Alison Murray

• MBChB, MRCP, FRCR, FRCP, PhD
• Professor at University of Aberdeen

Introduction: Greater late-life brain volumes are associated with resilience against dementia. We examined relationships between birth weight, lifelong socio-economic status, and health with late-life brain volumes. We hypothesised that early life factors directly affect late-life brain volumes. Methods: Adults aged 59-67 y underwent MRI and bra...

Background Alzheimer’s Disease (AD) frequently coexist with cerebrovascular disease (CVD) and makes it difficult for researchers to delineate the two pathologies with available diagnostic criteria. Neuroimaging techniques, especially FDG‐PET can help differentiate the two pathologies based on the characteristic temporo‐parietal metabolic deficitsin...

Objectives To determine factors influencing reader agreement in breast screening and investigate the relationship between agreement level and patient outcomes. Methods Reader pair agreement for 83 265 sets of mammograms from the Scottish Breast Screening service (2015-2020) was evaluated using Cohen’s kappa statistic. Each mammography examination...

Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector ge...

Preserved late-life brain volume is associated with resilience to dementia. We examined relationships between birthweight, socioeconomic status and adult health with late-life brain volumes. We hypothesised that early-life factors have direct and indirect effects on the aging brain. Neurotypical adults aged 61-67y underwent MRI and brain volumes me...

Background Multiple brain imaging studies of negative emotional bias in major depressive disorder (MDD) have used images of fearful facial expressions and focused on the amygdala and the prefrontal cortex. The results have, however, been inconsistent, potentially due to small sample sizes (typically N < 50). It remains unclear if any alterations ar...

Artificial intelligence (AI) tools may assist breast screening mammography programs, but limited evidence supports their generalizability to new settings. This retrospective study used a 3-year dataset (April 1, 2016-March 31, 2019) from a U.K. regional screening program. The performance of a commercially available breast screening AI algorithm was...

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 di...

Introduction Childhood trauma and adversity are common across societies and have strong associations with physical and psychiatric morbidity throughout the life-course. One possible mechanism through which childhood trauma may predispose individuals to poor psychiatric outcomes is via associations with brain structure. This study aimed to elucidate...

Objectives This study surveyed the views of breast screening readers in the UK on how to incorporate Artificial Intelligence (AI) technology into breast screening mammography. Methods An online questionnaire was circulated to the UK breast screening readers. Questions included their degree of approval of four AI implementation scenarios: AI as tri...

Background DNA methylation is an epigenetic mark associated with the repression of gene promoters. Its pattern in the genome is disrupted with age and these changes can be used to statistically predict age with epigenetic clocks. Altered rates of aging inferred from these clocks are observed in human disease. However, the molecular mechanisms under...

Background Major depressive disorder (MDD) was previously associated with negative affective biases. Evidence from larger population-based studies, however, is lacking, including whether biases normalise with remission. We investigated associations between affective bias measures and depressive symptom severity across a large community-based sample...

Introduction Vascular risk factors including hypertension, diabetes and dyslipidaemia promote diverse pathological mechanisms in the brain leading to cerebral hypoperfusion and ultimately cognitive decline in people. Medial temporal, medial frontal and anterior cingulate atrophy has been closely associated with diabetes and medial temporal lobe atr...

Changes in brain morphology have been reported during development, ageing and in relation to different pathologies. Brain morphology described by the shape complexity of gyri and sulci can be captured and quantified using fractal dimension (FD). This measure of brain structural complexity, as well as brain volume, are associated with intelligence,...

Study question What is the penetrance of variants in previously reported genes for premature ovarian insufficiency (POI) in the general population? Summary answer Heterozygous genetic variants in previously reported monogenic genes are not a common, highly penetrant cause of POI. What is known already Premature ovarian insufficiency (POI), define...

Background Fatigue is a common and burdensome symptom in Rheumatoid Arthritis (RA), yet is poorly understood. Currently, clinicians rely solely on fatigue questionnaires, which are inherently subjective measures. For the effective development of future therapies and stratification, it is of vital importance to identify biomarkers of fatigue. In thi...

Introduction Childhood trauma and adversity are common across societies and have strong associations with physical and psychiatric morbidity throughout the life-course. One mechanism through which childhood trauma may predispose individuals to poor psychiatric outcomes, such as raised risk of lifetime depression, could be via associations with brai...

Background: Radiomics is the high throughput analysis of medical images using computer algorithms, which specifically assess textural features. It has increasingly been proposed as a tool for the development of imaging biomarkers. However, an important acknowledged limitation of radiomics is the lack of reproducibility of features produced. Purpo...

The Aberdeen birth cohorts of 1921 and 1936 (ABC21 and ABC36) were subjected to IQ tests in 1932 or 1947 when they were aged about 11y. They were recruited between 1997–2001 among cognitively healthy community residents and comprehensively phenotyped in a long-term study of brain aging and health up to 2017. Here, we report associations between bas...

Introduction Haemoglobin concentrations decrease with age. Abnormally low and high haemoglobin concentrations are associated with reduced cognition; however, the evidence for these associations in cohort data is limited. This study aims to assess the relationship between haemoglobin concentration and cognition in a well-characterised cohort of olde...

Background: Crossed cerebellar diaschisis (CCD) is characterized by hypometabolism and hypoperfusion on molecular imaging in the cerebellum due to a supratentorial lesion on the contralateral side. CCD is a well-established phenomenon in acute or subacute conditions such as infarction but it has been less well described in chronic conditions such...

Background Blood-based markers of cognitive functioning might provide an accessible way to track neurodegeneration years prior to clinical manifestation of cognitive impairment and dementia. Results Using blood-based epigenome-wide analyses of general cognitive function, we show that individual differences in DNA methylation (DNAm) explain 35.0% o...

Background: Major Depressive Disorder (MDD) is associated with negative affective cognitive biases. Differences on population level however remain unclear, including whether they normalise with remission. This study investigated associations between affective cognition and MDD within a large community-based sample.Methods: Participants from Generat...

The behavioural variant of frontotemporal dementia is a clinical syndrome characterised by changes in behaviour, cognition and functional ability. Although atrophy in frontal and temporal regions would appear to be a defining feature, neuroimaging studies have identified volumetric differences distributed across large parts of the cortex, giving ri...

A complex interplay of genetic and environmental risk factors influence global brain structural alterations associated with brain health and disease. Epigenome-wide association studies (EWAS) of global brain imaging phenotypes have the potential to reveal the mechanisms of brain health and disease and can lead to better predictive analytics through...

Background Fatigue is a common and burdensome symptom in Rheumatoid Arthritis (RA), yet is poorly understood. Currently, clinicians rely solely on fatigue questionnaires, which are inherently subjective measures. For the effective development of future therapies and stratification, it is of vital importance to identify biomarkers of fatigue. In thi...

Development of cerebral small vessel disease, a major cause of stroke and dementia, may be influenced by early life factors. It is unclear whether these relationships are independent of each other, of adult socioeconomic status or of vascular risk factor exposures. We examined associations between factors from birth (ponderal index, birth weight),...

Development of cerebral small vessel disease (SVD), a major cause of stroke and dementia, may be influenced by early life factors. It is unclear whether these relationships are independent of each other, of adult socioeconomic status (SES) or of vascular risk factor exposures. We examined associations between factors from birth (ponderal index, bir...

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We...

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of Europe...

There is increasing interest in using data-driven unsupervised methods to identify structural underpinnings of common mental illnesses, including Major Depressive Disorder (MDD) and associated traits such as cognition. However, studies are often limited to severe clinical cases with small sample sizes and most do not include replication. Here, we e...

Alcohol use and smoking are leading causes of death and disability worldwide. Both genetic and environmental factors have been shown to influence individual differences in the use of these substances. In the present study we tested whether genetic factors, modelled alongside common family environment, explained phenotypic variance in alcohol use an...

STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS pro...

DNA methylation is an epigenetic mark associated with gene repression and genome stability. Its pattern in the genome is disrupted with age and these changes can be used to statistically predict age with epigenetic clocks. Rates of aging inferred from these clocks correlate with human health. However, the molecular mechanisms underpinning age-assoc...

Objectives Positron emission tomography–magnetic resonance imaging (PET/MRI) is an emerging hybrid imaging system in clinical nuclear medicine. Research demonstrates a comparative utility to current unimodal and hybrid methods, including PET-computed tomography (PET/CT), in several medical subspecialities such as neuroimaging. The aim of this revie...

Using blood-based epigenome-wide analyses of general cognitive function (g; n=9,162) we show that individual differences in DNA methylation (DNAm) explain 35.0% of the variance in g. A DNAm predictor explains ~4% of the variance in g, independently of a polygenic score, in two external cohorts. It also associates with circulating levels of neurolog...

A Correction to this paper has been published: https://doi.org/10.1038/s41588-021-00832-z.

Alzheimer's disease (AD) is the most common cause of dementia and accounts for approximately 50% to 80% of all cases of dementia. The diagnosis of probable AD is based on clinical criteria and overlapping clinical features pose a challenge to accurate diagnosis. However, neuroimaging has been included as a biomarker in various published criteria fo...

Epigenetic imprinting is important for neurogenesis and brain function. Hippocampal volumes and brain hyperintensities in late life have been associated with early life circumstances. Epigenetic imprinting may underpin these associations. Methylation was measured at 982 sites in 13 imprinted locations in blood samples from a longitudinal cohort by...

Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ~200,000 women of European ancestry...

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10⁻⁸), of which 32 were in new BP-associated loci...

Background Reduced cortical structural properties are recognised as potential imaging marker for neurodegenerative disorders. However, networks of correlated fluctuations in cortical structural properties in Alzheimer’s disease (AD) and behavioural variant frontotemporal dementia (bvFTD) have remained elusive. Here, we set out to investigate organi...

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci...

Objective: The successful creation and evaluation of AI solutions in healthcare depends on two main factors; access to large validated datasets, and the safe, well governed, and anonymised storage of that data. Most epidemiological studies depend on access to such data, however, with the recent advances in computing power and the emergence of AI,...

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We presen...

Background Our understanding of the potential harm of taking multiple medications in older, multi-morbid populations is limited. We aimed to investigate the prevalence of polypharmacy and its association with hospitalisation in a large cohort with linked health data. Methods Prescription data and hospital admission records of the Aberdeen Children...

Background The Aberdeen Children of the 1950s (ACONF) cohort comprises 12,150 people born in Scotland in the 50s. It contains rich early life data, questionnaire data from mid-life and linked electronic health records. Involving participants in designing future data collection is key to ensure research is acceptable and reflects public priorities....

Background Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods We constructed a polygenic risk score using a genome-wide assoc...

Major depressive disorder (MDD) has been the subject of many neuroimaging case–control classification studies. Although some studies report accuracies ≥80%, most have investigated relatively small samples of clinically‐ascertained, currently symptomatic cases, and did not attempt replication in larger samples. We here first aimed to replicate previ...

A high rate of polypharmacy is, in part, a consequence of the increasing proportion of multimorbidity in the ageing population worldwide. Our understanding of the potential harm of taking multiple medications in an older, multi-morbid population, who are likely to be on a polypharmacy regime, is limited. This is a narrative literature review that a...

Background The underlying mechanisms leading to dementia and Alzheimer's Disease (AD) are unclear. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, may be associated with cognitive decline, but population‐based evidence is lacking. Methods Change in cognitive performance was assessed in participants of the Aber...

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have no...

Major depressive disorder is a leading cause of disability and significant mortality, yet mechanistic understanding remains limited. Over the past decade evidence has accumulated from case-control studies that depressive illness is associated with blunted reward activation in the basal ganglia and other regions such as the medial prefrontal cortex....

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on inciden...

Background Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins. Objective To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD. Methods We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compar...

Objectives: Cardiovascular risk is associated with cognitive decline and this effect is attributed to brain pathology, including white matter hyperintensity (WMH) burden. Low-dose aspirin is frequently recommended for reducing vascular events. We investigated the effect of taking aspirin on the association between cardiovascular risk, WMH burden a...

Eating disorders and substance use disorders frequently co‐occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin‐based = 0.23‐0.53). We estimated the genetic correlation...

Variation in the klotho gene is linked to differences in health outcomes: klotho allele KL-VS heterozygosity is associated with longevity, better cognition and greater right frontal grey matter volume in late life. Contradicting reports, however, suggest that KL-VS’s effect on health might be age-dependent. Here we examine the relationship between...

Purpose Hyperintensities are common in neuroimaging scans of patients with mild acute focal neurology. However, their pathogenic role and clinical significance is not well understood. We assessed whether there was an association between hyperintensity score with diagnostic category and clinical assessments/measures. Methods One hundred patients (5...

Background: Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA meth...

Objective Rheumatoid arthritis (RA) patients with concomitant fibromyalgia (FM) exhibit alterations in brain connectivity synonymous with central sensitization. This study was undertaken to investigate how peripheral inflammation, the principal nociceptive stimulus in RA, interacts with brain connectivity in RA patients with FM. Methods RA patient...

STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS pro...

'Epigenetic age acceleration' is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-...

Background The Aberdeen Children of the 1950s (ACONF) cohort contains 12,150 individuals born in Aberdeen, Scotland in the 1950s. The study includes rich early life data, information from questionnaire in middle age, and linkage to electronic healthcare records. Involving the participants in designing future data collection and research is key to...

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding...

Background Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer’s disease (AD) comparing doses in the range 150–250 mg/day with 8 mg/day intended as a control. Objective To determine how drug exposure is related to treatment response. Methods A...

Objectives: White matter hyperintensities (WMH) are a common imaging finding indicative of cerebral small vessel disease. Lesion segmentation algorithms have been developed to overcome issues arising from visual rating scales. In this study, we evaluated two automated methods and compared them to visual and manual segmentation to determine the mos...

Background: The relationship between obesity and adverse health is well established, but little is known about the contribution of DNA methylation to obesity-related health outcomes. This study tests associations between an epigenetic score for body mass index (BMI) and health-related, cognitive, psychosocial and lifestyle outcomes in the Lothian...

Background: DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed 'epigenetic clocks'. The deviation of predicted age from the actual age ('age acceleration residual', AAR) has been reported to be associated with death. However, it is currently unclear how a better prediction of chronological age affe...

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa (BN) and problem alcohol use (genetic correlation [rg], twin-based=0.23-0.53). We estimated the genetic correlati...

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality 1,2 . We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, disco...

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Objectives: Fatigue is a major burden among patients with RA, yet is poorly understood. We sought to conduct the first imaging study to investigate the neurobiological correlates of fatigue in RA and to improve upon the methodological limitations of previous neuroimaging studies that have investigated this symptom in other populations. Methods:...

Introduction Advanced age is associated with cognitive and physical decline, and is a major risk factor for a multitude of disorders including neurodegenerative diseases such as Alzheimer’s disease. There is also a gap in life-expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. H...

[This corrects the article DOI: 10.1371/journal.pone.0211799.].

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene–smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. C...

Measures of fMRI brain entropy have been used to investigate age and disease related neural changes. However, it is unclear if movement in the scanner is associated with brain entropy after geometric correction for movement. As age and disease can affect motor control, quantifying and correcting for the influence of movement will avoid false findin...

Insulin resistance, broadly defined as the reduced ability of insulin to exert its biological action, has been associated with depression and cognitive dysfunction in observational studies. However, it is unclear whether these associations are causal and whether they might be underpinned by other shared factors. To address this knowledge gap, we ca...

‘Epigenetic age acceleration’ is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-...