Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease.

BACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included. RESULTS: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.

Associations between plasma fatty acid concentrations and schizophrenia: a two-sample Mendelian randomisation study.

BACKGROUND: Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia. METHODS: We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides. FINDINGS: Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75-0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98-1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58-0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02-1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71-1·01]). INTERPRETATION: Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia. FUNDING: National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.

Mendelian randomisation for nutritional psychiatry.

Nutritional psychiatry is a growing area of research, with several nutritional factors implicated in the cause of psychiatric ill-health. However, nutritional research is highly complex, with multiple potential factors involved, highly confounded exposures and small effect sizes for individual nutrients. This Personal View considers whether Mendelian randomisation provides a solution to these difficulties, by investigating causality in a low-risk and low-cost way. We reviewed studies using Mendelian randomisation in nutritional psychiatry, along with the potential opportunities and challenges of using this approach for investigating the causal effects of nutritional exposures. Several studies have identified nutritional exposures that are potentially causal by using Mendelian randomisation in psychiatry, offering opportunities for further mechanistic research, intervention development, and replication. The use of Mendelian randomisation as a foundation for intervention development facilitates the best use of resources in an emerging discipline in which opportunities are rich, but resources are often poor.

Effects of exposure to bodies of different sizes on perception of and satisfaction with own body size: two randomized studies.

Body dissatisfaction is prevalent among women and associated with subsequent obesity and eating disorders. Exposure to images of bodies of different sizes has been suggested to change the perception of 'normal' body size in others. We tested whether exposure to different-sized (otherwise identical) bodies changes perception of own and others' body size, satisfaction with body size and amount of chocolate consumed. In Study 1, 90 18-25-year-old women with normal BMI were randomized into one of three groups to complete a 15 min two-back task using photographs of women either of 'normal weight' (Body Mass Index (BMI) 22-23 kg m-2), or altered to appear either under- or over-weight. Study 2 was identical except the 96 participants had high baseline body dissatisfaction and were followed up after 24 h. We also conducted a mega-analysis combining both studies. Participants rated size of others' bodies, own size, and satisfaction with size pre- and post-task. Post-task ratings were compared between groups, adjusting for pre-task ratings. Participants exposed to over- or normal-weight images subsequently perceived others' bodies as smaller, in comparison to those shown underweight bodies (p < 0.001). They also perceived their own bodies as smaller (Study 1, p = 0.073; Study 2, p = 0.018; mega-analysis, p = 0.001), and felt more satisfied with their size (Study 1, p = 0.046; Study 2, p = 0.004; mega-analysis, p = 0.006). There were no differences in chocolate consumption. This study suggests that a move towards using images of women with a BMI in the healthy range in the media may help to reduce body dissatisfaction, and the associated risk of eating disorders.

Prevalence of Prenatal Depression Symptoms Among 2 Generations of Pregnant Mothers: The Avon Longitudinal Study of Parents and Children.

Importance: Depression during pregnancy (prenatal depression) is common and has important consequences for mother and child. Evidence suggests an increasing prevalence of depression, especially in young women. It is unknown whether this is reflected in an increasing prevalence of prenatal depression. Objective: To compare the prevalence of depression during pregnancy in today's young mothers with their mothers' generation. Design, Setting, and Participants: In a longitudinal cohort study, we compared prenatal depressive symptoms in 2 generations of women who participated in the Avon Longitudinal Study of Parents and Children. Participants were the original mothers (recruited when they were pregnant) and their female offspring, or female partners of male offspring, who became pregnant. Both groups were limited to the same age range (19-24 years). The first generation of pregnancies occurred in 1990 to 1992 (n = 2390) and the second in 2012 to 2016 (n = 180). In both generations, women were born in the same geographical area (southwest England). Main Outcomes and Measures: Depressed mood measured prenatally using the Edinburgh Postnatal Depression Scale in self-reported surveys in both generations. A score of 13 or greater on a scale of 0 to 30 indicated depressed mood. Results: Of 2390 pregnant women in the first generation who were included in analysis (mean [SD] age, 22.1 [2.5] years), 408 (17%) had high depressive symptom scores (≥13). Of 180 pregnant women in the second generation who were included in the analysis (mean [SD] age, 22.8 [1.3] years), 45 (25%) had high depressive symptom scores. Having high depressive symptom scores was more common in the second generation of young pregnant women than in their mothers' generation (relative risk, 1.51; 95% CI, 1.15-1.97), with imputation for missing confounding variable data and adjustment for age, parity, education, smoking, and body mass index not substantially changing this difference. Results were essentially the same when analyses were restricted to the 66 mother-offspring pairs. Maternal prenatal depression was associated with daughters' prenatal depression (relative risk, 3.33; 95% CI, 1.65-6.67). Conclusions and Relevance: In this unique study of 2 generations of women who answered identical questionnaires in pregnancy, evidence was found that depressed mood may be higher in young pregnant women today than in their mothers' generation. Because of the multiple and diverse consequences of prenatal depression, an increase in prevalence has important implications for families, health care professionals, and society.

Changing mothers' perception of infant emotion: a pilot study.

Cognitive bias modification (CBM) techniques, which experimentally retrain abnormal processing of affective stimuli, are becoming established for various psychiatric disorders. Such techniques have not yet been applied to maternal processing of infant emotion, which is affected by various psychiatric disorders. In a pilot study, mothers of children under 3 years old (n = 2) were recruited and randomly allocated to one of three training exercises, aiming either to increase or decrease their threshold of perceiving distress in a morphed continuum of 15 infant facial images. Differences between pre- and post-training threshold were analysed between and within subjects. Compared to baseline thresholds, the threshold for perceiving infant distress decreased in the lowered threshold group (mean difference -1.7 frames, 95 % confidence intervals (CI) -3.1 to -0.3, p = 0.02), increased in the raised threshold group (1.3 frames, 95 % CI 0.6 to 2.1, p < 0.01) and was unchanged in the control group (0.1 frames, 95 % CI -0.8 to 1.1, p = 0.80). Between-group differences were similarly robust in regression models and were not attenuated by potential confounders. The findings suggest that it is possible to change the threshold at which mothers perceive ambiguous infant faces as distressed, either to increase or decrease sensitivity to distress. This small study was intended to provide proof of concept (i.e. that it is possible to alter a mother's perception of infant distress). Questions remain as to whether the effects persist beyond the immediate experimental session, have an impact on maternal behaviour and could be used in clinical samples to improve maternal sensitivity and child outcomes.

Risk of depression and self-harm in teenagers identifying with goth subculture: a longitudinal cohort study.

BACKGROUND: Previous research has suggested that deliberate self-harm is associated with contemporary goth subculture in young people; however, whether this association is confounded by characteristics of young people, their families, and their circumstances is unclear. We aimed to test whether self-identification as a goth is prospectively associated with emergence of clinical depression and self-harm in early adulthood. METHODS: We used data from the Avon Longitudinal Study of Parents and Children, a UK community-based birth cohort of 14 541 pregnant women with expected delivery between April 1, 1991, and Dec 31, 1992. All children in the study were invited to attend yearly follow-up visits at the research clinic from age 7 years. At 15 years of age, participants reported the extent to which they self-identified as a goth. We assessed depressive mood and self-harm at 15 years with the Development and Wellbeing Assessment (DAWBA) questionnaire, and depression and self-harm at 18 years using the Clinical Interview Schedule-Revised. We calculated the prospective association between goth identification at 15 years and depression and self-harm at 18 years using logistic regression analyses. FINDINGS: Of 5357 participants who had data available for goth self-identification, 3694 individuals also had data for depression and self-harm outcomes at 18 years. 105 (6%) of 1841 adolescents who did not self-identify as goths met criteria for depression compared with 28 (18%) of 154 who identified as goths very much; for self-harm, the figures were 189 (10%) of 1841 versus 57 (37%) of 154. We noted a dose-response association with goth self-identification both for depression and for self-harm. Compared with young people who did not identify as a goth, those who somewhat identified as being a goth were 1·6 times more likely (unadjusted odds ratio [OR] 1·63, 95% CI 1·14-2·34, p<0·001), and those who very much identified as being a goth were more than three times more likely (unadjusted OR 3·67, 2·33-4·79, p<0·001) to have scores in the clinical range for depression at 18 years; findings were similar for self-harm. Associations were not attenuated after adjustment for a range of individual, family, and social confounders. INTERPRETATION: Our findings suggest that young people identifying with goth subculture might be at an increased risk for depression and self-harm. Although our results suggest that some peer contagion operates within the goth community, our observational findings cannot be used to claim that becoming a goth increases risk of self-harm or depression. Working with young people in the goth community to identify those at increased risk of depression and self-harm and provide support might be effective. FUNDING: Wellcome Trust, Medical Research Council Programme.

Association between early temperament and depression at 18 years.

BACKGROUND: Early childhood temperament, particularly negative emotionality (high tendency to show distress), may be a risk factor for subsequent depression. METHODS: Using data from a large UK cohort (Avon Longitudinal Study of Parents and Children), we examined the association between temperament on the Emotionality Activity Sociability Questionnaire at age 6 and ICD-10 depression at 18. Results were adjusted for a range of confounders. RESULTS: Children with high emotionality scores at age 6 had a 20% (7-36%) increase in the odds of being diagnosed with depression at age 18. CONCLUSIONS: Depression at 18 years has an early developmental diathesis, which means we may be able to identify children at risk of developing depression in young adulthood.

Cortisol awakening response and subsequent depression: prospective longitudinal study.

BACKGROUND: Some studies have found an association between elevated cortisol and subsequent depression, but findings are inconsistent. The cortisol awakening response may be a more stable measure of hypothalamic-pituitary-adrenal function and potentially of stress reactivity. AIMS: To investigate whether salivary cortisol, particularly the cortisol awakening response, is associated with subsequent depression in a large population cohort. METHOD: Young people (aged 15 years, n = 841) from the Avon Longitudinal Study of Parents and Children (ALSPAC) collected salivary cortisol at four time points for 3 school days. Logistic regression was used to calculate odds ratios for developing depression meeting ICD-10 criteria at 18 years. RESULTS: We found no evidence for an association between salivary cortisol and subsequent depression. Odds ratios for the cortisol awakening response were 1.24 per standard deviation (95% CI 0.93-1.66, P = 0.14) before and 1.12 (95% CI 0.73-1.72, P = 0.61) after adjustment for confounding factors. There was no evidence that the other cortisol measures, including cortisol at each time point, diurnal drop and area under the curve, were associated with subsequent depression. CONCLUSIONS: Our findings do not support the hypothesis that elevated salivary cortisol increases the short-term risk of subsequent depressive illness. The results suggest that if an association does exist, it is small and unlikely to be of clinical significance.