The three main alleles of the APOE gene (ε4, ε3 and ε2) carry differential risks for conditions including Alzheimer's disease (AD) and cardiovascular disease. Due to their clinical significance, we explored disease associations of the APOE genotypes using a hypothesis-free, data-driven, phenome-wide association study (PheWAS) approach. We used data from the UK Biobank to screen for associations between APOE genotypes and over 950 disease outcomes using genotype ε3ε3 as a reference. Data was restricted to 337,484 white British participants (aged 37–73 years). After correction for multiple testing, PheWAS analyses identified associations with 37 outcomes, representing 18 distinct diseases. As expected, ε3ε4 and ε4ε4 genotypes associated with increased odds of AD (p ≤ 7.6 × 10−46), hypercholesterolaemia (p ≤ 7.1 × 10−17) and ischaemic heart disease (p ≤ 2.3 × 10−4), while ε2ε3 provided protection for the latter two conditions (p ≤ 3.7 × 10−10) compared to ε3ε3. In contrast, ε4-associated disease protection was seen against obesity, chronic airway obstruction, type 2 diabetes, gallbladder disease, and liver disease (all p ≤ 5.2 × 10−4) while ε2ε2 homozygosity increased risks of peripheral vascular disease, thromboembolism, arterial aneurysm, peptic ulcer, cervical disorders, and hallux valgus (all p ≤ 6.1 × 10−4). Sensitivity analyses using brain neuroimaging, blood biochemistry, anthropometric, and spirometric biomarkers supported the PheWAS findings on APOE associations with respective disease outcomes. PheWAS confirms strong associations between APOE and AD, hypercholesterolaemia, and ischaemic heart disease, and suggests potential ε4-associated disease protection and harmful effects of the ε2ε2 genotype, for several conditions. National Health and Medical Research Council of Australia.

Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women. We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to ‘uncouple’ the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways. Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m²) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P < 0.05. Using a metabolically favourable adiposity genetic risk score, and meta-analysing data from the UK biobank and PGC, a genetically determined 1 SD higher BMI (4.9 kg/m²) was associated with higher odds of depression in all individuals (OR: 1.26, 95% CI: 1.06, 1.50], P = 0.010), but with weaker statistical confidence. Higher BMI, with and without its adverse metabolic consequences, is likely to have a causal role in determining the likelihood of an individual developing depression.

Mendelian randomisation allows for the testing of causal effects in situations where clinical trials are challenging to do. In this hypothesis-free, data-driven phenome-wide association study (PheWAS), we sought to assess possible associations of high body-mass index (BMI) with multiple disease outcomes. For this registry-based case-control PheWAS, we used genome-wide data available from the UK Biobank to construct a genetic risk score of 76 variants related to BMI. Eligible UK Biobank participants were aged 37-73 years during recruitment, were white British, were unrelated to each other, and had available genetic information. Disease outcomes from these participants were mapped to a phenotype code (phecode). Participants with a phecode of interest were recoded as cases, whereas participants without a phecode of interest or any codes under a parent phecode were classified as controls. We did a PheWAS to analyse possible associations between the BMI genetic risk score and a range of disease outcomes. Disease associations passing stringent correction for multiple testing (Bonferroni corrected threshold p<5·4 × 10^-5, false discovery rate corrected p<0·0074) were assessed for causal association with use of inverse-variance weighted mendelian randomisation. We did sensitivity analyses to assess pleiotropy and stability of estimation with use of weighted median, weighted mode, Egger regression, and mendelian randomisation pleiotropy residual sum and outlier methods. Our study population comprised 337 536 UK Biobank participants, and analyses were done for 925 unique phecodes from 17 different disease categories. After Bonferroni correction, PheWAS identified that BMI genetic risk score was associated with hospital-diagnosed obesity and 58 other outcomes; 30 distinct disease associations were supported by the mendelian randomisation analyses. 30 distinct disease associations were supported by the mendelian randomisation analyses. In inverse-variance weighted mendelian randomisation, genetically determined BMI was associated with endocrine disorders (odds ratio per one SD or 4·1 kg/m² higher BMI 2·72, 95% CI 2·33-3·29 for type 2 diabetes; 2·11, 1·62-2·76 for type 1 diabetes; and 1·46, 1·25-1·70 for hypothyroidism), circulatory diseases (1·96, 1·53-2·51 for phlebitis and thrombophlebitis; 1·89, 1·39-2·57 for cardiomegaly; 1·68, 1·35-2·09 for congestive heart failure; 1·55, 1·37-1·76 for hypertension; 1·31, 1·13-1·52 for ischaemic heart disease; and 1·25, 1·14-1·37 for cardiac dysrhythmias), and inflammatory or dermatological conditions (2·00, 1·72-2·23 for superficial cellulitis and abscess; 3·37, 2·17-5·25 for chronic ulcers of leg and foot; 4·99, 2·54-9·82 for gangrene; and 2·24, 1·53-3·28 for atopy). Mendelian randomisation analyses provided further support for a causal effect of BMI on renal failure, osteoarthrosis, neurological (insomnia and peripheral nerve disorders) and respiratory diseases (asthma and chronic bronchitis), structural problems (hernias and knee derangement), and chemotherapy treatment. Mendelian randomisation with Egger regression produced consistently wider CIs compared with those of other methods. 26 of 72 distinct diseases detected under false discovery rate correction produced consistent estimates across at least four mendelian randomisation methods, and consistent evidence across all five approaches was obtained for 14 diseases. Our data-driven approach identified a range of diseases as possibly affected by high BMI. This population-level screening approximated the accumulated consequences of high BMI, whereas the true effects might be more complex and vary by life stage. Our results highlight the importance of obesity prevention and effective management of obesity-related comorbidities. National Health and Medical Research Council of Australia.

About one-third of the world’s population lack access to essential medicines and this is further compounded by inappropriate prescription, dispensing, sale and use of the available medicines. The objective of the study was to assess the patterns of medicine use among health facilities in eastern Ethiopia using World Health Organization’s Prescribing, Patient Care and Health facility indicators. A cross sectional study was carried out in eight randomly selected health centers and data were collected retrospectively as well as prospectively. Prescribing indicators were assessed retrospectively using 636 prescriptions selected by systematic random sampling technique among prescriptions filled between September 2013 and September 2014. Patient care indicators were assessed prospectively by interviewing 708 patients from the health facilities. Health facilities were assessed through observation. Data were entered and analyzed using Statistical Packages for Social Sciences version 20. P-value less than 0.05 at 95 % confidence interval considered for significance of relationships for associations in statistical tests. The average number of medicines per prescription was 2.2 with standard deviation of 0.8. The proportion of medicines prescribed by generic name was 97 and 92 % of the prescribed medicines were included in List of Essential Medicines for Ethiopia, Prescriptions containing antibiotics and injections constituted (82.5 and 11.2 %) respectively. Of the total of 1426 medicines prescribed, 49.6 % were antibiotics, with amoxicillin (33.3 %) and co-trimoxazole (16.0 %) being the most commonly prescribed agents. The average consultation and dispensing times were 5.6 and 2.7 min, respectively. Among the medicines dispensed, 64.0 % were adequately labeled and the proportion of patients with adequate knowledge about medicines was 69 %. The prescribing and dispensing practices in the health facilities are fairly good and are not that far from the standard WHO requirements. However, there is a need to do more on some issues, including prescribing practice of antibiotics, average number of medicines per prescription, and patients’ dosage form knowledge.

Obesity and depression are both highly prevalent public health disorders and evidence on their relationship is inconsistent. This study examined whether depressive symptoms are associated with current obesity, and further, whether obesity in turn is associated with an increased odds of depressive symptoms five years later after accounting for potential lifestyle confounders and depressive symptoms at baseline. Data were obtained from the 1958 British birth cohort (N = 9217 for cross-sectional and 7340 for prospective analysis). Clinical Interview Schedule-Revised and Mental Health Inventory-5 were used for screening depressive symptoms at ages 45 and 50 years, respectively. General and central obesity were defined using measurements of body mass index (BMI) and waist circumference (WC) at 45 years, respectively. There was a cross-sectional association between depressive symptoms and obesity: participants with ≥2 depressive symptoms had 31% (95%CI 11% to 55%) higher odds of general and 26% higher odds of central obesity (95%CI 8% to 47%). In prospective analyses, both general and central obesity were associated with higher odds of depressive symptoms five years later among women but not in men (Pinteraction < 0.01). After adjustment for depressive symptoms at baseline, sociodemographic and lifestyle factors, women with general obesity had 38% (95% CI 7% to 77%) and women with central obesity 34% (95%CI 9% to 65%) higher odds of depression compared to others. Depressive symptoms are associated with concurrent obesity and related lifestyle factors among women and men in mid-life. Our study suggests that obesity in turn affects long-term risk of depressive symptoms in women but not in men, independently of concurrent associations, providing an important target group for the implementation of preventative strategies.