Long-Term Risk of Type 2 Diabetes After Preterm Delivery or Hypertensive Disorders of Pregnancy.

OBJECTIVE: To examine long-term diabetes risk after preterm delivery or hypertensive disorders of pregnancy in a large population-based cohort. METHODS: This retrospective cohort study included all women with a singleton delivery in Sweden during 1973-2015 and no preexisting diabetes mellitus. Participants were followed up for development of type 2 diabetes identified from nationwide outpatient and inpatient diagnoses through 2018. Cox regression was used to compute hazard ratios (HRs) for the association between preterm delivery or hypertensive disorders of pregnancy and type 2 diabetes with adjustment for gestational diabetes and other maternal factors. Co-sibling analyses assessed for confounding by shared familial (genetic or environmental) factors. RESULTS: Overall, 2,184,417 women were included. Within 10 years after delivery, adjusted HRs for type 2 diabetes associated with specific pregnancy outcomes were as follows: any preterm delivery (before 37 weeks of gestation), 1.96 (95% CI, 1.83-2.09); extremely preterm delivery (22-27 weeks), 2.53 (95% CI, 2.03-3.16); and hypertensive disorders of pregnancy, 1.52 (95% CI, 1.43-1.63). All HRs remained significantly elevated (1.1-1.7-fold) 30-46 years after delivery. These findings were largely unexplained by shared familial factors. CONCLUSION: In this large national cohort, preterm delivery and hypertensive disorders of pregnancy were associated with increased risk for type 2 diabetes up to 46 years later. Women with these pregnancy complications are candidates for early preventive actions and long-term monitoring for type 2 diabetes.

Increased risk of venous thromboembolism in young and middle-aged individuals with hereditary angioedema: a family study.

Hereditary angioedema (HAE) due to C1 inhibitor protein (C1-INH) deficiency was recently shown to be associated with increased risk of venous thromboembolism (VTE). This is the first national family study of HAE with the aim to determine the familial risk of VTE. The Swedish Multi-Generation Register was linked to the Swedish National Patient Register during the period 1964-2018. Only HAE patients with a validated diagnosis were included in the study and were linked to their family members. Hazard ratios (HRs) and 95% confidence intervals (CIs) for VTE were calculated for HAE patients compared with relatives without HAE. Among 2,006 individuals (from 276 pedigrees of 365 patients with HAE), 103 individuals were affected by VTE. In total 35 (9.6%) of HAE patients compared to 68 (4.1%) of non-HAE relatives were affected by VTE (p<0.001). The adjusted HR for VTE among HAE patients was 2.51 (95% CI 1.67-3.77). HAE patients were younger at the first VTE than their non-HAE relatives (mean age 51 versus 63 years, p<0.001). Before the age of 70 years the HR for VTE among HAE patients was 3.62 (95%CI 2.26-5.80). The HR for VTE for HAE patients born after 1964 was 8.29 (95%CI 2.90-23.71). The HR for VTE for HAE patients born 1964 or earlier was 1.82 (95%CI 1.14-2.91). HAE is associated with VTE among young and middle-aged individuals in Swedish families with HAE. The effect size of the association is in the order of other thrombophilias. We suggest that HAE may be considered a new rare thrombophilia.

Association of Levonorgestrel-Releasing Intrauterine Device with Gynecologic and Breast Cancers: National Cohort Study in Sweden.

BACKGROUND: The levonorgestrel-releasing intrauterine device (LNG-IUD) is widely used for the treatment of menorrhagia, dysmenorrhea, and for contraception. However, the association between the use of LNG-IUD and the risk of site-specific gynecologic and breast cancers remains inconclusive. OBJECTIVE: We aim to address this knowledge gap by investigating whether the use of LNG-IUD is associated with a significant risk of site-specific gynecologic and breast cancers. This will be achieved by accessing the nationwide Swedish Registers, with consideration given to the influence and potential interaction of family history of cancer. STUDY DESIGN: A total of 514719 women aged 18 to 50 years who have used LNG-IUD between July 2005 and December 2018 were identified from the Swedish Prescribed Drug Register and randomly matched with 1544157 comparisons who did not use LNG-IUD at a ratio of 1:3. The propensity score was calculated and matched among women who used LNG-IUD and the matched comparisons. The follow-up period started from the date of the first prescription of LNG-IUD for users as well as for their matched comparisons and ended at the date of diagnosis of gynecologic and breast cancers, date of death from any cause, and the end of the study period, whichever came first. The Cox proportional hazard model with a competing risk analysis was used to calculate hazard ratios and 95% confidence intervals. Additive interaction was calculated as the relative excess risk for interaction, while multiplicative interaction was calculated by including a product term in the regression model. RESULTS: The use of LNG-IUD was associated with a 13% higher risk of breast cancer (adjusted HR, 1.13; 95% CI, 1.10-1.17), a 33% lower risk of endometrial cancer (adjusted HR, 0.67; 95% CI, 0.56-0.80), a 14% lower risk of ovarian cancer (adjusted HR, 0.86; 95% CI, 0.75-0.99) and a 9% reduced risk of cervical cancer (adjusted HR, 0.91; 95% CI, 0.84-0.99) compared to women who did not use LNG-IUD. A significant additive interaction between LNG-IUD use and family history of cancer was observed in breast cancer, indicating a relative 19% excess risk for interaction (P < 0.002), and 1.63 additional cases per 10,000 person-years. CONCLUSIONS: The risk of gynecologic and breast cancers exhibits a site-specific effect among LNG-IUD users. It's important to note that the observed effect is small for breast cancer and the results are limited by the observational study design. Clinical recommendations regarding the use of LNG-IUD should carefully weigh its potential benefits and risks. Close monitoring is advisable for the potential development of breast cancer, particularly among women with a family history of breast cancer.

Longer Interval Between First Colonoscopy With Negative Findings for Colorectal Cancer and Repeat Colonoscopy.

Importance: For individuals without a family history of colorectal cancer (CRC), colonoscopy screening every 10 years is recommended to reduce CRC incidence and mortality. However, debate exists about whether and for how long this 10-year interval could be safely expanded. Objective: To assess how many years after a first colonoscopy with findings negative for CRC a second colonoscopy can be performed. Design, Setting, and Participants: This cohort study leveraged Swedish nationwide register-based data to examine CRC diagnoses and CRC-specific mortality among individuals without a family history of CRC. The exposed group included individuals who had a first colonoscopy with findings negative for CRC at age 45 to 69 years between 1990 and 2016. The control group included individuals matched by sex, birth year, and baseline age (ie, the age of their matched exposed individual when the exposed individual's first colonoscopy with findings negative for CRC was performed). Individuals in the control group either did not have a colonoscopy during the follow-up or underwent colonoscopy that resulted in a CRC diagnosis. Up to 18 controls were matched with each exposed individual. Individuals were followed up from 1990 to 2018, and data were analyzed from November 2022 to November 2023. Exposure: A first colonoscopy with findings negative for CRC, defined as a first colonoscopy without a diagnosis of colorectal polyp, adenoma, carcinoma in situ, or CRC before or within 6 months after screening. Main Outcomes and Measures: The primary outcomes were CRC diagnosis and CRC-specific death. The 10-year standardized incidence ratio and standardized mortality ratio were calculated to compare risks of CRC and CRC-specific death in the exposed and control groups based on different follow-up screening intervals. Results: The sample included 110 074 individuals (65 147 females [59.2%]) in the exposed group and 1 981 332 (1 172 646 females [59.2%]) in the control group. The median (IQR) age for individuals in both groups was 59 (52-64) years. During up to 29 years of follow-up of individuals with a first colonoscopy with findings negative for CRC, 484 incident CRCs and 112 CRC-specific deaths occurred. After a first colonoscopy with findings negative for CRC, the risks of CRC and CRC-specific death in the exposed group were significantly lower than those in their matched controls for 15 years. At 15 years after a first colonoscopy with findings negative for CRC, the 10-year standardized incidence ratio was 0.72 (95% CI, 0.54-0.94) and the 10-year standardized mortality ratio was 0.55 (95% CI, 0.29-0.94). In other words, the 10-year cumulative risk of CRC in year 15 in the exposed group was 72% that of the 10-year cumulative risk of CRC in the control group. Extending the colonoscopy screening interval from 10 to 15 years in individuals with a first colonoscopy with findings negative for CRC could miss the early detection of only 2 CRC cases and the prevention of 1 CRC-specific death per 1000 individuals, while potentially avoiding 1000 colonoscopies. Conclusions and Relevance: This cohort study found that for the population without a family history of CRC, the 10-year interval between colonoscopy screenings for individuals with a first colonoscopy with findings negative for CRC could potentially be extended to 15 years. A longer interval between colonoscopy screenings could be beneficial in avoiding unnecessary invasive examinations.

Risk of depression in persons with Alzheimer's disease: A national cohort study.

INTRODUCTION: Depression is a risk factor and possible prodromal symptom of Alzheimer's disease (AD), but little is known about subsequent risk of developing depression in persons with AD. METHODS: National matched cohort study was conducted of all 129,410 persons diagnosed with AD and 390,088 with all-cause dementia during 1998-2017 in Sweden, and 3,900,880 age- and sex-matched controls without dementia, who had no prior depression. Cox regression was used to compute hazard ratios (HRs) for major depression through 2018. RESULTS: Cumulative incidence of major depression was 13% in persons with AD and 3% in controls. Adjusting for sociodemographic factors and comorbidities, risk of major depression was greater than two-fold higher in women with AD (HR, 2.21; 95% confidence interval [CI], 2.11-2.32) or men with AD (2.68; 2.52-2.85), compared with controls. Similar results were found for all-cause dementia. DISCUSSION: Persons diagnosed with AD or related dementias need close follow-up for timely detection and treatment of depression. Highlights: In a large cohort, women and men with AD had >2-fold subsequent risk of depression.Risks were highest in the first year (>3-fold) but remained elevated ≥3 years later.Risk of depression was highest in persons aged ≥85 years at AD diagnosis.Persons with AD need close follow-up for detection and treatment of depression.

Multimorbidity disease clusters are associated with venous thromboembolism: an extended cross-sectional national study.

Multimorbidity, i.e., two or more non-communicable diseases (NCDs), is an escalating challenge for society. Venous thromboembolism (VTE) is a common cardiovascular disease and it is unknown which multimorbidity clusters associates with VTE. Our aim was to examine the association between different common disease clusters of multimorbidity and VTE. The study is an extended (1997-2015) cross-sectional Swedish study using the National Patient Register and the Multigeneration Register. A total of 2,694,442 Swedish-born individuals were included in the study. Multimorbidity was defined by 45 NCDs. A principal component analysis (PCA) identified multimorbidity disease clusters. Odds ratios (OR) for VTE were calculated for the different multimorbidity disease clusters. There were 16% (n = 440,742) of multimorbid individuals in the study population. Forty-four of the individual 45 NCDs were associated with VTE. The PCA analysis identified nine multimorbidity disease clusters, F1-F9. Seven of these multimorbidity clusters were associated with VTE. The adjusted OR for VTE in the multimorbid patients was for the first three clusters: F1 (cardiometabolic diseases) 3.44 (95%CI 3.24-3.65), F2 (mental disorders) 2.25 (95%CI 2.14-2.37) and F3 (digestive system diseases) 4.35 (95%CI 3.63-5.22). There was an association between multimorbidity severity and OR for VTE. For instance, the occurrence of at least five diseases was in F1 and F2 associated with ORs for VTE: 8.17 (95%CI 6.32-10.55) and 6.31 (95%CI 4.34-9.17), respectively. In this nationwide study we have shown a strong association between VTE and different multimorbidity disease clusters that might be useful for VTE prediction.

Randomised controlled trial of lifestyle interventions for abdominal obesity in primary health care.

AIM: Assess effects on waist circumference from diet with or without cereal grains and with or without long-term physical exercise. BACKGROUND: Elevated waist circumference is an indicator of increased abdominal fat storage and is accordingly associated with increased cardiovascular mortality. This is likely due to the association between lifestyle-induced changes in waist circumference and cardiovascular risk factors. Reductions in waist circumference may be facilitated by diet without cereal grains combined with long-term physical exercise. METHODS: Two-year randomised controlled trial with factorial trial design in individuals at increased risk of cardiovascular disease with increased waist circumference. Participants were allocated diet based on current Swedish dietary guidelines with or without cereal grains (baseline diet information supported by monthly group sessions) and with or without physical exercise (pedometers and two initial months of weekly structured exercise followed by written prescription of physical activity) or control group. The primary outcome was the change in waist circumference. FINDINGS: The greatest mean intervention group difference in the change in waist circumference among the 73 participants (47 women and 26 men aged 23-79 years) was at one year between participants allocated a diet without cereal grains and no exercise and participants allocated a diet with cereal grains and no exercise [M = -5.3 cm and -0.9 cm, respectively; mean difference = 4.4 cm, 4.0%, 95% CI (0.0%, 8.0%), P = 0.051, Cohen's d = 0.75]. All group comparisons in the change in waist circumference were non-significant despite the greatest group difference being more than double that estimated in the pre-study power calculation. The non-significance was likely caused by too few participants and a greater than expected variability in the change in waist circumference. The greatest mean intervention group difference strengthens the possibility that dietary exclusion of cereal grains could be related to greater reduction in waist circumference.

Sarcoidosis in first- and second-generation immigrants: a cohort study of all adults 18 years of age and older in Sweden.

BACKGROUND: There is a lack of studies on sarcoidosis among immigrants, which is of interest as there may be genetic and environmental characteristics affecting immigrants from certain countries. We aimed to study hazard ratios (HRs) of sarcoidosis in first- and second-generation immigrants, comparing them with native Swedes in the total adult Swedish population. METHODS: We conducted a nationwide study of individuals ≥18 y of age. Sarcoidosis was defined as at least two registered diagnoses in the National Patient Register between 1 January 1998 and 31 December 2018. Cox regression analysis was used to estimate HRs with 99% confidence intervals (CIs) of first registration of sarcoidosis in first- and second-generation immigrants compared with native Swedes. The Cox regression models were stratified by sex and adjusted for age, comorbidities and sociodemographic characteristics. RESULTS: In total, 6 175 251 were included in the first-generation study, with 12 617 cases of sarcoidosis, and 4 585 529 in the second-generation study, with 12 126 cases. The overall sarcoidosis risk was lower in foreign-born men (fully adjusted HR 0.63 [99% CI 0.57 to 0.69]) but not in foreign-born women (fully adjusted HR 0.98 [99% CI 0.90 to 1.06]). The overall risk was slightly lower in second-generation immigrants (HR 0.82 [99% CI 0.78 to 0.88]). Women from Asia exhibited a higher risk (HR 1.25 [99% CI 1.02 to 1.53)], while a potential trend was observed among women from Africa (HR 1.47 [99% CI 0.99 to 2.19]). CONCLUSIONS: Sarcoidosis risk was lower in foreign-born men but not in women and also lower in second-generation immigrants.

Adverse Pregnancy Outcomes and Long-Term Mortality in Women.

Importance: Women with adverse pregnancy outcomes, such as preterm delivery or preeclampsia, have higher future risks of cardiometabolic disorders; however, little is known about their long-term mortality risks. A better understanding of such risks is needed to facilitate early identification of high-risk women and preventive actions. Objective: To determine long-term mortality risks associated with 5 major adverse pregnancy outcomes in a large population-based cohort of women. Design, Setting, and Participants: This national cohort study in Sweden used the Swedish Medical Birth Register, containing prenatal and birth information for nearly all deliveries in Sweden since 1973, to identify women who had a singleton delivery during 1973 to 2015. All 2 195 667 such women with information for pregnancy duration and infant birth weight were included in the study. Data were analyzed from March to September 2023. Exposure: Adverse pregnancy outcomes (preterm delivery, small for gestational age, preeclampsia, other hypertensive disorders, and gestational diabetes), identified from nationwide birth records. Main Outcome and Measures: All-cause and cause-specific mortality through December 31, 2018. Cox regression was used to compute hazard ratios (HRs) for mortality associated with specific adverse pregnancy outcomes, adjusted for other maternal factors. Cosibling analyses assessed for confounding by shared familial (genetic or environmental) factors. Results: In 56 million person-years of follow-up to a median (IQR) age of 52 (42-61) years, 88 055 women (4%) died (median [IQR] age at death, 59 [50-67] years). All 5 adverse pregnancy outcomes were independently associated with increased mortality. Across the entire follow-up (≤46 years after delivery), adjusted HRs for all-cause mortality associated with specific adverse pregnancy outcomes were as follows: gestational diabetes, 1.52 (95% CI, 1.46-1.58); preterm delivery, 1.41 (95% CI, 1.37-1.44); small for gestational age, 1.30 (95% CI, 1.28-1.32); other hypertensive disorders, 1.27 (95% CI, 1.19-1.37); and preeclampsia, 1.13 (95% CI, 1.10-1.16). All HRs remained significantly elevated even 30 to 46 years after delivery. These effect sizes were only partially (0%-45%) reduced after controlling for shared familial factors in cosibling analyses. Women who experienced multiple adverse pregnancy outcomes had further increases in risk. Several major causes of death were identified, including cardiovascular and respiratory disorders and diabetes. Conclusions and Relevance: In this large national cohort study, women who experienced any of 5 major adverse pregnancy outcomes had increased mortality risks that remained elevated more than 40 years later. Women with adverse pregnancy outcomes need early preventive evaluation and long-term follow-up for detection and treatment of chronic disorders associated with premature mortality.

Mortality Risks Associated with Depression in Men with Prostate Cancer.

BACKGROUND: Men diagnosed with prostate cancer (PC) have an increased risk of depression; however, it is unclear to what extent depression affects long-term survival. A better understanding of such effects is needed to improve long-term care and outcomes for men with PC. OBJECTIVE: To determine the associations between major depression and mortality in a national cohort of men with PC. DESIGN, SETTING, AND PARTICIPANTS: A national cohort study was conducted of all 180 189 men diagnosed with PC in Sweden during 1998-2017. Subsequent diagnoses of major depression were ascertained from nationwide outpatient and inpatient records through 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Deaths were identified from nationwide records through 2018. Cox regression was used to compute hazard ratios (HRs) for all-cause mortality associated with major depression, adjusting for sociodemographic factors and comorbidities. Subanalyses assessed differences by PC treatment during 2005-2017. PC-specific mortality was examined using competing risks models. RESULTS AND LIMITATIONS: In 1.3 million person-years of follow-up, 16 134 (9%) men with PC were diagnosed with major depression and 65 643 (36%) men died. After adjusting for sociodemographic factors and comorbidities, major depression was associated with significantly higher all-cause mortality in men with high-risk PC (HR, 1.50; 95% confidence interval [CI], 1.44-1.55) or low- or intermediate-risk PC (1.64; 1.56-1.71). These risks were elevated regardless of PC treatment or age at PC diagnosis, except for youngest men (<55 yr) in whom the risks were nonsignificant. Major depression was also associated with increased PC-specific mortality in men with either high-risk PC (HR, 1.35; 95% CI, 1.28-1.43) or low- or intermediate-risk PC (1.42; 1.27-1.59). This study was limited to Sweden and will need replication in other countries when feasible. CONCLUSIONS: In this national cohort of men with PC, major depression was associated with ∼50% higher all-cause mortality. Men with PC need timely detection and treatment of depression to support their long-term outcomes and survival. PATIENT SUMMARY: In this report, we examined the effects of depression on survival in men with prostate cancer. We found that among all men with prostate cancer, those who developed depression had a 50% higher risk of dying than those without depression. Men with prostate cancer need close monitoring for the detection and treatment of depression to improve their long-term health outcomes.

Socioeconomic position indicators and risk of alcohol-related medical conditions: A national cohort study from Sweden.

BACKGROUND: Alcohol consumption contributes to excess morbidity and mortality in part through the development of alcohol-related medical conditions (AMCs, including alcoholic cardiomyopathy, hepatitis, cirrhosis, etc.). The current study aimed to clarify the extent to which risk for these outcomes differs as a function of socioeconomic position (SEP), as discrepancies could lead to exacerbated health disparities. METHODS AND FINDINGS: We used longitudinal Swedish national registries to estimate the individual and joint associations between 2 SEP indicators, educational attainment and income level, and risk of AMC based on International Classification of Diseases codes, while controlling for other sociodemographic covariates and psychiatric illness. We conducted Cox proportional hazards models in sex-stratified analyses (N = 1,162,679 females and N = 1,196,659 males), beginning observation at age 40 with follow-up through December 2018, death, or emigration. By the end of follow-up, 4,253 (0.37%) females and 11,183 (0.93%) males had received an AMC registration, corresponding to overall AMC incidence rates among females and males of 2.01 and 5.20, respectively. In sex-stratified models adjusted for birth year, marital status, region of origin, internalizing and externalizing disorder registrations, and alcohol use disorder (AUD) registration, lower educational attainment was associated with higher risk of AMC in both females (hazard ratios [HRs] = 1.40 to 2.46 for low- and mid-level educational attainment across 0 to 15 years of observation) and males (HRs = 1.13 to 1.48). Likewise, risk of AMC was increased for those with lower income levels (females: HRs = 1.10 to 5.86; males: HRs = 1.07 to 6.41). In secondary analyses, we further adjusted for aggregate familial risk of AUD by including family genetic risk scores for AUD (FGRSAUD), estimated using medical, pharmacy, and criminal registries in extended families, as covariates. While FGRSAUD were associated with risk of AMC in adjusted models (HR = 1.17 for females and HR = 1.21 for males), estimates for education and income level remained largely unchanged. Furthermore, FGRSAUD interacted with income level, but not education level, such that those at higher familial liability to AUD were more susceptible to the adverse effect of low income. Limitations of these analyses include the possibility of false negatives for psychiatric illness registrations, changes in income after age 40 that were not accounted for due to modeling restrictions, restriction to residents of a high-income country, and the inability to account for individual-level alcohol consumption using registry data. CONCLUSIONS: Using comprehensive national registry data, these analyses demonstrate that individuals with lower levels of education and/or income are at higher risk of developing AMC. These associations persist even when accounting for a range of sociodemographic, psychiatric, and familial risk factors. Differences in risk could contribute to further health disparities, potentially warranting increased screening and prevention efforts in clinical and public health settings.

Critical survival periods in prostate cancer in Sweden explored by conditional survival analysis.

BACKROUND: We wanted to characterize conditional survival in prostate cancer (PC) in Sweden around and after 2005 when the vast increase in incidence due to the opportunistic testing for prostate specific antigen (PSA) culminated. We hypothesize that analyzing survival data during that time period may help interpret survival trends. We focus on stage-specific analysis using conditional survival in order to define the periods when deaths most commonly occurred. METHODS: Data on PC patients were obtained from the Swedish cancer registry for analysis of 1-, 2.5- and 5-year relative survival and conditional relative survival between years 2004 and 2018. Tumor-node-metastatic stage classification at diagnosis was used to specify survival. RESULTS: Small improvements were observed in stage- and age-related relative survival duriring the study period. Applying conditional relative survival showed that survival in stage T3 up to 2.5 years was better than survival between years 2.5 and 5. Survival in stage T4 was approximately equal in the first and the subsequent 2.5-year period. For M1, the first 2.5 year survival period was worse than the subsequent one. The proportion of high risk and M1 disease in old patients (80+ years) remained very high and their survival improved only modestly. CONCLUSIONS: The data indicate that M1 metastases kill more patients in the first 2.5 years than between years 2.5 and 5 after diagnosis; T4 deaths are equal in the two periods, and in T3 mortality in the first 2.5-year period is lower than between years 2.5 and 5 after diagnosis. Conditional survival could be applied to explore critical survival periods even past 5 years after diagnoses and to monitor success in novel diagnostic and treatment practices. Improvement of survival in elderly patients may require clinical input.

A Swedish population-based study to evaluate the usefulness of resting heart rate in the prediction of suicidal behavior among males.

INTRODUCTION: Resting heart rate has been distinctly related to both internalizing (high pulse) and externalizing (low pulse) disorders. We aimed to explore the associations between resting heart rate and suicidal behavior (nonfatal suicide attempt [SA] and suicide death [SD]) and evaluate if such associations exist beyond the effects of internalizing/externalizing symptomatology. METHOD: We used Cox proportional hazards models to evaluate the associations between resting heart rate (age 19) and later SA/SD in 357,290 Swedish men. Models were controlled for internalizing disorders, externalizing disorders, and resilience (the ability to deal with adversity). Co-relative analysis (comparing pairs of different genetic relatedness) was used to control for unmeasured family confounders and improve causal inference. RESULTS: In baseline models, low resting heart rate was associated with SA (HR = 0.96; 95% CI: 0.95,0.98) and high resting heart rate with SD (HR = 1.04; 95% CI: 1.002,1.07). The association with SA remained after adjustment for all confounders (HR = 0.98). However, the association with SD did not persist after controlling for covariates. Co-relative analysis did not support causal associations. CONCLUSIONS: Our findings raise interesting etiological questions for the understanding of suicidal behaviors but do not support the usefulness of resting heart rate in suicide prediction.

Alcohol use disorder and risk of specific methods of suicide death in a national cohort.

INTRODUCTION: Alcohol use disorder (AUD) is among the strongest correlates of suicide death, but it is unclear whether AUD status is differentially associated with risk of suicide by particular methods. METHODS: The authors used competing risks models to evaluate the association between AUD status and risk of suicide by poisoning, suffocation, drowning, firearm, instruments, jumping, or other means in a large Swedish cohort born 1932-1995 (total N = 6,581,827; 48.8% female). Data were derived from Swedish national registers, including the Cause of Death Register and a range of medical registers. RESULTS: After adjusting for sociodemographic factors and familial liability to suicidal behavior, AUD was positively associated with risk of suicide for each method evaluated (cumulative incidence differences: 0.006-1.040 for females, 0.046-0.680 for males), except the association with firearm suicide in females. AUD was most strongly associated with risk of suicide by poisoning. Sex differences in the effects of AUD and family liability were observed for some, but not all, methods. Furthermore, high familial liability for suicidal behavior exacerbated AUD's impact on risk for suicide by poisoning (both sexes) and suffocation and jumping (males only), while the inverse interaction was observed for firearm suicide (males only). CONCLUSIONS: AUD increases risk of suicide by all methods examined and is particularly potent with respect to risk of suicide by poisoning. Differences in risk related to sex and familial liability to suicidal behavior underscore AUD's nuanced role in suicide risk. Future research should investigate targeted means restriction effectiveness among persons with AUD.

Revealing genes associated with cervical cancer in distinct immune cells: A comprehensive Mendelian randomization analysis.

Human papillomavirus can be contracted by sexually active women. However, only a small proportion of these infections persist and have the potential to progress into cervical cancers, indicating a significant involvement of the immune system in cervical cancer development. Despite this, our understanding of the precise contributions of genes from different immune cell types in cervical cancers remains limited. Therefore, the primary objective of our study was to investigate the potential causal relationships between specific immune cell genes and the development of cervical cancers. By accessing expression quantitative trait loci datasets of 14 distinct immune cell types and genome wide association study of cervical cancers, we employed the summary data-based Mendelian randomization (SMR) along with multi-single nucleotide polymorphism (SNP)-based SMR to identify significant genes associated with cervical cancers. Colocalization analysis was further conducted to explore the shared genetic causality. A total of 10 genes across 11 immune cell types (26 significant gene-trait associations) were found to be associated with cervical cancers after false discovery rate correction. Notably, the ORMDL3, BRK1 and HMGN1 gene expression levels showed significant association with cervical cancer in specific immune cell types, respectively. These associations were supported by strong evidence of colocalization analyses. Our study has identified several genes in different immune cells that were associated with cervical cancer. However, further research is necessary to confirm these findings and provide more comprehensive insights into the association between these gene expressions and cervical cancer risk.

Antihypertensive drug targets and breast cancer risk: a two-sample Mendelian randomization study.

Findings on the correlation between the use of antihypertensive medication and the risk of breast cancer (BC) have been inconsistent. We performed a two-sample Mendelian randomization (MR) using instrumental variables to proxy changes in gene expressions of antihypertensive medication targets to interrogate this. Genetic instruments for expression of antihypertensive drug target genes were identified with expression quantitative trait loci in blood, which should be associated with systolic blood pressure to proxy for the effect of antihypertensive drug. The association between genetic variants and BC risk were obtained from genome-wide association study summary statistics. The summary-based MR was employed to estimate the drug effects on BC risk. We further performed sensitivity analyses to confirm the discovered MR associations such as assessment of horizontal pleiotropy, colocalization, and multiple tissue enrichment analyses. The overall BC risk was only associated with SLC12A2 gene expression at a Bonferroni-corrected threshold. One standard deviation (SD) decrease of SLC12A2 gene expression in blood was associated with a decrease of 1.12 (95%CI, 0.80-1.58) mmHg of systolic blood pressure, but a 16% increased BC risk (odds ratio, 1.16, 95% confidential interval, 1.06-1.28). This signal was further observed for estrogen receptor positive (ER +) BC (1.17, 1.06-1.28). In addition, one SD decrease in expression of PDE1B in blood was associated with 7% decreased risk of ER + BC (0.93, 0.90-0.97). We detected no evidence of horizontal pleiotropy for these associations and the probability of the causal variants being shared between the gene expression and BC risk was 81.5, 40.5 and 66.8%, respectively. No significant association was observed between other target gene expressions and BC risk. Changes in expression of SLC12A2 and PDE1B mediated possibly via antihypertensive drugs may result in increased and decreased BC risk, respectively.

The predictive effect of family genetic risk scores as an indirect measure of causal effects of one disorder on another.

BACKGROUND: One potential cause of comorbidity is the direct causal effect of one disorder - A - on risk for subsequent onset of disorder B. Could genetic risk scores be utilized to test for such an effect? If disorder A causally impacts on risk for disorder B, then genetic risk for disorder A should be lower in cases of disorder A with v. without a prior onset of B. METHODS: In all individuals (n = 905 736) born in Sweden from 1980 to 1990, from six psychiatric and drug use disorders (major depression, anxiety disorders, alcohol use disorder, drug use disorder, bipolar disorder, and schizophrenia), we formed 14 pairs of disorders A and B. In these pairs, we compared, using Cox proportional hazards models, the predictive effect of the familial-genetic risk score (FGRS) for disorder B in those who had v. had not had a prior onset of disorder A. RESULTS: In all pairs, the impact of the FGRS for disorder B was significantly stronger in cases without v. with a prior history of disorder A. These effects were similar across sex, stable across levels of FGRS and not likely due to clinician bias. In many of our disorder pairs, previous clinical studies suggest a mechanism for a causal effect of disorder A on B. CONCLUSIONS: Our findings provide indirect evidence that the occurrence of one psychiatric or substance use disorder often has a causal effect on risk for subsequent disorders. This mechanism may substantially contribute to the widespread comorbidity among psychiatric conditions.

The genetic epidemiology of schizotypal personality disorder.

BACKGROUND: The concept of schizotypal personality disorder (SPD) emerged from observations of personality characteristics common in relatives of schizophrenic patients. While often studied in family designs, few studies and none with genetic measures, have examined SPD in epidemiological samples. METHODS: We studied individuals born in Sweden 1940-2000 with an ICD-10 diagnosis of SPD with no prior schizophrenia (SZ) diagnosis (n = 2292). Demographic features, patterns of comorbidity, and Family Genetic Risk Scores (FGRS) were assessed from multiple Swedish registries. Prediction of progression to SZ was assessed by Cox models. RESULTS: SPD was rare, with a prevalence of 0.044%, and had high levels of comorbidity with autism spectrum disorder (ASD), OCD, ADHD, and major depression (MD), and increased rates of being single, unemployed and in receipt of welfare. Affected individuals had elevated levels of FGRS for SZ (+0.42), ASD (+0.30), MD (+0.29), and ADHD (+0.20). Compared to cases of schizophrenia, they had significantly lower rates of FGRSSZ, but significantly elevated rates of genetic risk for ASD, MD, and ADHD. Over a mean follow-up of 8.7 years, 14.6% of SPD cases received a first diagnosis of SZ, the risk for which was significantly increased by levels of FGRSSZ, male sex, young age at SPD diagnosis and an in-patient SPD diagnosis and significantly decreased by comorbidity with MD, ASD, and ADHD. CONCLUSIONS: Our results not only support the designation of SPD as a schizophrenia spectrum disorder but also suggest potentially important etiologic links between SPD and ASD and, to a lesser extent, ADHD, OCD, and MD.