 1932–1995 and followed through 2017 (n = 7 661 519), we calculate family genetic risk scores (FGRS) for SA, SD, MD, BD, SZ, AUD, and DUD. Registration for SA and SD was assessed from Swedish national registers.ResultsIn univariate and multivariate models predicting SA, FGRS were highest for SA, AUD, DUD, and MD. In univariate models predicting SD, the strongest FGRS were AUD, DUD, SA, and SD. In multivariate models, the FGRS for SA and AUD were higher in predicting SA while the FGRS for SD, BD, and SZ were higher in predicting SD. Higher FGRS for all disorders significantly predicted both younger age at first SA and frequency of attempts. For SD, higher FGRS for MD, AUD, and SD predicted later age at SD. Mediation of FGRS effects on SA and SD was more pronounced for SD than SA, strongest for AUD, DUD, and SZ FGRS and weakest for MD.ConclusionsFGRS for both SA and SD and for our five psychiatric disorders impact on risk for SA and SD in a complex manner. While some of the impact of genetic risk factors for psychiatric disorders on risk for SA and SD is mediated through developing the disorders, these risks also predispose directly to suicidal behaviors.

Background and Purpose: Clinicians will increasingly encounter adult patients who were born preterm and will need to understand their long-term sequelae. Adult survivors of preterm birth have been reported to have increased risks of hypertension and other stroke risk factors. However, their stroke risks have seldom been examined and the findings are discrepant, possibly due to small sample sizes, insufficient follow-up, or survivor bias. We examined whether preterm birth is associated with stroke in a large population-based cohort. Methods: A national cohort study was conducted of all 2 140 866 singletons born in Sweden from 1973 to 1994 who survived to age 18 years, who were followed up for first-time stroke through 2015 (maximum age 43 years). Cox regression was used to examine stroke risks associated with gestational age at birth, adjusting for other perinatal and parental factors. Cosibling analyses assessed for potential confounding by shared familial (genetic or environmental) factors. Results: In 28.0 million person-years of follow-up, 4861 (0.2%) people were diagnosed with stroke. At ages 18 to 43 years, the adjusted hazard ratio for stroke associated with preterm birth (P P =0.005) for early preterm (22–33 weeks) and 1.22 (1.06–1.40; P =0.004) for late preterm (34–36 weeks), compared with full-term (39–41 weeks). Positive associations were found with both hemorrhagic stroke (early preterm: adjusted hazard ratio, 1.42 [95% CI, 1.04–1.94]; any preterm: 1.15 [0.97–1.35]) and ischemic stroke (early preterm: adjusted hazard ratio, 1.33 [95% CI, 0.87–2.03]; any preterm: 1.31 [1.07–1.60]). These findings were similar in men and women and only partially explained by shared determinants of preterm birth and stroke within families. Conclusions: In this large national cohort, preterm birth was associated with increased risks of both hemorrhagic and ischemic stroke in adulthood. Preterm birth survivors need early preventive evaluation and long-term clinical follow-up to reduce their lifetime risk of stroke.

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.

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.

To clarify the structure of genetic risks for 11 major psychiatric disorders, we calculated, from morbidity risks for disorders in 1st–5th degree relatives controlling for cohabitation effects, in the Swedish population born between 1932 and 1995 (n = 5,830,014), the family genetic risk scores (FGRS) for major depression (MD), anxiety disorders (AD), obsessive-compulsive disorder (OCD), bipolar disorder (BD), schizophrenia (SZ), bulimia (BUL), anorexia nervosa (AN), alcohol use disorder (AUD), drug use disorder (DUD), ADHD, and autism-spectrum disorder (ASD). For all affected individuals, we calculated their mean standardized FGRS for each disorder. The patterns of FGRS were quite similar for MD and AD, and for AUD and DUD, but substantially less similar for BUL and AN, BD and SZ, and ADHD and ASD. While OCD had high levels of FGRS for MD and AD, the overall FGRS profile differed considerably from MD and AD. ADHD FGRS scores were substantially elevated in AUD and DUD. FGRS scores for BD, OCD, AN, ASD, ADHD, and especially SZ were relatively disorder-specific while genetic risk for MD and AD had more generalized effects. The levels of FGRS for BMI, coronary artery disease, and educational attainment across our disorders replicated prior associations found using molecular genetic methods. All diagnostic categories examined had elevated FGRS for many disorders producing, for each condition, an informative FGRS profile. Using a novel method which approximates, from pedigree data, aggregate genetic risk, we have replicated and extended prior insights into the structure of genetic risk factors for key psychiatric illnesses.

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.

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.

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.

Background Population-based levels of the chronic low-grade systemic inflammation biomarker, C-reactive protein (CRP), vary widely among traditional populations, despite their apparent absence of chronic conditions associated with chronic low-grade systemic inflammation, such as type 2 diabetes, metabolic syndrome and cardiovascular disease. We have previously reported an apparent absence of aforementioned conditions amongst the traditional Melanesian horticulturalists of Kitava, Trobriand Islands, Papua New Guinea. Our objective in this study was to clarify associations between chronic low-grade systemic inflammation and chronic cardiometabolic conditions by measuring CRP in a Kitava population sample. For comparison purposes, CRP was also measured in Swedish controls matched for age and gender. Methods Fasting levels of serum CRP were measured cross-sectionally in ≥ 40-year-old Kitavans (N = 79) and Swedish controls (N = 83). Results CRP was lower for Kitavans compared to Swedish controls (Mdn 0.5 mg/L range 0.1—48 mg/L and Mdn 1.1 mg/L range 0.1—33 mg/L, respectively, r = .18 p = .02). Among Kitavans, there were small negative associations between lnCRP for CRP values Conclusions Chronic low-grade systemic inflammation, measured as CRP, was lower among Kitavans compared to Swedish controls, indicating a lower and average cardiovascular risk, respectively, for these populations.

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.

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.

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.

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.

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.

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.

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)

Purpose A growing number of young patients with central nervous system (CNS) tumour survived for more than five years. However, these long-term survivors might be at risk of multiple late effects thus leading to a higher risk of late mortality. We aimed to explore the risk of late mortality and the pattern of mortality among long-term survivors of childhood or adolescent CNS tumour. Methods We identified 5-year survivors with childhood or adolescent CNS tumour before age 20 years through the Swedish Cancer Registry. Five controls were randomly matched for each patient to generate the reference group. We retrieved information about death via Cause of Death Register. We calculated the absolute excess risk (AER) of death and the hazard ratio (HR) of death using Cox proportional hazard model. Results Long-term survivors with CNS tumour suffered a significant higher risk of overall mortality (HR 6.56, 95% CI 5.71–7.53; AER 5.89, 95% CI 5.03–6.87). The mortality rate declined with the increasing survival time, but it was still higher even after 30 years of follow-up. Malignant neoplasms contributed mostly to late mortality with an AER of 3.75 (95% CI 2.95–4.75). Female survivors, survivors diagnosed at a younger age and survivors with medulloblastoma were particularly strongly associated with a higher risk of death. Conclusions Long-term survivors of childhood and adolescent CNS tumours are at a higher risk of late mortality, and the risk of death is affected by gender, age at diagnosis and types of CNS tumour.

Background Patients with atrial fibrillation (AF) have an increased dementia risk dementia. We aimed to study the effect of antihypertensive drugs on dementia in AF patients. Methods Included patients were ≥45 years diagnosed with AF in Swedish National Patient Register (n = 160,251; 89,723 men and 70,528 women) and alive on January 1, 2007. We excluded patients with dementia before onset of AF. Cox regression was used (hazard ratios, HRs, and 99% confidence interval, CI) with adjustments for sex, age, socioeconomic factors and co-morbidities, using incident dementia diagnosis until December 31, 2015 as outcome. Cardiovascular pharmacotherapies were obtained from the Swedish Prescribed Drug Register. Results Incident dementia occurred in 9532 patients (5.9%), 4669 men (5.2%) and 4863 women (6.9%). ARBs were associated with lower risk for all patients (HR 0.87, 99% CI 0.78–0.98), especially in the ages 65–84 years of age (HR 0.87, 99% CI 0.76–0.99). Loop-diuretics were associated with higher risk for all dementia among patients 65–84 years of age (HR 1.16, 99% CI 1.00–1.35), and in the sub-group of other causes of dementia than Alzheimer Disease (AD) and vascular dementia (VaD) (HR 1.14, 99% CI 1.00–1.30), but with a lower risk in the sub-group of AD and VaD (HR 0.81, 99% CI 0.68–0.95). Conclusion ARBs were associated with a decreased incidence of dementia, and loop diuretics with a higher risk in general but lower risk in the AD and VaD sub-group. ARBs could have specific advantages in prevention of dementia, but the results need confirmation in further studies.

Substance use disorders (SUDs) are important risk factors for suicide, yet little is known about how suicide risks vary by specific SUDs. We examined these risks for the first time in a large general population to facilitate comparisons across SUDs. A national cohort study was conducted of all 6,947,191 adults in Sweden. SUDs (opioid, sedative/hypnotic, hallucinogen, cannabis, amphetamine, cocaine, and alcohol use disorders) were identified using inpatient, outpatient, and crime data, and suicide deaths using nationwide death data with follow-up during 2003-2016. Cox regression was used to compute hazard ratios (HRs) for suicide death while adjusting for sociodemographic factors and psychiatric, SUD, and somatic comorbidities. Co-sibling analyses assessed for confounding by unmeasured shared familial (genetic and/or environmental) factors. In 79.8 million person-years of follow-up, 15,616 (0.2%) suicide deaths were identified. All SUDs were associated with significantly increased risks, with HRs ranging from 12- to 26-fold and 2.5- to 6.4-fold before and after adjusting for covariates, respectively. After adjusting for all covariates, opioid use disorder was the strongest risk factor (HR, 6.39; 95% CI, 5.53-7.38) (P ≤ 0.002 compared with any other SUD), followed by sedative/hypnotic use disorder (4.62; 4.06-5.27) (P ≤ 0.009 compared with any other SUD except opioid or hallucinogen). Most associations persisted after controlling for shared familial factors, consistent with causal effects. In this large national cohort, all SUDs were associated with significantly increased risks of suicide death, especially opioid and sedative/hypnotic use disorders. These findings may improve risk stratification and inform interventions to prevent suicide in the highest-risk subgroups with SUDs.

The anti-cancer potential of dipyridamole has been suggested from experiments, but evidence from population-based studies is still lacking. We aimed to explore if dipyridamole use was related to a lower risk of lymphoid neoplasms. We identified individuals with prescription of aspirin after diagnosis of ischaemic cerebrovascular disease since 2006 by linking several Swedish registers. In these aspirin users, those with dipyridamole prescription were further identified as the study group and patients without dipyridamole were randomly selected as reference group with 1:1 ratio using a propensity score-matching approach. After a median of 6·67 years of follow-up, a total of 46 patients with dipyridamole use developed lymphoid neoplasms with an incidence rate of 0·49 per 1 000 person-years, while the rate in the matched group was 0·74 per 1 000 person-years. As compared to non-users, dipyridamole users were associated with a significantly decreased risk of lymphoid neoplasms [hazard ratio (HR) = 0·65; 95% confidence interval (CI) = 0·43-0·98]. Specifically, the reduced risk was observed for non-Hodgkin lymphomas (HR = 0·64; 95% CI = 0·42-0·94), especially B-cell lymphomas (HR = 0·56; 95% CI = 0·35-0·88). Dipyridamole use was related to a lower risk of lymphoid neoplasms, indicating a clinical potential of dipyridamole to be an adjunct anti-tumour agent against lymphoid neoplasms.

Simple Summary Head and neck cancers are cancers that arise between the mouth and larynx. Risk factors for these include smoking, alcohol, human papilloma virus (HPV) infection and family history. Because families can be identified for the whole Swedish population, we wanted to analyzed familial risks for HNC with same and different cancers among first-degree relatives. When a parent or sibling was diagnosed with HNC, other family members had a two-fold risk of being diagnosed with HNC, but the risk was higher when specific types of HNC, such as oral or nasopharyngeal cancers, were analyzed. Husbands of wives with cervical cancer had an increased risk of oropharyngeal cancer which may be related to shared HPV infection. In the Swedish population with low smoking levels, HPV is becoming a dominant risk factor, emphasizing the need for sexual hygiene and HPV vaccination. Background: Head and neck cancers (HNCs) encompass a heterogeneous group of cancers between the mouth and larynx. Familial clustering in HNCs has been described, but how it influences individual sites and to which extent known risk factors, such as human papilloma virus (HPV) infection, may contribute is not well established. Patients/methods: We employed standardized incidence ratios (SIRs) to estimate familial risks for HNC with same (concordant) and different (discordant) cancers among first-degree relatives using data from the Swedish Cancer Registry from 1958 to 2018. Results: Incidence for male and female oropharyngeal cancer increased close to four-fold in the past 39 years. Familial HNC was found in 3.4% of the study population, with an overall familial SIR of 1.78. Patients with concordant nasopharyngeal cancer showed a high risk of 23.97, followed by hypopharyngeal cancer (5.43). The husbands of wives with cervical cancer had an increased risk of oropharyngeal cancer. Discussion/Conclusion: Nasopharyngeal cancers lacked associations with lifestyle or HPV associated cancers, suggesting a role for germline genetics, which was also true for the high-risk families of three HNC patients. In the Swedish population with low smoking levels, HPV is becoming a dominant risk factor, emphasizing the need for sexual hygiene and HPV vaccination.

The authors examined the extent to which the genetic and environmental etiology of suicide attempt and suicide death is shared or unique.The authors used Swedish national registry data for a large cohort of twins, full siblings, and half siblings (N=1,314,990) born between 1960 and 1990 and followed through 2015. They conducted twin-family modeling of suicide attempt and suicide death to estimate heritability for each outcome, along with genetic and environmental correlations between them. They further assessed the relationship between suicide attempt by young people compared with adults.In bivariate models, suicide attempt and death were moderately heritable among both women (attempt: additive genetic variance component [A]=0.52, 95% CI=0.44, 0.56; death: A=0.45, 95% CI=0.39, 0.59) and men (attempt: A=0.41, 95% CI=0.38, 0.49; death: A=0.44, 95% CI=0.43, 0.44). The outcomes were substantially, but incompletely, genetically correlated (women: rA=0.67, 95% CI=0.55, 0.67; men: rA=0.74, 95% CI=0.63, 0.87). Environmental correlations were weaker (women: rE=0.36, 95% CI=0.29, 0.45; men: rE=0.21, 95% CI=0.19, 0.27). Heritability of suicide attempt was stronger among people ages 10-24 (A=0.55-0.62) than among those age 25 and older (A=0.36-0.38), and the genetic correlation between attempt during youth and during adulthood was stronger for women (rA=0.79, 95% CI=0.72, 0.79) than for men (rA=0.39, 95% CI=0.26, 0.47).The genetic and environmental etiologies of suicide attempt and death are partially overlapping, exhibit modest sex differences, and shift across the life course. These differences must be considered when developing prevention efforts and risk prediction algorithms. Where feasible, suicide attempt and death should be considered separately rather than collapsed, including in the context of gene identification efforts.

Aims Women who deliver pre-term have higher future risks of hypertension and ischaemic heart disease, but long-term risks of heart failure (HF) are unknown. We examined these risks in a large national cohort. Methods and results All 2 201 284 women with a singleton delivery in Sweden during 1973–2015 were followed up for inpatient or outpatient HF diagnoses through 2015. Cox regression was used to compute hazard ratios (HRs) for HF associated with pregnancy duration, adjusting for other maternal factors. Co-sibling analyses assessed for confounding by shared familial (genetic and/or environmental) factors. In 48.2 million person-years of follow-up, 19 922 women were diagnosed with HF (median age: 60.7 years). Within 10 years after delivery, the adjusted HR was 2.96 [95% confidence interval (CI): 2.48–3.53] for HF associated with pre-term (gestational age: Conclusion Pre-term and early term delivery were associated with markedly increased future hazards for HF, which persisted after adjusting for other maternal and familial factors and remained elevated 40 years later. Pre-term and early-term delivery should be recognized as risk factors for HF across the life course. Key Question What are the long-term hazards for heart failure (HF) across the life course in women who deliver preterm? Key Finding Preterm and early term delivery were associated with ∼3- and 1.7-fold adjusted hazards for HF in the next 10 years vs. full-term delivery. These hazards declined but remained elevated 40 years later, and were not explained by shared familial factors. Take Home Message Preterm and early term delivery were associated with increased future hazards for HF, which persisted for 40 years after adjusting for other maternal and familial factors. Preterm and early term delivery should be recognized as lifelong risk factors for HF.

The association between having a sibling diagnosed with alcohol use disorder (AUD) and risk for suicide attempt may be attributable to shared genetic liability between AUD and suicidal behavior, effects of environmental exposure to a sibling’s AUD, or both. To distinguish between these alternatives, we conducted a series of Cox regression models using data derived from Swedish population-based registers with national coverage. Among full sibling pairs (656,807 males and 607,096 females), we found that, even after we accounted for the proband’s AUD status, the proband’s risk for suicide attempt was significantly elevated when the proband’s sibling was affected by AUD. Furthermore, the proband’s risk for suicide attempt was consistently higher when the sibling’s AUD registration had occurred more recently. Our findings provide evidence for exposure to sibling AUD as an environmental risk factor for suicide attempt and suggest that clinical outreach may be warranted following a sibling’s diagnosis with AUD.

Open access funding provided by Lund University. The study was supported by ALF medel from Region Skane to Susanna Calling and Kristina Sundquist and by the Swedish Heart-Lung Foundation to Kristina Sundquist. The funders had no role in study design, analysis, interpretation of data or preparation of the manuscript., The association between type 2 diabetes (T2D) and ischemic heart disease (IHD) is well established but the potential causal association needs further studying. In an attempt to elucidate the causal effect of T2D on IHD, we used three different analytical approaches in two different datasets. A well-defined cohort of 6047 women aged 50–59 years were included at baseline (1995 to 2000) and followed until 2015 for IHD. The median follow-up was 16.3 years. We used a Marginal Structural Cox model (MSM Cox) to account for time-varying exposure (time at onset of T2D) and for ten confounders (using inverse probability weighting, IPW). We also compared the MSM-Cox models with traditional Cox regression modelling in the cohort. Finally, we analyzed information on individuals from Swedish population-based registers with national coverage in a comprehensive co-relative design and extrapolated the results to MZ twins. The Hazard Ratio (HR) for IHD in relation to T2D at baseline and T2D occurring during the follow-up in the MSM Cox model weighted by IPW (based on the ten included confounders) was 1.43 (95% confidence interval [CI] 1.07–1.92). The corresponding HR from the traditional Cox regression model was of similar effect size. The average extrapolated MZ twin estimate from our co-relative model was 1.61 (95% CI 1.48–1.86). Our findings, based on a triangular approach, support the existence of a causal association between T2D and IHD and that preventive long-term measures in order to avoid or postpone IHD should include monitoring and treatment of both the T2D itself as well as other cardiovascular risk factors., Lund University, ALF medel from Region Skane, Swedish Heart-Lung Foundation

Aims: Previous studies on major depressive disorder (MDD) among immigrants have reported mixed results. Using data from primary healthcare settings in Sweden, we compared the incidence of MDD among first- and second-generation immigrants aged 15–39 years with natives. Methods: This was a retrospective nationwide open cohort study. Eligible individuals were born 1965–1983, aged 15–39 years at baseline, and resided in Sweden for at least one year during the study period 2000–2015. We identified MDD cases through the Primary Care Registry (PCR). The follow-up for each individual started when they met the inclusion criteria and were registered in the PCR and ended at MDD diagnosis, death, emigration, moving to a county without PCR coverage, or the end of the study period, whichever came first. Results: The final sample included 1,341,676 natives and 785,860 immigrants. The MDD incidence rate per 1000 person-years ranged from 6.1 (95% confidence intervals: 6.1, 6.2) to 16.6 (95% confidence intervals: 16.2, 17.0) in native males and second-generation female immigrants with a foreign-born father, respectively. After adjusting for income, the MDD risk did not differ substantially between first-generation male and female immigrants and natives. However, male and female second-generation immigrants had a 16–29% higher adjusted risk of MDD than natives. Conclusions: This cohort study using primary healthcare data in Sweden, albeit incomplete, indicated that second-generation immigrants seem to be at a particularly high risk of MDDs. The underlying mechanisms need further investigation.

OBJECTIVE: The purpose of this study was to clarify the mediational pathways from genetic risk for alcohol use disorder (AUD) to AUD itself. METHOD: Using information on AUD status from first- through fourth-degree relatives obtained from national registries, we created a genetic risk score for AUD for the Swedish population. We first tested a simple mediational path model in males and females separately, with early onset externalizing psychopathology (EPP), internalizing psychopathology (IPP), and poor educational attainment (EA). We then tested a more complex model in a smaller, older sample of males that contained additional self-report measures from late adolescence. RESULTS: In our basic model, the largest mediational pathway from AUD genetic risk to AUD in both sexes was via high EPP followed by low EA and high IPP. The EPP pathway was considerably stronger in males, the low EA pathway was modestly stronger in females, and the IPP pathway was identical in both sexes. Our more complex model replicated the strong externalizing pathway to AUD, showing that it connected to key downstream risk factors such as early drug and alcohol use and low resilience. CONCLUSIONS: Our models concurred in showing that the strongest mediational pathway for genetic risk to AUD includes externalizing symptoms and disorders, which in turn predict further key downstream risk factors. Pathways through lower EA and IPP had smaller effects. IPP had mixed effects (partly predisposing and partly protective) on downstream risk factors. The largest sex difference was a stronger externalizing pathway to genetic risk to AUD in males than in females.

Background Evidence-based guidance for starting ages of screening for first-degree relatives (FDRs) of patients with prostate cancer (PCa) to prevent stage III/IV or fatal PCa is lacking in current PCa screening guidelines. We aimed to provide evidence for risk-adapted starting age of screening for relatives of patients with PCa. Methods and findings In this register-based nationwide cohort study, all men (aged 0 to 96 years at baseline) residing in Sweden who were born after 1931 along with their fathers were included. During the follow-up (1958 to 2015) of 6,343,727 men, 88,999 were diagnosed with stage III/IV PCa or died of PCa. The outcomes were defined as the diagnosis of stage III/IV PCa or death due to PCa, stratified by age at diagnosis. Using 10-year cumulative risk curves, we calculated risk-adapted starting ages of screening for men with different constellations of family history of PCa. The 10-year cumulative risk of stage III/IV or fatal PCa in men at age 50 in the general population (a common recommended starting age of screening) was 0.2%. Men with ≥2 FDRs diagnosed with PCa reached this screening level at age 41 (95% confidence interval (CI): 39 to 44), i.e., 9 years earlier, when the youngest one was diagnosed before age 60; at age 43 (41 to 47), i.e., 7 years earlier, when ≥2 FDRs were diagnosed after age 59, which was similar to that of men with 1 FDR diagnosed before age 60 (41 to 45); and at age 45 (44 to 46), when 1 FDR was diagnosed at age 60 to 69 and 47 (46 to 47), when 1 FDR was diagnosed after age 69. We also calculated risk-adapted starting ages for other benchmark screening ages, such as 45, 55, and 60 years, and compared our findings with those in the guidelines. Study limitations include the lack of genetic data, information on lifestyle, and external validation. Conclusions Our study provides practical information for risk-tailored starting ages of PCa screening based on nationwide cancer data with valid genealogical information. Our clinically relevant findings could be used for evidence-based personalized PCa screening guidance and supplement current PCa screening guidelines for relatives of patients with PCa., Xing Xu and co-workers assess prostate cancer risk in relatives of men with prostate cancer., Author summary Why was this study done? Family history is the strongest known risk factor for prostate cancer (PCa), and current guidelines concur that an earlier screening for men with a family history of PCa is necessary. However, limited evidence-based guidance is available on at what age actually this early screening should start. This study was conducted to provide precise recommendations about at what age should relatives of PCa patients start screening based on the number of affected relatives and the age at onset of PCa in the family. What did the researchers do and find? In this nationwide study on 6,343,727 men, the risk of stage III/IV or fatal PCa in close family members of patients with PCa was estimated. It was observed that men with family history of PCa reach the screening risk threshold up to 12 years earlier than the general population. This study found that age, age at diagnosis of PCa in relative/s, and number of affected first-degree relatives (FDRs) are important elements in increased risk of stage III/IV or fatal PCa, and these factors accordingly resulted in different risk-adapted starting ages of PCa screening. Comparison between our evidence-based risk-adapted starting age of screening and recommended age of PCa screening by different guidelines showed a difference ranging from −2 to 11 years. What do these findings mean? This study made use of the largest dataset available, to our knowledge, to identify the optimal age for starting PCa screening in relatives of patients with PCa. This study took into account not only the number of relatives but also age at onset of PCa in the family members, which is an additional important piece of information for the guidelines. The results may contribute to a more evidence-based personalized PCa screening guidance in real-world settings, and clinicians could inform patients with PCa about this possibility and encourage individualized counseling for their relatives.

Literature on familial risk of carcinomas in situ (CISs) is limited because many cancer registries do not collect information on CIS. In Sweden CISs are collected, and we used these data to analyze familial relative risks (RRs) for concordant (CIS-CIS) types of anogenital (cervical, other female and male genital and anal) and skin squamous cell CIS; additionally RRs were assessed between CIS types and between CIS and invasive forms. RRs were calculated for the offspring generations when family members were diagnosed CIS. Case numbers for CIS ranged from 330 in anal to 177,285 in cervical CIS. Significant concordant CIS-CIS RRs were 2.74 for female genital, 1.77 for cervical and 2.29 for SCC skin CISs. The CIS forms associated also with each other, except for cervical and skin CIS types. RRs for concordant CIS-invasive cancer associations were lower than CIS-CIS associations. Cervical CIS associated with non-Hodgkin CIS which may suggest immune dysfunction as a contributing factors. The results for anogenital CIS types suggest that life style related human papilloma virus infections contributed to the observed familial associations. Lower risks for CIS-invasive cancer than CIS-CIS suggest that CIS and invasive cancers share only partially risk factors that underlie familial clustering.

An increasing number of patients with central nervous system (CNS) tumor could survive to reproductive age. However, it is largely unknown whether the history of CNS tumor might affect pregnancy outcome. We aimed to explore the risk of being born preterm among children of CNS tumor survivors. By linking several nationwide registers in Sweden, we identified 1,369 children whose parents were childhood or adolescent CNS tumor survivors. Children whose parents did not have CNS tumor were matched randomly with a 5:1 ratio to generate the reference group. Conditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI). The prevalence of preterm birth (PTB) was 6.9% among children of survivors with CNS tumor and 5.2% among the matched controls. Children of survivors had an increased risk of PTB (adjusted OR = 1.29, 95%CI 1.01-1.65) compared to the matched controls. This risk was increased specifically among offspring of those diagnosed in childhood (adjusted OR = 1.53, 95%CI 1.14-2.06) but not adolescence (adjusted OR = 0.89, 95%CI 0.56-1.41). For families with more than one child, the risk was slightly lower among the second child as compared to the first child. The risk was negatively associated with time interval between parental diagnosis and childbirth. Parental medulloblastoma and ependymoma were most strongly associated with a higher risk of PTB. Children of survivors with CNS tumor experienced an elevated risk of PTB. However, the risk diminishes gradually after parental diagnosis of CNS tumor. Offspring of childhood CNS tumor survivors and medulloblastoma or ependymoma survivors may have the highest risk of PTB.

The objective of this study was to clarify the etiology of substance-induced psychotic disorder and its progression to schizophrenia in a Swedish national sample.Individuals with a registration of substance-induced psychotic disorder between 1997 and 2015 in national medical registries (N=7,606) were followed up for a mean of 84 months. Data from medical, criminal, and pharmacy registries on first-degree through third-degree relatives were used to calculate familial risk scores for nonaffective psychosis, drug abuse, and alcohol use disorder.Individuals with substance-induced psychotic disorder had large elevations in standardized familial risk scores for drug abuse (+1.09, 95% CI=1.02, 1.15) and alcohol use disorder (+0.98, 95% CI=0.93, 1.03) and modest elevations for nonaffective psychosis (+0.35, 95% CI=0.30, 0.41). The cumulative risk for progression to schizophrenia was 11.3%; it was lowest for alcohol-induced and highest for cannabis-induced psychotic disorder, and it was predicted by early age at diagnosis of substance-induced psychotic disorder, male sex, and further registrations for episodes of drug abuse, alcohol use disorder, and substance-induced psychotic disorder. A risk prediction model found that 47% of individuals who converted to schizophrenia were in the upper 20% of risk. Familial risk scores for drug abuse and alcohol use disorder did not significantly discriminate those who converted to schizophrenia from those who did not, while familial risk score for nonaffective psychosis did (0.67, 95% CI=0.40, 0.95, versus 0.33, 95% CI=0.28, 0.39). Familial risk scores for nonaffective psychosis were indistinguishable between individuals with schizophrenia with and without prior substance-induced psychosis. Assignment of early retirement by the Swedish Social Insurance Agency strongly discriminated between individuals with substance-induced psychotic disorder with and without later schizophrenia.Substance-induced psychotic disorder appears to result from substantial drug exposure in individuals at high familial risk for substance abuse and moderately elevated familial risk for psychosis. Familial risk for psychosis, but not substance abuse, predicts progression from substance-induced psychosis to schizophrenia. Schizophrenia following substance-induced psychosis is likely a drug-precipitated disorder in highly vulnerable individuals, not a syndrome predominantly caused by drug exposure.