Assessing causal links between age at menarche and adolescent mental health: a Mendelian randomisation study.

BACKGROUND: The timing of puberty may have an important impact on adolescent mental health. In particular, earlier age at menarche has been associated with elevated rates of depression in adolescents. Previous research suggests that this relationship may be causal, but replication and an investigation of whether this effect extends to other mental health domains is warranted. METHODS: In this Registered Report, we triangulated evidence from different causal inference methods using a new wave of data (N = 13,398) from the Norwegian Mother, Father, and Child Cohort Study. We combined multiple regression, one- and two-sample Mendelian randomisation (MR), and negative control analyses (using pre-pubertal symptoms as outcomes) to assess the causal links between age at menarche and different domains of adolescent mental health. RESULTS: Our results supported the hypothesis that earlier age at menarche is associated with elevated depressive symptoms in early adolescence based on multiple regression (ß = - 0.11, 95% CI [- 0.12, - 0.09], pone-tailed < 0.01). One-sample MR analyses suggested that this relationship may be causal (ß = - 0.07, 95% CI [- 0.13, 0.00], pone-tailed = 0.03), but the effect was small, corresponding to just a 0.06 standard deviation increase in depressive symptoms with each earlier year of menarche. There was also some evidence of a causal relationship with depression diagnoses during adolescence based on one-sample MR (OR = 0.74, 95% CI [0.54, 1.01], pone-tailed = 0.03), corresponding to a 29% increase in the odds of receiving a depression diagnosis with each earlier year of menarche. Negative control and two-sample MR sensitivity analyses were broadly consistent with this pattern of results. Multivariable MR analyses accounting for the genetic overlap between age at menarche and childhood body size provided some evidence of confounding. Meanwhile, we found little consistent evidence of effects on other domains of mental health after accounting for co-occurring depression and other confounding. CONCLUSIONS: We found evidence that age at menarche affected diagnoses of adolescent depression, but not other domains of mental health. Our findings suggest that earlier age at menarche is linked to problems in specific domains rather than adolescent mental health in general.

Childhood maltreatment and health in the UK Biobank: triangulation of outcome-wide and polygenic risk score analyses.

BACKGROUND: Childhood maltreatment is common globally and impacts morbidity, mortality, and well-being. Our understanding of its impact is constrained by key substantive and methodological limitations of extant research, including understudied physical health outcomes and bias due to unmeasured confounding. We address these limitations through a large-scale outcome-wide triangulation study. METHODS: We performed two outcome-wide analyses (OWAs) in the UK Biobank. First, we examined the relationship between self-reported maltreatment exposure (number of maltreatment types, via Childhood Trauma Screener) and 414 outcomes in a sub-sample of 157,316 individuals using generalized linear models ("observational OWA"). Outcomes covered a broad range of health themes including health behaviors, cardiovascular disease, digestive health, socioeconomic status, and pain. Second, we examined the relationship between a polygenic risk score for maltreatment and 298 outcomes in a non-overlapping sample of 243,006 individuals ("genetic OWA"). We triangulated results across OWAs based on differing sources of bias. RESULTS: Overall, 23.8% of the analytic sample for the observational OWA reported at least one maltreatment type. Of 298 outcomes examined in both OWAs, 25% were significant in both OWAs and concordant in the direction of association. Most of these were considered robust in the observational OWA according to sensitivity analyses and included outcomes such as marital separation (OR from observational OWA, ORo = 1.25 (95% CI: 1.21, 1.29); OR from genetic OWA, ORg = 1.06 (1.03, 1.08)), major diet changes due to illness (ORo = 1.27 (1.24, 1.29); ORg = 1.01 (1.00, 1.03)), certain intestinal diseases (ORo = 1.14 (1.10, 1.18); ORg = 1.03 (1.01, 1.06)), hearing difficulty with background noise (ORo = 1.11 (1.11, 1.12); ORg = 1.01 (1.00, 1.01)), knee arthrosis (ORo = 1.13 (1.09, 1.18); ORg = 1.03 (1.01, 1.05)), frequent sleeplessness (ORo = 1.21 (1.20, 1.23); ORg = 1.02 (1.01, 1.03)), and low household income (ORo = 1.28 (1.26, 1.31); ORg = 1.02 (1.01, 1.03)). Approximately 62% of results were significant in the observational OWA but not the genetic OWA, including numerous cardiovascular outcomes. Only 6 outcomes were significant in the genetic OWA and null in the observational OWA; these included diastolic blood pressure and glaucoma. No outcomes were statistically significant in opposite directions in the two analyses, and 11% were not significant in either OWA. CONCLUSIONS: Our findings underscore the far-reaching negative effects of childhood maltreatment in later life and the utility of an outcome-wide triangulation design with sensitivity analyses for improving causal inference.

Post-traumatic stress disorder symptom remission and cognition in a large cohort of civilian women.

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with cognitive impairments. It is unclear whether problems persist after PTSD symptoms remit. METHODS: Data came from 12 270 trauma-exposed women in the Nurses' Health Study II. Trauma and PTSD symptoms were assessed using validated scales to determine PTSD status as of 2008 (trauma/no PTSD, remitted PTSD, unresolved PTSD) and symptom severity (lifetime and past-month). Starting in 2014, cognitive function was assessed using the Cogstate Brief Battery every 6 or 12 months for up to 24 months. PTSD associations with baseline cognition and longitudinal cognitive changes were estimated by covariate-adjusted linear regression and linear mixed-effects models, respectively. RESULTS: Compared to women with trauma/no PTSD, women with remitted PTSD symptoms had a similar cognitive function at baseline, while women with unresolved PTSD symptoms had worse psychomotor speed/attention and learning/working memory. In women with unresolved PTSD symptoms, past-month PTSD symptom severity was inversely associated with baseline cognition. Over follow-up, both women with remitted and unresolved PTSD symptoms in 2008, especially those with high levels of symptoms, had a faster decline in learning/working memory than women with trauma/no PTSD. In women with remitted PTSD symptoms, higher lifetime PTSD symptom severity was associated with a faster decline in learning/working memory. Results were robust to the adjustment for sociodemographic, biobehavioral, and health factors and were partially attenuated when adjusted for depression. CONCLUSION: Unresolved but not remitted PTSD was associated with worse cognitive function assessed six years later. Accelerated cognitive decline was observed among women with either unresolved or remitted PTSD symptoms.

Associations between health behaviours, fertility and reproductive outcomes: triangulation of evidence in the Norwegian Mother, Father and Child Cohort Study (MoBa).

BACKGROUND: Guidance to improve fertility includes reducing alcohol and caffeine consumption, achieving healthy weight-range and stopping smoking. Advice is informed by observational evidence, which is often biased by confounding. METHODS: This study primarily used data from a pregnancy cohort, the Norwegian Mother, Father and Child Cohort Study. First, we conducted multivariable regression of health behaviours (alcohol and caffeine consumption, body-mass index (BMI), and smoking) on fertility outcomes (e.g. time to conception) and reproductive outcomes (e.g. age at first birth) (n = 84,075 females, 68,002 males), adjusting for birth year, education and attention-deficit and hyperactive-impulsive (ADHD) traits. Second, we used individual-level Mendelian randomisation (MR) to explore possible causal effects of health behaviours on fertility/reproductive outcomes (n = 63,376 females, 45,460 males). Finally, we performed summary-level MR for available outcomes in UK Biobank (n = 91,462-1,232,091) and controlled for education and ADHD liability using multivariable MR. RESULTS: In multivariable regression analyses, higher BMI associated with fertility (longer time to conception, increased odds of infertility treatment and miscarriage), and smoking was associated with longer time to conception. In individual-level MR analyses, there was strong evidence for effects of smoking initiation and higher BMI on younger age at first birth, of higher BMI on increased time to conception, and weak evidence for effects of smoking initiation on increased time to conception. Age at first birth associations were replicated in summary-level MR analysis; however, effects attenuated using multivariable MR. CONCLUSIONS: Smoking behaviour and BMI showed the most consistent associations for increased time to conception and a younger age at first birth. Given that age at first birth and time to conception are positively correlated, this suggests that the mechanisms for reproductive outcomes are distinct to the mechanisms acting on fertility outcomes. Multivariable MR suggested that effects on age at first birth might be explained by underlying liability to ADHD and education.

Intimate Partner Violence, Mental Health Symptoms, and Modifiable Health Factors in Women During the COVID-19 Pandemic in the US.

Importance: During the COVID-19 pandemic, the prevalence and severity of intimate partner violence (IPV) increased. Associations between IPV and mental health symptoms and modifiable health factors early in the pandemic have yet to be explored. Objective: To prospectively investigate the association of IPV with greater risk of mental health symptoms and adverse health factors during the COVID-19 pandemic in 3 cohorts of female participants. Design, Setting, and Participants: This cohort study used observational data from 3 prospective, population-based, longitudinal cohorts in the US: the Nurses' Health Study II, Growing Up Today Study, and Nurses' Health Study 3. Data analyzed included baseline and follow-up survey responses about IPV experiences early in the pandemic (March-September 2020); mental health domains of depression, anxiety, and posttraumatic stress symptoms (PTSS); and modifiable health factors (May 2020-October 2021). Female participants (both health care professionals and non-health care workers) aged 21 to 60 years from the 3 cohorts were included in the full analytic sample. Exposures: Experience of IPV measured by the Relationship Assessment Tool and fear of partner. Main Outcomes and Measures: Mental health symptoms, including depression, anxiety, and PTSS, and modifiable health factors, including sleep duration, sleep quality, physical activity, alcohol use, and use of alcohol or other substances to cope with stress. Results: The full analytic sample included 13 597 female participants with a mean (SD) age of 44 (10.6) years. Accounting for sociodemographic factors and prepandemic mental health symptoms and correcting for multiple testing, experiencing IPV was associated with higher endorsement of depression (odds ratio [OR], 1.44; 95% CI, 1.38-1.50), anxiety (OR, 1.31; 95% CI, 1.26-1.36), and PTSS (OR, 1.22; 95% CI, 1.15-1.29) in random-effects meta-analyses across the 3 cohorts. The IPV experience was also associated with poorer sleep quality (OR, 1.21; 95% CI, 1.16-1.26), shorter sleep duration (OR, 1.13; 95% CI, 1.08-1.19), increased use of alcohol (OR, 1.10; 95% CI, 1.06-1.14), and use of alcohol or other substances to cope with stress (OR, 1.13; 95% CI, 1.08-1.18) across all cohorts as well as decreased physical activity (OR, 1.17; 95% CI, 1.09-1.26) in the Nurses' Health Study II only. Conclusions and Relevance: Results of the study showed that IPV experiences at the start of the pandemic were associated with worse mental health symptoms and modifiable health factors for female participants younger than 60 years. Screening and interventions for IPV and related health factors are needed to prevent severe, long-term health consequences.

Trauma, psychological distress and markers of systemic inflammation among US women: A longitudinal study.

BACKGROUND: Prior evidence links posttraumatic stress disorder (PTSD) and depression, separately, with chronic inflammation. However, whether effects are similar across each independently or potentiated when both are present is understudied. We evaluated combined measures of PTSD and depression in relation to inflammatory biomarker concentrations. METHODS: Data are from women (n's ranging 628-2797) in the Nurses' Health Study II. Trauma exposure, PTSD, and depression symptoms were ascertained using validated questionnaires. We examined (a) a continuous combined psychological distress score summing symptoms for PTSD and depression, and (b) a categorical cross-classified measure of trauma/PTSD symptoms/depressed mood status (reference group: no trauma or depressed mood). Three inflammatory biomarkers (C-reactive protein [CRP], interleukin-6 [IL-6], tumor necrosis factor alpha receptor 2 [TNFR2]) were assayed from at least one of two blood samples collected 10-16 years apart. We examined associations of our exposures with levels of each biomarker concentration (log-transformed and batch-corrected) as available across the two time points (cross-sectional analyses; CRP, IL-6 and TNFR2) and with rate of change in biomarkers across time (longitudinal analyses; CRP and IL-6) using separate linear mixed effects models. RESULTS: In sociodemographic-adjusted models accounting for trauma exposure, a one standard deviation increase in the continuous combined psychological distress score was associated with 10.2% (95% confidence interval (CI): 5.2-15.4%) higher CRP and 1.5% (95% CI: 0.5-2.5%) higher TNFR2 concentrations cross-sectionally. For the categorical exposure, women with trauma/PTSD symptoms/ depressed mood versus those with no trauma or depressed mood had 29.5% (95% CI: 13.3-47.9%) higher CRP and 13.1% (95% CI: 5.1-21.7%) higher IL-6 cross-sectionally. In longitudinal analysis, trauma/PTSD symptoms/depressed mood was associated with increasing CRP levels over time. CONCLUSIONS: High psychological distress levels with trauma exposure is associated with elevated inflammation and is a potential biologic pathway by which distress can impact development of inflammatory-related chronic diseases, such as cardiovascular disease. Considering multiple forms of distress in relation to these pathways may provide greater insight into who is at risk for biologic dysregulation and later susceptibility to chronic diseases.

Association of Posttraumatic Stress Disorder With Accelerated Cognitive Decline in Middle-aged Women.

Importance: Posttraumatic stress disorder (PTSD) has been hypothesized to lead to impaired cognitive function. However, no large-scale studies have assessed whether PTSD is prospectively associated with cognitive decline in middle-aged adults. Objective: To assess the association between PTSD and decline in cognitive function over time. Design, Setting, and Participants: This cohort study included participants from the Nurses' Health Study II, an ongoing longitudinal cohort study involving community-dwelling middle-aged female nurses residing in the US who had at least a 2-year nursing degree at the time of enrollment in 1989. The present study included 12 270 trauma-exposed women who were enrolled in the PTSD substudy of the Nurses' Health Study II and completed 1 to 5 cognitive assessments. Data were collected from March 1, 2008, to July 30, 2019. Exposures: Lifetime PTSD symptoms, assessed using a validated questionnaire between March 1, 2008, and February 28, 2010. Main Outcomes and Measures: The main outcome was evaluated using the Cogstate Brief Battery, a self-administered online cognitive battery. Cognitive function was measured by a psychomotor speed and attention composite score and a learning and working memory composite score. Women completed the Cogstate Brief Battery every 6 or 12 months (up to 24 months) from October 3, 2014, to July 30, 2019. Linear mixed-effects models were used to evaluate the association of PTSD symptoms with the rate of change in cognition over follow-up, considering a broad range of relevant covariates, including the presence of depression symptoms and history of clinician-diagnosed depression. The rate of cognitive change was adjusted for potential practice effects (ie, potential changes in test results that occur when a test is taken more than once) by including indicators for the number of previous tests taken. Results: Among 12 270 women, the mean (SD) age at the baseline cognitive assessment was 61.1 (4.6) years; 125 women (1.0%) were Asian, 75 (0.6%) were Black, 156 (1.3%) were Hispanic, 11 767 (95.9%) were non-Hispanic White, and 147 (1.2%) were of other race and/or ethnicity. A higher number of PTSD symptoms was associated with worse cognitive trajectories. Compared with women with no PTSD symptoms, women with the highest symptom level (6-7 symptoms) had a significantly worse rate of change in both learning and working memory (ß = -0.08 SD/y; 95% CI, -0.11 to -0.04 SD/y; P < .001) and psychomotor speed and attention (ß = -0.05 SD/y; 95% CI, -0.09 to -0.01 SD/y; P = .02), adjusted for demographic characteristics. Associations were unchanged when additionally adjusted for behavioral factors (eg, 6-7 symptoms in the analysis of learning and working memory: ß = -0.08 SD/y; 95% CI, -0.11 to -0.04 SD/y; P < .001) and health conditions (eg, 6-7 symptoms in the analysis of learning and working memory: ß = -0.08 SD/y; 95% CI, -0.11 to -0.04 SD/y; P < .001) and were partially attenuated but still evident when further adjusted for practice effects (eg, 6-7 symptoms in the analysis of learning and working memory: ß = -0.07 SD/y; 95% CI, -0.10 to -0.03 SD/y; P < .001) and comorbid depression (eg, 6-7 symptoms in the analysis of learning and working memory: ß = -0.07 SD/y; 95% CI, -0.11 to -0.03 SD/y; P < .001). Conclusions and Relevance: In this large-scale prospective cohort study, PTSD was associated with accelerated cognitive decline in middle-aged women, suggesting that earlier cognitive screening among women with PTSD may be warranted. Given that cognitive decline is strongly associated with subsequent Alzheimer disease and related dementias, better understanding of this association may be important to promote healthy aging.

Posttraumatic stress disorder symptoms and timing of menopause and gynecological surgery in the Nurses' Health Study II.

BACKGROUND: Earlier menopause, either natural or through gynecologic surgeries, has been associated with various negative health sequelae. While posttraumatic stress disorder (PTSD) has been linked to dysregulated biological processes, including reproductive system changes that could alter menopausal timing, little work has examined whether trauma and PTSD are associated with greater risk of early cessation of menses. METHODS: Data are from 46,639 women in the Nurses' Health Study II, a prospective cohort study of women followed for up to 26 years. Lifetime trauma and PTSD symptoms were assessed with the Brief Trauma Questionnaire and a PTSD symptom screener in 2008. Age at cessation of menses and reason for cessation of menses (i.e., natural menopause, gynecologic surgery including hysterectomy and/or bilateral salpingo-oophorectomy [BSO]) were assessed. Cox proportional hazards models estimated hazards ratios (HR) of cessation of menses (separately for naturally or surgically) associated with trauma alone or PTSD symptoms, relative to no trauma, adjusting for covariates. RESULTS: Trauma/PTSD status was associated with earlier cessation of menses due to surgery, but not natural menopause. Women with trauma exposure, low, and high PTSD symptoms had higher hazard of cessation of menses due to surgery relative to those with no trauma exposure (HRtrauma = 1.16, 95%CI 1.07-1.26; HRlow PTSD = 1.25, 95%CI 1.15-1.36; HRhigh PTSD = 1.29, 95%CI 1.17-1.42). Trauma exposure and PTSD symptoms were associated with similarly increased risk of hysterectomy and BSO surgeries. CONCLUSIONS: Women who experienced trauma and PTSD may be at elevated risk for common gynecological surgeries premenopausally, potentially due to increased clinical indications or gynecological conditions.

Sexual violence and hypertension risk in women: an interview with Rebecca Lawn.

Dr Rebecca Lawn is a Postdoctoral Research Fellow at the Harvard T.H. Chan School of Public Health. She gained a first-class BSc (hons) in Psychology from Newcastle University and received her PhD from the University of Bristol, where she worked between the School of Psychological Science and the Medical Research Council (MRC) Integrative Epidemiology Unit. Dr Lawn's PhD research applied Mendelian randomization to investigate causal relationships in evolutionary theories of development and behavior with a focus on life history theory (concentrating on age at menarche and age at first sexual intercourse) and the schizophrenia paradox. Her current research interests include the relation of trauma and post-traumatic stress disorder with health over the life course.

Sexual Violence and Risk of Hypertension in Women in the Nurses' Health Study II: A 7-Year Prospective Analysis.

Background Hypertension is a prevalent condition in women and an important modifiable risk factor for cardiovascular disease. Despite women's experiences of sexual violence being common, no prospective studies have examined lifetime sexual assault and workplace sexual harassment in relationship to hypertension in large civilian samples with extended follow-up. Here, we examined whether these experiences were prospectively associated with greater risk of developing hypertension over 7 years. Methods and Results Data are from a substudy of the Nurses' Health Study II and include women free of hypertension at the time of sexual assault and workplace sexual harassment assessment in 2008 (n=33 127). Hypertension was defined as self-reported doctor diagnosis or initiating antihypertensive medication use, assessed biennially through 2015. We performed Cox proportional hazards regression models to predict time to developing hypertension associated with sexual violence exposure, adjusting for relevant covariates. Over follow-up, 7096 women developed hypertension. Sexual assault and workplace sexual harassment were prevalent (23% and 12%, respectively; 6% of women experienced both). Compared with women with no exposure, women who experienced both sexual assault and workplace sexual harassment had the highest risk of developing hypertension (hazard ratio [HR], 1.21; 95% CI, 1.09-1.35), followed by women who experienced workplace sexual harassment (HR, 1.15; 95% CI, 1.05-1.25) and then by women who experienced sexual assault (HR, 1.11; 95% CI, 1.03-1.19), after adjusting for relevant covariates. Conclusions Sexual assault and workplace sexual harassment are prospectively associated with greater risk of hypertension. Reducing such violence is important in its own right and may also improve women's cardiovascular health.

The association of posttraumatic stress disorder, depression, and head injury with mid-life cognitive function in civilian women.

BACKGROUND: Despite evidence linking posttraumatic stress disorder (PTSD), depression, and head injury, separately, with worse cognitive performance, investigations of their combined effects on cognition are limited in civilian women. METHODS: The Cogstate Brief Battery assessment was administered in 10,681 women from the Nurses' Health Study II cohort, mean age 64.9 years (SD = 4.6). Psychological trauma, PTSD, depression, and head injury were assessed using online questionnaires. In this cross-sectional analysis, we used linear regression models to estimate mean differences in cognition by PTSD/depression status and stratified by history of head injury. RESULTS: History of head injury was prevalent (36%), and significantly more prevalent among women with PTSD and depression (57% of women with PTSD and depression, 21% of women with no psychological trauma or depression). Compared to having no psychological trauma or depression, having combined PTSD and depression was associated with worse performance on psychomotor speed/attention ( ß = -.15, p = .001) and learning/working memory ( ß = -.15, p < .001). The joint association of PTSD and depression on worse cognitive function was strongest among women with past head injury, particularly among those with multiple head injuries. CONCLUSIONS: Head injury, like PTSD and depression, was highly prevalent in this sample of civilian women. In combination, these factors were associated with poorer performance on cognitive tasks, a possible marker of future cognitive health. Head injury should be further explored in future studies of PTSD, depression and cognition in women.

Trauma, Post-Traumatic Stress Disorder, and Treatment Among Middle-Aged and Older Women in the Nurses' Health Study II.

OBJECTIVE: Trauma and post-traumatic stress disorder (PTSD) are common among women and associated with negative health outcomes across the life course. Relatively few studies, however, have examined the epidemiology of trauma, PTSD, and treatment among middle-aged and older civilian women, who are at elevated risk for adverse health outcomes. We aimed to characterize trauma, PTSD, and trauma-related treatment prevalence and correlates in a large cohort of middle-aged and older women. DESIGN: Cross-sectional, nested substudy within the Nurses' Health Study II cohort. SETTING: United States, 2018-2020. PARTICIPANTS: 33,327 current or former nurses, aged 53-74 years. MEASUREMENTS: 16-item modified version of the Brief Trauma Questionnaire; modified PTSD Checklist for the Diagnostic and Statistical Manual, Version 5. RESULTS: The majority (82.2%) of women reported one or more lifetime traumas. The most common trauma types were unexpected death of a loved one (44.9%) and interpersonal violence (43.5%). Almost 30% reported occupational (nursing-related) trauma. Among the trauma-exposed, 10.5% met criteria for lifetime PTSD and 1.5% had past-month PTSD. One-third of lifetime PTSD cases were due to interpersonal violence event types. One-third of women with lifetime PTSD-and nearly half of those with PTSD from a nursing-related trauma-reported never receiving trauma-related treatment. Women aged 65 years and older with PTSD were less likely to be in treatment than those aged less than 65 years. CONCLUSION: History of trauma and PTSD is prevalent in this population, and a treatment gap persists. Addressing this treatment gap is warranted, particularly among older women and those with nursing-related trauma.

Posttraumatic Stress Disorder and Likelihood of Hormone Therapy Use among Women in the Nurses' Health Study II: A 26-Year Prospective Analysis.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with higher risk of certain chronic diseases, including ovarian cancer, but underlying mechanisms remain unclear. Although prior work has linked menopausal hormone therapy (MHT) use with elevated ovarian cancer risk, little research considers PTSD to likelihood of MHT use. We examined whether PTSD was prospectively associated with greater likelihood of initiating MHT use over 26 years. METHODS: Using data from the Nurses' Health Study II, with trauma and PTSD (symptoms and onset date) assessed by screener in 2008 and MHT assessed via biennial survey (from 1989), we performed Cox proportional regression models with women contributing person-years from age 36 years. Relevant covariates were assessed at biennial surveys. We considered potential effect modification by race/ethnicity, age at baseline, and period (1989-2002 vs. 2003-2015). RESULTS: Over follow-up, 22,352 of 43,025 women reported initiating MHT use. For example, compared with women with no trauma, the HR for initiating MHT was 1.18 for those with trauma/1-3 PTSD symptoms [95% confidence interval (CI), 1.13-1.22] and 1.31 for those with trauma/4-7 PTSD symptoms (95% CI, 1.25-1.36; P trend < 0.001), adjusting for sociodemographic factors. Associations were maintained when adjusting for reproductive factors and health conditions. We found evidence of effect modification by age at baseline. CONCLUSIONS: Trauma and number of PTSD symptoms were associated with greater likelihood of initiating MHT use in a dose-response manner. IMPACT: MHT may be a pathway linking PTSD to altered chronic disease risk. It is important to understand why women with PTSD initiate MHT use.

The effects of age at menarche and first sexual intercourse on reproductive and behavioural outcomes: A Mendelian randomization study.

There is substantial variation in the timing of significant reproductive life events such as menarche and first sexual intercourse. Life history theory explains this variation as an adaptive response to an individual's environment and it is important to examine how traits within life history strategies affect each other. Here we applied Mendelian randomization (MR) methods to investigate whether there is a causal effect of variation in age at menarche and age at first sexual intercourse (markers or results of exposure to early life adversity) on outcomes related to reproduction, education and risky behaviour in UK Biobank (N = 114 883-181 255). Our results suggest that earlier age at menarche affects some traits that characterize life history strategies including earlier age at first and last birth, decreased educational attainment, and decreased age at leaving education (for example, we found evidence for a 0.26 year decrease in age at first birth per year decrease in age at menarche, 95% confidence interval: -0.34 to -0.17; p < 0.001). We find no clear evidence of effects of age at menarche on other outcomes, such as risk taking behaviour. Age at first sexual intercourse was also related to many life history outcomes, although there was evidence of horizontal pleiotropy which violates an assumption of MR and we therefore cannot infer causality from this analysis. Taken together, these results highlight how MR can be applied to test predictions of life history theory and to better understand determinants of health and social behaviour.

Identifying potential causal effects of age at menarche: a Mendelian randomization phenome-wide association study.

BACKGROUND: Age at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner. METHODS: We conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations. RESULTS: Of the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null. CONCLUSIONS: The genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available.

Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study.

BACKGROUND: Smoking prevalence is higher amongst individuals with schizophrenia and depression compared with the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS). METHODS: We conducted two-sample MR to explore the bi-directional effects of smoking on schizophrenia and depression. For smoking behaviour, we used (1) smoking initiation GWAS from the GSCAN consortium and (2) we conducted our own GWAS of lifetime smoking behaviour (which captures smoking duration, heaviness and cessation) in a sample of 462690 individuals from the UK Biobank. We validated this instrument using positive control outcomes (e.g. lung cancer). For schizophrenia and depression we used GWAS from the PGC consortium. RESULTS: There was strong evidence to suggest smoking is a risk factor for both schizophrenia (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.67-3.08, p < 0.001) and depression (OR 1.99, 95% CI 1.71-2.32, p < 0.001). Results were consistent across both lifetime smoking and smoking initiation. We found some evidence that genetic liability to depression increases smoking (ß = 0.091, 95% CI 0.027-0.155, p = 0.005) but evidence was mixed for schizophrenia (ß = 0.022, 95% CI 0.005-0.038, p = 0.009) with very weak evidence for an effect on smoking initiation. CONCLUSIONS: These findings suggest that the association between smoking, schizophrenia and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking on mental health.