Anwar Mulugeta

Background Many observational studies support light-to-moderate alcohol intake as potentially protective against premature death. We used a genetic approach to evaluate the linear and nonlinear relationships between alcohol consumption and mortality from different underlying causes. Methods We used data from 278 093 white-British UK Biobank participants, aged 37–73 years at recruitment and with data on alcohol intake, genetic variants, and mortality. Habitual alcohol consumption was instrumented by 94 variants. Linear Mendelian randomization (MR) analyses were conducted using five complementary approaches, and nonlinear MR analyses by the doubly-ranked method. Results There were 20 834 deaths during the follow-up (median 12.6 years). In conventional analysis, the association between alcohol consumption and mortality …

Background Ovarian cancer (OC) is commonly diagnosed among older women who have comorbidities. This hypothesis‐free phenome‐wide association study (PheWAS) aimed to identify comorbidities associated with OC, as well as traits that share a genetic architecture with OC. Methods We used data from 181,203 white British female UK Biobank participants and analysed OC and OC subtype‐specific genetic risk scores (OC‐GRS) for an association with 889 diseases and 43 other traits. We conducted PheWAS and colocalization analyses for individual variants to identify evidence for shared genetic architecture. Results The OC‐GRS was associated with 10 diseases, and the clear cell OC‐GRS was associated with five diseases at the FDR threshold (p = 5.6 × 10−4). Mendelian randomizaiton analysis (MR) provided robust evidence for the association of OC with higher risk of “secondary malignant …

BackgroundStudies on the pharmacogenomic of psychiatric drugs have slowly identified genetic variations that influence drug metabolism and treatment outcomes, including response, remission, and side effects. However, most of these studies predominantly entered on populations of European descent. As a result, there remains a significant knowledge gap pertaining to the extent of pharmacogenomic diversity among African populations and this raises a major question about the validity of translating the current evidence to enable pharmacogenomic genetic testing (PGx) for this population. The objective of this review was to appraise previous pharmacogenomic studies conducted in the African population, with a focus on psychiatric medications.MethodsA systematic search was conducted on PubMed, Scopus, and Web of Science to identify studies published in the English language from inception up to February 06, 2023. The primary outcomes were treatment response, remission, side effects, and drug metabolism in African patients with major psychiatric disorders, such as depression and schizophrenia. Conference papers, abstracts, or articles lacking full text were excluded. To ensure data accuracy, two reviewers independently performed data extraction using the PRISMA reporting guideline.ResultsThe review included 42 pharmacogenetics and pharmacogenomics studies that explored the genetic profiles of African psychiatric patients who received pharmacological therapy. While we found a limited number of studies, they provided strong evidence of pharmacogenomic diversity in African populations, highlighting the importance of …

MethodsA combination of machine learning and conventional statistical methods were used to identify predictors of low hippocampal volume. We run gradient boosting decision tree modelling including 2891 input features measured before magnetic resonance imaging assessments (median 9.2 years, range 4.2-13.8 years) using data from 42,152 dementia-free UK Biobank participants. Logistic regression analyses were run on 87 factors identified as important for prediction based on Shapley values. False discovery rate adjusted P-value< 0.05 was used to declare statistical significance.ResultsOlder age, male sex, greater height, and whole-body fat free mass were the main predictors of low hippocampal volume with the model also identifying associations with lung function and lifestyle factors including smoking, physical activity, and coffee intake (corrected P< 0.05 for all). Red blood cell count and several red blood cell indices such as haemoglobin concentration, mean corpuscular haemoglobin, mean corpuscular volume, mean reticulocyte volume, mean sphered cell volume, and red blood cell distribution width were among many biomarkers associated with low hippocampal volume.ConclusionLifestyles, physical measures, and biomarkers may affect hippocampal volume, with many of the characteristics potentially reflecting oxygen supply to the brain. Further studies are required to establish causality and clinical relevance of these findings.

Aims To evaluate associations of metabolic profiles and biomarkers with brain atrophy, lesions, and iron deposition to understand the early risk factors associated with dementia. Materials and methods Using data from 26 239 UK Biobank participants free from dementia and stroke, we assessed the associations of metabolic subgroups, derived using an artificial neural network approach (self‐organizing map), and 39 individual biomarkers with brain MRI measures: total brain volume (TBV), grey matter volume (GMV), white matter volume (WMV), hippocampal volume (HV), white matter hyperintensity (WMH) volume, and caudate iron deposition. Results In metabolic subgroup analyses, participants characterized by high triglycerides and liver enzymes showed the most adverse brain outcomes compared to the healthy reference subgroup with high‐density lipoprotein cholesterol and low body mass index (BMI …

Schizophrenia is a chronic debilitating psychiatric disorder with significant morbidity and mortality. In this study, we used information from 337,484 UK Biobank participants and performed PheWAS using schizophrenia genetic risk score on 1135 disease outcomes. Signals that passed the false discovery rate threshold were further analyzed for evidence on the causality of the association. We extended the analysis to 30 serum, four urine, and six neuroimaging biomarkers to identify biomarkers that could be affected by schizophrenia. Schizophrenia GRS was associated with 54 (39 distinct) disease outcomes including schizophrenia in the PheWAS analysis. Of these, a causal association were found with 10 distinct diseases in the MR analysis. Schizophrenia causally linked with higher odds of anxiety (OR = 1.41, 95%CI 1.12 to 1.21), bipolar disorder (OR = 1.52, 95%CI 1.36 to 1.70), major depressive disorder (OR = 1 …

Background An unfavourable lipid profile has been associated with the increased risk of dementia or Alzheimer’s disease in both observational and genetic studies1,2. However, it is challenging to investigate each serum lipid measure individually due to the high correlation between the lipid traits. We aimed to discover causal associations between genetically instrumented serum lipid measures (low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), triglycerides, apolipoprotein‐A1 (apoA) and apolipoprotein‐B (apoB)) and the risk of dementia. Method We conducted multivariable and univariable Mendelian randomisation (MR) analyses on 329,896 UK Biobank participants (age 37‐73 years) to examine the associations between each serum lipid measure and the risk of dementia. The multivariable approach allows us to assess the association of each lipid measure with the …

Objective In this Mendelian randomization (MR) study, the objective was to investigate the causal effect of metabolically different adiposity subtypes on osteoarthritis. Methods We performed 2‐sample MR using summary‐level data for osteoarthritis (10,083 cases and 40,425 controls) from a genome‐wide association using the UK Biobank, and for site‐specific osteoarthritis from the Arthritis Research UK Osteoarthritis Genetics consortium. We used 3 classes of genetic instruments, which all increase body mass index but are associated with different metabolic profiles (unfavorable, neutral, and favorable). Primary analysis was performed using inverse variance weight (IVW), with additional sensitivity analysis from different MR methods. We further applied a nonlinear MR using UK Biobank data to understand the nature of the adiposity–osteoarthritis relationship. Results Greater metabolically unfavorable and …

Background Cancer is a leading cause of morbidity and mortality worldwide, and better understanding of the risk factors could enhance prevention. Methods We conducted a hypothesis‐free analysis combining machine learning and statistical approaches to identify cancer risk factors from 2828 potential predictors captured at baseline. There were 459,169 UK Biobank participants free from cancer at baseline and 48,671 new cancer cases during the 10‐year follow‐up. Logistic regression models adjusted for age, sex, ethnicity, education, material deprivation, smoking, alcohol intake, body mass index and skin colour (as a proxy for sun sensitivity) were used for obtaining adjusted odds ratios, with continuous predictors presented using quintiles (Q). Results In addition to smoking, older age and male sex, positively associating features included several anthropometric characteristics, whole body water mass, pulse …

Background & aimsMilk consumption is a modifiable lifestyle factor that has been associated with several cancer types in observational studies. Limited evidence exists regarding the causality of these relationships. Using a genetic variant (rs4988235) near the lactase gene (LCT) locus that proxies milk consumption, we conducted a comprehensive survey to assess potential causal relationships between milk consumption and 12 types of cancer.MethodsOur analyses were conducted using white British participants of the UK Biobank (n = up to 255,196), the FinnGen cohort (up to 260,405), and available cancer consortia. We included cancers with previous evidence of an association with milk consumption in observational studies, as well as cancers common in both UK Biobank and FinnGen populations (>1000 cases). We evaluated phenotypic associations of milk intake and cancer incidence in the UK Biobank …

Aims Lipid‐lowering medications are widely used to control blood cholesterol levels and manage a range of cardiovascular and lipid disorders. We aimed to explore the possible associations between LDL lowering and multiple disease outcomes or biomarkers. Methods We performed a Mendelian randomization phenome‐wide association study (MR‐PheWAS) in 337 475 UK Biobank participants to test for associations between four proposed LDL‐C‐lowering genetic risk scores (PCSK9, HMGCR, NPC1L1 and LDLR) and 1135 disease outcomes, with follow‐up MR analyses in 52 serum, urine, imaging and clinical biomarkers. We used inverse‐variance weighted MR in the main analyses and complementary MR methods (weighted median, weighted mode, MR‐Egger and MR‐PRESSO) as sensitivity analyses. We accounted for multiple testing with false discovery rate correction (P < 2.0 × 10−4 for …

Background and aimsAnalyses to predict the risk of cancer typically focus on single biomarkers, which do not capture their complex interrelations. We hypothesized that the use of metabolic profiles may provide new insights into cancer prediction.MethodsWe used information from 290,888 UK Biobank participants aged 37 to 73 years at baseline. Metabolic subgroups were defined based on clustering of biochemical data using an artificial neural network approach and examined for their association with incident cancers identified through linkage to cancer registry. In addition, we evaluated associations between 38 individual biomarkers and cancer risk.ResultsIn total, 21,973 individuals developed cancer during the follow-up (median 3.87 years, interquartile range [IQR] = 2.03–5.58). Compared to the metabolically favorable subgroup (IV), subgroup III (defined as “high BMI, C-reactive protein & cystatin C") was …

Corrigendum to "Schizophrenia and co-morbidity risk: Evidence from a data driven phenomewide association study" [J. Psychiatr. Res. 162 (2023) 1-10] Corrigendum to "Schizophrenia and co-morbidity risk: Evidence from a data driven phenomewide association study" [J. Psychiatr. Res. 162 (2023) 1-10] J Psychiatr Res. 2023 Aug 12;165:344. doi: 10.1016/j.jpsychires.2023.08.001. Online ahead of print. Authors Anwar Mulugeta 1 , Vijayaprakash Suppiah 2 , Elina Hyppönen 3 Affiliations 1 Australian Centre for Precision Health, University of South Australia, Adelaide, Australia; Department of Pharmacology, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia. 2 Australian Centre for Precision Health, University of South Australia, Adelaide, Australia; Clinical and Health Sciences, University of South Australia, Adelaide, Australia. Electronic address: vijay.suppiah@unisa.edu.au. 3 Australian …

Hormone-related cancers, including cancers of the breast, prostate, ovaries, uterine, and thyroid, globally contribute to the majority of cancer incidence. We hypothesize that hormone-sensitive cancers share common genetic risk factors that have rarely been investigated by previous genomic studies of site-specific cancers. Here, we show that considering hormone-sensitive cancers as a single disease in the UK Biobank reveals shared genetic aetiology. We observe that a significant proportion of variance in disease liability is explained by the genome-wide single nucleotide polymorphisms (SNPs), i.e., SNP-based heritability on the liability scale is estimated as 10.06% (SE 0.70%). Moreover, we find 55 genome-wide significant SNPs for the disease, using a genome-wide association study. Pair-wise analysis also estimates positive genetic correlations between some pairs of hormone-sensitive cancers although …

We assigned 329,908 UK Biobank participants into six subgroups based on a self-organizing map of 51 biochemical measures (blinded for clinical outcomes). The subgroup with the most favorable metabolic traits was chosen as the reference. Hazard ratios (HR) for incident disease were modeled by Cox regression. Enrichment ratios (ER) of incident multi-morbidity versus randomly expected co-occurrence were evaluated by permutation tests; ER is like HR but captures co-occurrence rather than event frequency. The subgroup with high urinary excretion without kidney stress (HR = 1.24) and the subgroup with the highest apolipoprotein B and blood pressure (HR = 1.52) were associated with ischemic heart disease (IHD). The subgroup with kidney stress, high adiposity and inflammation was associated with IHD (HR = 2.11), cancer (HR = 1.29), dementia (HR = 1.70) and mortality (HR = 2.12). The …

Variation in genes involved in the absorption, distribution, metabolism, and excretion of drugs (ADME) can influence individual response to a therapeutic treatment. The study of ADME genetic diversity in human populations has led to evolutionary hypotheses of adaptation to distinct chemical environments. Population differentiation in measured drug metabolism phenotypes is, however, scarcely documented, often indirectly estimated via genotype-predicted phenotypes. We administered seven probe compounds devised to target six cytochrome P450 enzymes and the P-glycoprotein (P-gp) activity to assess phenotypic variation in four populations along a latitudinal transect spanning over Africa, the Middle East, and Europe (349 healthy Ethiopian, Omani, Greek, and Czech volunteers). We demonstrate significant population differentiation for all phenotypes except the one measuring CYP2D6 activity. Genome …

There has been an increased interest in health technology assessment and economic evaluations for health policy in Ethiopia over the last few years. In this systematic review, we examined the scope and quality of healthcare economic evaluation studies in Ethiopia. We searched seven electronic databases (PubMed/MEDLINE, EMBASE, PsycINFO, CINHAL, Econlit, York CRD databases and CEA Tufts) from inception to May 2021 to identify published full health economic evaluations of a health-related intervention or programme in Ethiopia. This was supplemented with forward and backward citation searches of included articles, manual search of key government websites, the Disease Control Priorities-Ethiopia project and WHO-CHOICE programme. The quality of reporting of economic evaluations was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist …

BackgroundCoffee is a highly popular beverage worldwide, containing caffeine which is a central nervous system stimulant.ObjectivesWe examined whether habitual coffee consumption is associated with differences in brain volumes or the odds of dementia or stroke.MethodsWe conducted prospective analyses of habitual coffee consumption on 398,646 UK Biobank participants (age 37–73 years), including 17,702 participants with MRI information. We examined the associations with brain volume using covariate adjusted linear regression, and with odds of dementia (4,333 incident cases) and stroke (6,181 incident cases) using logistic regression.ResultsThere were inverse linear associations between habitual coffee consumption and total brain (fully adjusted β per cup −1.42, 95% CI −1.89, −0.94), grey matter (β −0.91, 95% CI −1.20, −0.62), white matter (β −0.51, 95% CI −0.83, −0.19) and hippocampal volumes …

Genetic susceptibility and lifestyle affect the risk of dementia but there is little direct evidence for their associations with preclinical changes in brain structure. We investigated the association of genetic dementia risk and healthy lifestyle with brain morphometry, and whether effects from elevated genetic risk are modified by lifestyle changes. We used prospective data from up to 25,894 UK Biobank participants (median follow-up of 8.8 years), and defined healthy lifestyle according to American Heart Association criteria as BMI < 30, no smoking, healthy diet and regular physical activity). Higher genetic risk was associated with lower hippocampal volume (beta −0.16 cm3, 95% CI −0.22, −0.11) and total brain volume (−4.34 cm3, 95% CI −7.68, −1.01) in participants aged ≥60 years but not <60 years. Healthy lifestyle was associated with higher total brain, grey matter and hippocampal volumes, and lower volume of white matter hyperintensities, with no effect modification by age or genetic risk. In conclusion, adverse effects of high genetic risk on brain health were only found in older participants, while adhering to healthy lifestyle recommendations is beneficial regardless of age or genetic risk.

BackgroundHigher vitamin D status has been suggested to have beneficial effects on the brain.ObjectivesTo investigate the association between 25-hydroxyvitamin D [25(OH)D], neuroimaging features, and the risk of dementia and stroke.MethodsWe used prospective data from the UK Biobank (37–73 y at baseline) to examine the association between 25(OH)D concentrations with neuroimaging outcomes (N = 33,523) and the risk of dementia and stroke (N = 427,690; 3414 and 5339 incident cases, respectively). Observational analyses were adjusted for age, sex, ethnicity, month, center, and socioeconomic, lifestyle, sun behavior, and illness-related factors. Nonlinear Mendelian randomization (MR) analyses were used to test for underlying causality for neuroimaging outcomes (N = 23,901) and dementia and stroke (N = 294,514; 2399 and 3760 cases, respectively).ResultsAssociations between 25(OH)D and total …