Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.

PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR). METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status. RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: ß = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: ß = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (ß = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (ß = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches. CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.

Genetic Risk, Health-Associated Lifestyle, and Risk of Early-onset Total Cancer and Breast Cancer.

Importance: Early-onset cancer (diagnosed under 50 years of age) is associated with aggressive disease characteristics and its rising incidence is a global concern. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants is unknown. Objective: To examine the associations between genetic risk, lifestyle, and risk of early-onset cancers. Design Setting and Participants: We analyzed a prospective cohort of 66,308 white British participants who were under age 50 and free of cancer at baseline in the UK Biobank. Exposures: Sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs, which summarize smoking status, body mass index [males only], physical activity, alcohol consumption, and diet). Main Outcomes and Measures: Hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer. Results: A total of 1,247 incident invasive early-onset cancer cases (female: 820, male: 427, breast: 386) were documented. In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs. lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI: 1.85, 1.50-2.29) and males (1.94, 1.45-2.59) as well as early-onset breast cancer in females (3.06, 2.20-4.25). An unfavorable lifestyle (highest vs. lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer was stronger in the highest genetic risk category than the lowest: HRs in females and men were 1.85 (1.02, 3.36), 3.27 (0.78, 13.72) in the highest genetic risk category and 1.15 (0.44, 2.98), 1.16 (0.39, 3.40) in the lowest. Conclusions and Relevance: Both genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Compared to those with low genetic risk, individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer.

NON-ADDITIVE EFFECTS OF COMMON GENETIC VARIANTS HAVE A NEGLIGENT CONTRIBUTION TO CANCER HERITABILITY.

BACKGROUND: The contribution of dominance effects to cancer heritability is unknown. We leveraged existing genome-wide association data for seven cancers to estimate the contribution of dominance effects to the heritability of individual cancer types. METHODS: We estimated the proportion of phenotypic variation due to dominance genetic effects using genome-wide association data for seven cancers (breast, colorectal, lung, melanoma, non-melanoma skin, ovarian, and prostate) in a total of 166,772 cases and 284,824 controls. RESULTS: We observed no evidence of a meaningful contribution of dominance effects to cancer heritability. In contrast, additive effects ranged between 0.11 and 0.34. CONCLUSIONS: In line with studies of other human traits, dominance effects of common genetic variants play a minimal role in cancer etiology. IMPACT: These results support the assumption of an additive inheritance model when conducting cancer association studies with common genetic variants.

Last general practitioner consultation during the final month of life: a national medical record review of suicides in Sweden.

OBJECTIVES: Individuals who die by suicide often consult their general practitioners (GPs) in their final weeks of life. The aim of this study was to gain a deeper knowledge of the clinical characteristics and GP assessments and treatments among individuals who consulted their GPs during the month preceding suicide. Further, we compared these features in those with and without contact with psychiatric services (PC and NPC, respectively) during the two years that preceded the suicide. DESIGN: A nationwide retrospective explorative study investigating medical records. SETTING: Primary care in Sweden. PARTICIPANTS: Individuals who died by suicide in Sweden in 2015 with a GP visit within 30 days of death. RESULTS: The study cohort corresponds to one fifth (n = 238) of all suicides that occurred in Sweden in 2015 (n = 1179), representing all those with available primary care records showing contact with a GP during the final 30 days of life (NPC: n = 125; PC: n = 113). The mean age was 58 years ± 19. Patients in the NPC group were older (NPC: 63 years ± 19 vs. PC: 53 years ± 18, p < 0.0001) and presented psychiatric symptoms less often (NPC: 50% vs. PC: 67%, p < 0.006). Somatic symptoms were as common as psychiatric symptoms for the whole sample, being present in more than half of individuals. Suicide risk was noted in only 6% of all individuals. Referral to psychiatric services occurred in 14%, less commonly for the NPC group (NPC: 6% vs. PC: 22%, p < 0.001). Cardiovascular or respiratory symptoms were noted in 19%, more often in the NPC group (NPC: 30% vs. PC: 6%, p < 0.001), as were diagnoses involving the circulatory system (all 10%, NPC:14% vs. PC: 5%, p < 0.020). CONCLUSION: A high level of somatic symptoms was observed in primary care patients both with and without psychiatric contact, and this might have influenced GPs' management decisions. Psychiatric symptoms were noted in two thirds of those with psychiatric contact but only half of those without. While GPs noted psychiatric symptoms in over half of all individuals included in the study, they seldom noted suicide risk. These findings highlight the need for increased attention to psychiatric symptoms and suicide risk assessment, particularly among middle-aged and older individuals presenting with somatic symptoms. STRENGTHS AND LIMITATIONS OF THIS STUDY: The National Cause of Death Register has excellent coverage of suicide deaths and access to medical records was very good. The medical record review provided detailed information regarding primary care utilization before death by suicide. Because of the lack of statistical power, due to the limited number of persons with GP contact during the last month of life, we chose not to correct for multiple comparisons. Our study approach did not capture the reasons behind GPs' documentation of elevated suicide risk. No systematic inter-rater reliability (IRR) testing was made, however, reviewers received training and continuous support from the research group.

Anxiety symptoms preceding suicide: A Swedish nationwide record review.

BACKGROUND: The literature on the relationship between anxiety and suicidal behaviors is limited and findings are mixed. This study sought to determine whether physicians noted anxiety symptoms and suicidality in their patients in the weeks and months before suicide. METHODS: Data were derived from a nationwide medical record review of confirmed suicides in Sweden in 2015. Individuals with at least one documented physician consultation in any health care setting during 12 months before suicide (N = 956) were included. Clinical characteristics were compared between decedents with and without a notation of anxiety symptoms. Odds ratios were calculated to estimate associations between anxiety symptoms and suicidality in relation to suicide proximity. RESULTS: Anxiety symptoms were noted in half of individuals 1 week before suicide. Patients with anxiety were characterized by high rates of depressive symptoms, ongoing substance use issues, sleeping difficulties, and fatigue. After adjustment for mood disorders, the odds of having a notation of elevated suicide risk 1 week before death were doubled in persons with anxiety symptoms. Associations were similar across time periods (12 months - 1 week). Two-thirds had been prescribed antidepressants at time of death. LIMITATIONS: Data were based on physicians' notations which likely resulted in underreporting of anxiety depending on medical specialty. Records were not available for all decedents. CONCLUSIONS: Anxiety symptoms were common in the final week before suicide and were accompanied by increases in documented elevated suicide risk. Our findings can inform psychiatrists, non-psychiatric specialists, and GPs who meet and assess persons with anxiety symptoms.