David Melzer

David Melzer
University of Exeter | UoE · Medical School

MBBCh, PhD

About

498
Publications
112,742
Reads
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32,668
Citations
Citations since 2017
139 Research Items
17035 Citations
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201720182019202020212022202305001,0001,5002,0002,5003,000
201720182019202020212022202305001,0001,5002,0002,5003,000
Additional affiliations
January 2005 - January 2012
University of Exeter
Position
  • Professor (Full)
October 1995 - December 2004
University of Cambridge
Position
  • Clinical Senior Research Associate

Publications

Publications (498)
Preprint
Full-text available
Background: The iron overload disorder hereditary haemochromatosis (HH) is primarily caused by the homozygous HFE p.C282Y variant, but the scale of excess related musculoskeletal morbidity is uncertain. Methods: We estimated HH-genotype associations with clinically diagnosed musculoskeletal outcomes and joint replacement surgeries in the UK Biobank...
Article
Background: Pharmacogenetic variants impact dihydropyridine calcium channel blockers (dCCB) (i.e. amlodipine) treatment efficacy, yet evidence on clinical outcomes in routine primary care is limited. Reported associations in PharmGKB have weak supporting evidence. We aimed to estimate associations between reported pharmacogenetic variants and inci...
Conference Paper
Background Hereditary haemochromatosis (HH) is a disorder of iron overload and is the most common genetic disorder of northern Europeans. HH is predominantly caused by the HFE p.C282Y genetic variant but also to a lesser extent by the p.H63D genetic variant. The UK has the second highest prevalence of this mutation worldwide, with or 1 in 150 being...
Conference Paper
Background There is no cure for dementia, so finding elements of care that make a difference to patients remains a priority. Treatment of patients with dementia is often complicated by additional medical conditions and they have double the risk of being prescribed inappropriate medication. Higher continuity of general practitioner care (CGPC), that...
Article
Background: In European ancestry populations, iron overload disorder Hereditary Hemochromatosis (HH) is predominantly caused by HFE p.C282Y and p.H63D mutations. Male p.C282Y homozygotes have markedly increased hepatic malignancy incidence but risks for other cancers in male and female homozygotes are unclear. Methods: 451,143 UK Biobank Europea...
Article
Full-text available
Background: The iron overload condition Hereditary Heamochromatosis (HH) can cause liver cirrhosis and cancer, diabetes and arthritis. Male HFE p.C282Y homozygotes have greatest risk, yet only a minority develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or liver disease risk in the general popu...
Preprint
Full-text available
Background Dihydropiridine calcium channel blockers (dCCB) (e.g. amlodipine) are widely used for treating hypertension. Pharmacogenetic variants impact treatment efficacy, yet evidence on clinical outcomes in routine primary care is limited. We aimed to estimate associations between reported pharmacogenetic variants and incident adverse events in a...
Preprint
Full-text available
Background The iron overload condition Hereditary Heamochromatosis (HH) can cause liver cirrhosis and cancer, diabetes and arthritis. In Europeans, most HH disease occurs in male HFE p.C282Y homozygotes, yet only a minority of homozygotes in the general population develop these conditions. We aimed to determine whether common genetic variants influ...
Preprint
Full-text available
In European ancestry populations, the iron overload disorder Hereditary Haemochromatosis (HH) is predominantly caused by the HFE p.C282Y mutation. Male p.C282Y homozygotes have markedly increased hepatic malignancy risks but risks for other cancers in both male and female homozygotes are unclear. We studied data from 451,143 UK Biobank European anc...
Article
Full-text available
Objective: To estimate the effect of rs4149056 (SLCO1B1*5) genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications. Methods and analysis: 69,185 European-ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40...
Article
Full-text available
Background Higher continuity of GP care (CGPC), that is, consulting the same doctor consistently, can improve doctor–patient relationships and increase quality of care; however, its effects on patients with dementia are mostly unknown. Aim To estimate the associations between CGPC and potentially inappropriate prescribing (PIP), and with the incid...
Article
Full-text available
Age and disease prevalence are the two biggest risk factors for COVID-19 symptom severity and death. We therefore hypothesized that increased biological age, beyond chronological age, may be driving disease-related trends in COVID-19 severity. Using the UK Biobank England data, we tested whether a biological age estimate (PhenoAge) measured more th...
Article
Full-text available
Age and disease prevalence are the two biggest risk factors for COVID-19 symptom severity and death. We therefore hypothesized that increased biological age, beyond chronological age, may be driving disease-related trends in COVID-19 severity. Using the UK Biobank England data, we tested whether a biological age estimate (PhenoAge) measured more th...
Article
Full-text available
Hospitalized COVID-19 patients tend to be older and frequently have hypertension, diabetes or CHD, but whether these co-morbidities are more common than in the general older population is unclear. We estimated associations between pre-existing diagnoses and hospitalized COVID-19 alone or with mortality (during the first COVID-19 outbreak, tests per...
Article
Full-text available
Objective To determine whether CYP2C19 loss-of-function (LoF) alleles increase risk of ischaemic stroke and myocardial infarction (MI) in UK primary care patients prescribed clopidogrel. Design Retrospective cohort analysis. Setting Primary care practices in the UK from January 1999 to September 2017. Participants 7483 European-ancestry adults f...
Preprint
Full-text available
Objective: To estimate the effect of the SLCO1B1*5 genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications. Methods and Analysis: 69,185 European-ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40 to 79 year...
Article
Full-text available
In this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the ‘genetically moderated treatment effect’ (GMTE). Whe...
Article
Full-text available
Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has be...
Article
People with Type 2 diabetes (T2D) are at high risk of many other long term conditions (LTC). These LTCs include Osteoarthritis, Alzheimer’s disease and Depression as well as cardiovascular conditions but the causes of these higher risks are uncertain and hard to study in trials or observational studies. We aimed to use a genetic approach to test th...
Preprint
Full-text available
In this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the `genetically mediated treatment effect' (GMTE). When...
Preprint
Full-text available
Background The antiplatelet drug clopidogrel is commonly prescribed for stroke and myocardial infarction (MI) prevention. Clopidogrel prodrug is predominantly activated by liver enzyme CYP2C19. CYP2C19 Loss-of-function (LoF) genetic variants have been linked to excess morbidity mainly in patients hospitalized for acute ischemic events and related i...
Article
Introduction During the COVID-19 pandemic, pre-existing dementia was associated with a 3x increase in risk of hospitalisation and (25.6%) of COVID-19 related deaths had dementia. However, it is unclear whether people living with dementia are at higher risk of COVID-19 due to dementia or whether there may be a biologically plausible link between dem...
Article
Background Older adults are at increased risk of COVID-19, resulting in public health shielding measures for all adults over 70 in the UK. Frailty has been proposed for risk stratification in COVID-19 with limited evidence. Cardiovascular risk factors hypertension, diabetes and raised BMI have been associated with increased COVID-19 risk. We sought...
Article
Background Age and disease prevalence are the two biggest risk factors for COVID-19 symptom severity and death. We therefore hypothesized that increased biological age, beyond chronological age, may be driving disease-related trends in COVID-19 severity. Methods Using the UK Biobank England data, we tested whether a biological age estimate (PhenoA...
Article
Full-text available
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n...
Article
Full-text available
Background: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. Objective: To estimated p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. Methods: UK...
Article
Full-text available
A few studies report that parental longevity is associated with faster gait speed, less memory decline, a lower risk of Alzheimer’s disease, and lower white matter hyperintensities. Data on structural neuroimaging correlates of parental longevity and its spatial distribution are limited. This study aims to examine relationships of parental longevit...
Article
Importance Hereditary hemochromatosis is predominantly caused by the HFE p.C282Y homozygous pathogenic variant. Liver carcinoma and mortality risks are increased in individuals with clinically diagnosed hereditary hemochromatosis, but risks are unclear in mostly undiagnosed p.C282Y homozygotes identified in community genotyping. Objective To estim...
Article
Full-text available
Background/objectives: Delirium is common in older adults, especially following hospitalization. Because low vitamin D levels may be associated with increased delirium risk, we aimed to determine the prognostic value of blood vitamin D levels, extending our previous genetic analyses of this relationship. Design: Prospective cohort analysis. Set...
Article
Importance: treatment of dementia in individuals with comorbidities is complex, leading to potentially inappropriate prescribing (PIP). The impact of PIP in this population is unknown. Objective: to estimate the rate of PIP and its effect on adverse health outcomes (AHO). Design: retrospective cohort. Setting: primary care electronic health...
Article
Full-text available
Background Hospitalized COVID-19 patients tend to be older and frequently have hypertension, diabetes or coronary heart disease (CHD), but whether these co-morbidities are true risk factors (i.e. more common than in the general older population) is unclear. We estimated associations between pre-existing diagnoses and hospitalized COVID-19 alone or...
Article
A few studies report that parental longevity is associated with preserved cognition and physical function and lower risk of Alzheimer’s disease. However, data on structural neuroimaging correlates of parental longevity and its spatial distribution are limited. This study aims to examine relationships of parental longevity with regional brain struct...
Preprint
Full-text available
With no known treatments or vaccine, COVID-19 presents a major threat, particularly to older adults, who account for the majority of severe illness and deaths. The age-related susceptibility is partly explained by increased comorbidities including dementia and type II diabetes. While it is unclear why these diseases predispose risk, we hypothesize...
Preprint
Full-text available
We previously reported that the ApoE e4e4 genotype was associated with COVID-19 test positivity (OR=2.31, 95% CI: 1.65 to 3.24, p=1.19×10 ⁻⁶ ) in the UK Biobank (UKB) cohort, during the epidemic peak in England, from March 16 to April 26, 2020. With more COVID-19 test results (March 16 to May 31, 2020) and mortality data (to April 26, 2020) linked...
Preprint
Full-text available
Importance: Brain iron deposition is common in dementia, but its causal significance is uncertain. The HFE p.C282Y homozygous mutation in European ancestry populations can lead to iron overload and hemochromatosis, mainly in males. Data on brain outcomes in homozygotes are scarce. Objective: To estimate HFE variant associations with MRI features pl...
Article
The Apolipoprotein E (APOE) e4 allele is associated with reduced longevity and increased Coronary Artery Disease (CAD) and Alzheimer's disease, with e4e4 having markedly larger effect sizes than e3e4. The e2 longevity promoting variant is less studied. We conducted a phenome-wide association study of ApoE e2e3 and e2e2 with aging phenotypes, to ass...
Preprint
Full-text available
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identified 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition:...
Preprint
Full-text available
The novel respiratory disease COVID-19 produces varying symptoms, with fever, cough, and shortness of breath being common. In older adults, we found that pre-existing dementia is a major risk factor (OR = 3.07, 95% CI: 1.71 to 5.50) for COVID-19 hospitalization in the UK Biobank (UKB). In another UK study of 16,749 patients hospitalized for COVID-1...
Preprint
Full-text available
Background: Older COVID-19 hospitalized patients frequently have hypertension, diabetes or coronary heart disease (CHD), but whether these are more common than in the population is unclear. During the initial epidemic in England, virus testing for older adults was restricted to symptomatic hospitalized patients. We aimed to estimate associations be...
Article
Full-text available
Importance: risk factors for delirium in hospital inpatients are well established, but less is known about whether delirium occurring in the community or during an emergency admission to hospital care might be predicted from routine primary-care records. Objectives: identify risk factors in primary-care electronic health records (PC-EHR) predict...
Article
Full-text available
Background: Blood pressure (BP) management in frail older people is challenging. An randomised controlled trial of largely non-frail older people found cardiovascular and mortality benefit with systolic (S) BP target <120 mmHg. However, all-cause mortality by attained BP in routine care in frail adults aged above 75 is unclear. Objectives: To es...
Preprint
Full-text available
The Apolipoprotein E (APOE) e4 allele is associated with reduced longevity and increased Coronary Heart disease (CHD) and Alzheimer's disease, with e4e4 having markedly larger effect sizes than e3e4. The e2 longevity promoting variant is less studied. We conducted a phenome-wide association study of ApoE e2e3 and e2e2 with aging phenotypes, to asse...
Article
Background Extensive work in basic and clinical science suggests that biological mechanisms of aging are causally related to the development of disease and disability in late life. Modulation of the biological mechanisms of aging can extend both life span and health span in animal models, but translation to humans has been slow. Methods Summary of...
Article
Full-text available
Frailty is an important and common geriatric syndrome, yet the mechanisms are multifactorial and not well understood. The Frailty Index (FI) is based on the Rockwood Index for accumulation of deficits, and we aimed to use genetics to gain mechanistic insights for interventions to prevent and delay frailty in older people. We performed a genomewide...
Article
Full-text available
Great progress has been made recently in identifying the genetic and likely biological mechanisms of aging traits in humans, thanks to the very large UK Biobank cohort of 500,000 persons. This symposium will discuss new results for known genetic loci influencing aging, including in-depth analysis of the APOE e2 “protective” allele and aging outcome...
Article
Full-text available
Thousands of loci across the genome have been identified for specific diseases in genome-wide association studies (GWAS), yet very few are associated with lifespan itself. We hypothesized that specific biological pathways transcend individual diseases and affect health and lifespan more broadly. Using the published results for the most recent GWAS...
Article
Full-text available
ApoeE2 (e2) has both protective and adverse effects on health outcomes, which needs to be considered when targeting e2. We aimed to understand the role of e2 in aging via associations between e2 and a selection of aging traits using UK older adults of European descent. e2e3 (n=32,262) and e2e2 (n=1,629) were compared to e3e3 (n=153,567), adjusted f...
Article
Full-text available
Genetic variants associated with multiple traits are potential targets to delay aging. Drugs supported by genetic evidence are twice as likely to succeed in human trials. Single nucleotide polymorphisms (SNPs) in the ABO gene were reported by genome-wide associations studies, associated with breast cancer, coronary artery disease, stroke, and type...
Article
Full-text available
Dynapenia or muscle weakness is a core feature of sarcopenia and frailty, and leads to significant functional impairment in older adults. We aimed to identify genetic variants associated with dynapenia in older adults, to shed light on the underlying mechanisms. A large-scale meta-analysis of >250,000 volunteers of European descent from 16 cohorts...
Article
The past two centuries have witnessed an unprecedented rise in human life expectancy. Sustaining longer lives with reduced periods of disability will require an understanding of the underlying mechanisms of ageing, and genetics is a powerful tool for identifying these mechanisms. Large-scale genome-wide association studies have recently identified...
Article
Full-text available
Dysregulation of splicing factor expression is emerging as a driver of human ageing; levels of transcripts encoding splicing regulators have previously been implicated in ageing and cellular senescence both in vitro and in vivo. We measured the expression levels of an a priori panel of 20 age- or senescence-associated splicing factors by qRT-PCR in...
Preprint
Full-text available
Frailty is a common geriatric syndrome, strongly associated with disability, mortality and hospitalisation. The mechanisms underlying frailty are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 19 and 45%. Understanding the genetic determinants and biological mechanisms underpinning...
Article
We read with interest the recent study by Sabia et al. showing that adherence to Life’s Simple 7 ideal cardiovascular health recommendations in midlife (age 50 years) was associated with a lower dementia risk in later life, with a 1 point increment in the cardiovascular health score being associated with an 11% reduction in dementia risk. Our simil...
Conference Paper
Full-text available
Background Hereditary haemochromatosis (HH) is the most common and probably the most treatable genetic disorder in Europe, but many patients are misdiagnosed or diagnosed too late. HH causes iron overload and is predominantly due to the HFE p.C282Y genetic variant. HH is easily prevented and treated with phlebotomy. We aimed to test HFE p.C282Y hom...
Article
Human SH2B3 is involved in growth factor and inflammation signaling. A SH2B3 missense variant (rs3184504) is associated with cardiovascular diseases plus breast, colorectal and lung cancers, with highly correlated variants across the ATXN2/SH2B3/BRAP locus linked to parental age at death, suggesting a geroscience common mechanism of aging and disea...
Article
Full-text available
Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging-related health outcomes in a large European ancest...
Article
Background Whereas the independent effects of biomarkers, including vitamin D (25(OH)D), insulin-like growth factor 1 (IGF-1), C-reactive protein (CRP) and interleukin 6 (IL-6), on gait speed in older adults have been evaluated, their joint effects on gait speed are not well understood. Methods Study subjects aged ≥ 65 at baseline (N = 970) were e...
Article
Full-text available
Background overweight or obesity at ages <65 years associates with increased dementia incidence, but at ≥65 years estimates are paradoxical. Weight loss before dementia diagnosis, plus smoking and diseases causing weight loss may confound associations. Objective to estimate weight loss before dementia diagnosis, plus short and longer-term body mas...
Article
Full-text available
Background: in chronic kidney disease (CKD), hypertension is associated with poor outcomes at ages <70 years. At older ages, this association is unclear. We tested 10-year mortality and cardiovascular outcomes by clinical systolic blood pressure (SBP) in older CKD Stages 3 and 4 patients without diabetes or proteinuria. Methods: retrospective co...
Article
Full-text available
Background Aging is characterized by chronic inflammation plus muscle mass and strength loss, termed sarcopenia. Human Leukocyte Antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants associate...
Article
Full-text available
Objective: To estimate effects of vitamin D levels on incident delirium hospital admissions using inherited genetic variants in mendelian randomization models, which minimize confounding and exclude reverse causation. Methods: Longitudinal analysis using the UK Biobank, community-based, volunteer cohort (2006-2010) with incident hospital-diagnos...
Article
Full-text available
Background Iron is essential for life but contributes to oxidative damage. In Northern-European ancestry populations, HFE gene C282Y mutations are relatively common (0.3%–0.6% rare homozygote prevalence) and associated with excessive iron absorption, fatigue, diabetes, arthritis, and liver disease, especially in men. Iron excess can be prevented or...