Heather C Whalley

The University of Edinburgh | UoE · Division of Psychiatry

Background Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status an...

There is an increasing expectation that advanced, computationally expensive machine learning (ML) techniques, when applied to large population-wide neuroimaging datasets, will help to uncover key differences in the human brain in health and disease. We take a comprehensive approach to explore how multiple aspects of brain structural connectivity ca...

Inflammation is implicated in depression and psychosis, including association of childhood inflammatory markers on the subsequent risk of developing symptoms. However, it is unknown whether early-life inflammatory markers are associated with the number of depressive and psychotic symptoms from childhood to adulthood. Using the prospective Avon Long...

Background: Preterm birth is closely associated with a phenotype that includes brain dysmaturation and neurocognitive impairment, commonly termed Encephalopathy of Prematurity (EoP), of which systemic inflammation is considered a key driver. DNA methylation (DNAm) signatures of inflammation from peripheral blood associate with poor brain imaging ou...

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...

The early life environment programmes cortical architecture and cognition across the life course. A measure of cortical organisation that integrates information from multi-modal MRI and is unbound by arbitrary parcellations has proven elusive, which hampers efforts to uncover the perinatal origins of cortical health. Here, we use the Vogt-Bailey in...

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), i...

Background: Major depressive disorder (MDD) is a polygenic disorder associated with brain alterations but until recently, there have been no brain-based metrics to quantify individual-level variation in brain morphology. Here, we evaluated and compared the performance of a new brain-based 'Regional Vulnerability Index' (RVI) with polygenic risk sc...

Background Schizophrenia is a heritable psychiatric disorder with a polygenic architecture. Genome-wide association studies (GWAS) have reported an increasing number of risk-associated variants and polygenic risk scores (PRS) now explain 17% of the variance in the disorder. There exists substantial heterogeneity in the effect of these variants and...

Background Inflammation is implicated in depression and psychosis, including association of childhood inflammatory markers on the subsequent risk of developing symptoms. However, it is unknown whether early-life inflammatory markers are associated with the number of depressive and psychotic symptoms from childhood to adulthood. Methods Using the p...

The brain-age-gap estimate (brainAGE) quantifies the difference between chronological age and age predicted by applying machine-learning models to neuroimaging data and is considered a biomarker of brain health. Understanding sex differences in brainAGE is a significant step toward precision medicine. Global and local brainAGE (G-brainAGE and L-bra...

Application of machine learning (ML) algorithms to structural magnetic resonance imaging (sMRI) data has yielded behaviorally meaningful estimates of the biological age of the brain (brain‐age). The choice of the ML approach in estimating brain‐age in youth is important because age‐related brain changes in this age‐group are dynamic. However, the c...

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,...

Irritability is a core symptom of adolescent depression, characterised by an increased proneness to anger or frustration. Irritability in youth is associated with future mental health problems and impaired social functioning, suggesting that it may be an early indicator of emotion regulation difficulties. Adolescence is a period during which behavi...

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 Accelerated aging has been proposed as a mechanism underlying the clinical and cognitive presentation of schizophrenia. The current study extends the field by examining both global and regional patterns of brain aging in schizophrenia, as inferred from brain structural data, and their association with cognitive and psychotic symptoms.Met...

Introduction Cognitive symptoms are a common feature of schizophrenia (Kahn 2013), that are already present in the early stages of the illness. However, there is significant heterogeneity amongst patients with prior studies distinguishing two subgroups; one with cognitive impairment and another with preserved cognition (Wenzel 2021). Here, we repli...

People living with HIV face a high risk of mental illness, especially depression. We do not yet know the precise neurobiological mechanisms underlying HIV-associated depression. Depression severity in the general population has been linked to acute and chronic markers of systemic inflammation. Given the associations between depression and periphera...

Mechanisms underpinning neurotypical age-related variations in cortical thickness in the human brain remain insufficiently specified. Here we used cell-specific marker genes, followed by gene ontology and enrichment analyses, to quantify the association between gene-expression levels and inter-regional age-related variations in neurotypical cortica...

Background: DNA methylation (DNAm) is associated with time-varying environmental factors that contribute to major depressive disorder (MDD) risk. We sought to test whether DNAm signatures of lifestyle and biochemical factors were associated with MDD to reveal dynamic biomarkers of MDD risk that may be amenable to lifestyle interventions. Methods: H...

Background Global brainAGE predictions using structural MRI (i.e., deviation between neuroimaging-predicted and actual age) have shown accelerated aging in early psychosis (EP) patients, but are not informative about regional differences. Additionally, the link between brain-ageing and cognition in EP has not been addressed. Here, we used machine l...

Background: Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status a...

Background: DNA methylation (DNAm) is associated with time-varying environmental factors that contribute to major depressive disorder (MDD) risk. We sought to test whether DNAm signatures of lifestyle and biochemical factors were associated with MDD to reveal dynamic biomarkers of MDD risk that may be amenable to lifestyle interventions. Methods:...

Depression is assessed in various ways in research, with large population studies often relying on minimal phenotyping. Genetic results suggest clinical diagnoses and self-report measures of depression show some core similarities, but also important differences. It is not yet clear how neuroimaging associations depend on levels of phenotyping. We s...

Background Depression is a disabling and highly prevalent condition where genetic and epigenetic, such as DNA methylation (DNAm), differences contribute to disease risk. DNA methylation is influenced by genetic variation but the association between polygenic risk of depression and DNA methylation is unknown. Methods We investigated the association...

Mechanisms underpinning age-related variations in cortical thickness in the human brain remain poorly understood. We investigated whether inter-regional age-related variations in cortical thinning (in a multicohort neuroimaging dataset from the ENIGMA Lifespan Working Group totalling 14,248 individuals, aged 4-89 years) depended on cell-specific ma...

There is increasing expectation that advanced, computationally expensive machine learning techniques, when applied to large population-wide neuroimaging datasets, will help to uncover key differences in the human brain in health and disease. We take a comprehensive approach to explore how multiple aspects of brain structural connectivity can predic...

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, using MRI data from 5,08...

Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongl...

Antidepressants are an effective treatment for major depressive disorder (MDD), although individual response is unpredictable and highly variable. Whilst the mode of action of antidepressants is incompletely understood, many medications are associated with changes in DNA methylation in genes that are plausibly linked to their mechanisms. Studies of...

Background The brain-age-gap estimate (brainAGE) quantifies the difference between chronological age and age predicted by applying machine-learning models to neuroimaging data, and is considered a biomarker of brain health. Understanding sex-differences in brainAGE is a significant step toward precision medicine. Methods Global and local brainAGE...

Background Depression is the leading cause of disability worldwide with > 50% of cases emerging before the age of 25 years. Large-scale neuroimaging studies in depression implicate robust structural brain differences in the disorder. However, most studies have been conducted in adults and therefore, the temporal origins of depression-related imagin...

This study aimed to investigate the functional imaging associations of autism in individuals with special educational needs and demonstrate the feasibility of such research. The study included 18 individuals (3 female,15 male; mean age 24.3; mean IQ 69.7) with special educational needs (SEN), of whom 9 met criteria for autism. The task examined the...

Peripheral biomarkers reflecting early neurodegeneration change are critical to the development of treatments for Alzheimer’s disease (AD). The most widely used indicator of AD neurodegeneration in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with ne...

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...

Application of machine learning algorithms to structural magnetic resonance imaging (sMRI) data has yielded behaviorally meaningful estimates of the biological age of the brain (brainage). The choice of the machine learning approach in estimating brain-age in children and adolescents is important because age-related brain changes in these age-group...

Background and Objectives To investigate chronic inflammation in relation to cognitive aging by comparison of an epigenetic and serum biomarker of C-reactive protein and their associations with neuroimaging and cognitive outcomes. Methods At baseline, participants (n = 521) were cognitively normal, around 73 years of age (mean 72.4, SD 0.716), and...

Background Psychotic-like experiences (PLEs) are risk factors for the development of psychiatric conditions like schizophrenia, particularly if associated with distress. As PLEs have been related to alterations in both white matter and cognition, we investigated whether cognition (g-factor and processing speed) mediates the relationship between whi...

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...

Abstract Hypothalamic–pituitary–adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematica...

Harmful alcohol use is a leading cause of premature death and is associated with age-related disease. Biological ageing is highly variable between individuals and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (derived from DNA methylation or brain structural measures) may be clinically relevant. Here, we inv...

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),...

Introduction: This study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology. Methods: Five thousand and thirty-two plasma proteins were measured in 1061 cognitively norm...

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...

Characterising associations between the epigenome, proteome and phenome may provide insight into molecular regulation of biological pathways governing health. However, epigenetic signatures for many neurologically-associated plasma protein markers remain uncharacterised. Here, we report an epigenome and phenome-wide association study of the circula...

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical an...

Variation in DNA methylation (DNAm) is associated with lifestyle factors such as smoking and body mass index (BMI) but there has been little research exploring its ability to identify individuals with major depressive disorder (MDD). Using penalised regression on genome-wide CpG methylation, we tested whether DNAm risk scores (MRS), trained on 1223...

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...

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...

Background: Depression is a disabling and highly prevalent condition where genetic and epigenetic differences, such as DNA methylation (DNAm), contribute to prediction of disease liability. Method: We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in G...

Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors and abnormalities in blood-based measures of inflammation and blood-brain barrier (BBB) permeability. The relationships between such genetic architectures and blood-based markers are however unclear. We investigated rel...

Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. However, cross-sectional brain data conflate information on ageing with patterns that are present throughout life. We characterised brain cortical agein...

It has been proposed that the Glutamate (Glu) system is implicated in autism spectrum disorders (ASD) via an imbalance between excitatory and inhibitory brain circuits, which impacts on brain function. Here, we investigated the excitatory-inhibitory imbalance theory by measuring Glu concentrations and the relationship with resting-state function. N...

Objective Neuroimaging studies of suicidal behavior have so far been conducted in small samples, prone to biases and false-positive associations, yielding inconsistent results. The ENIGMA-MDD working group aims to address the issues of poor replicability and comparability by coordinating harmonized analyses across neuroimaging studies of major depr...

There has been a substantial amount of research reporting the neuroanatomical associations of psychotic symptoms in people with schizophrenia. Comparatively little attention has been paid to the neuroimaging correlates of subclinical psychotic symptoms, so-called “psychotic-like experiences” (PLEs), within large healthy populations. PLEs are relati...

Background Depression is assessed in many different ways, with large population studies often relying on minimal phenotyping approaches. Genetic results suggest that more formal clinical diagnoses and simpler self-report measures of depression show some core similarities, but also important differences. It is not yet clear whether this is also the...

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcor...

Background Harmful alcohol use is a leading cause of premature death, and is associated with age-related disease. Ageing is highly variable between individuals, and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (based on DNA methylation or brain structural measures) may be clinically relevant. Here, we inves...

Background

Background: Within young individuals, mood disorder onset may be related to changes in trajectory of brain structure development. To date, however, longitudinal prospective studies remain scarce and show partly contradictory findings, with a lack of emphasis on changes at the level of global brain patterns. Cross-sectional adult studies have applie...

Background Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors and abnormalities in blood-based measures of inflammation and blood-brain barrier (BBB) permeability. The relationships between such genetic architectures and blood-based markers are however unclear. We inves...

Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers. Here, we report the first large-scale study of both serological and m...

Low-level chronic inflammation increases with age and is associated with cognitive decline. DNA methylation (DNAm) levels may provide more stable reflections of cumulative inflammatory burden than traditional serum approaches. Using structural and diffusion MRI data from 521 individuals aged 73, we demonstrate that a DNAm proxy of C-Reactive Protei...