
Michael C NealeVirginia Commonwealth University | VCU · Department of Psychiatry
Michael C Neale
PhD
About
956
Publications
236,847
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
80,296
Citations
Introduction
Most of my published articles can be downloaded here: https://vipbg.vcu.edu/vipbg/Articles/
Enjoy!
Publications
Publications (956)
Background
Genetically informative twin studies have consistently found that individual differences in anxiety and depression symptoms are stable and primarily attributable to time-invariant genetic influences, with non-shared environmental influences accounting for transient effects.
Methods
We explored the etiology of psychological and somatic d...
Cigarette smoking is associated with numerous differentially-methylated genomic loci in multiple human tissues. These associations are often assumed to reflect the causal effects of smoking on DNA methylation (DNAm), which may underpin some of the adverse health sequelae of smoking. However, prior causal analyses with Mendelian Randomisation (MR) h...
Psychiatric disorders are highly comorbid, heritable, and genetically correlated [1–4]. The primary objective of cross-disorder psychiatric genetics research is to identify and characterize both the shared genetic factors that contribute to convergent disease etiologies and the unique genetic factors that distinguish between disorders [4, 5]. This...
Background
Past studies indicate daily increases in estrogen across the menstrual cycle protect against binge-eating (BE) phenotypes (e.g. emotional eating), whereas increases in progesterone enhance risk. Two previous studies from our laboratory suggest these associations could be due to differential genomic effects of estrogen and progesterone. H...
Causal inference is inherently complex and relies on key assumptions that can be difficult to validate. One strong assumption is population homogeneity, which assumes that the causal direction remains consistent across individuals. However, there may be variation in causal directions across subpopulations, leading to potential heterogeneity. In psy...
Prior studies have shown strong genetic effects on cortical thickness (CT), structural covariance, and neurodevelopmental trajectories in childhood and adolescence. However, the importance of genetic factors on the induction of spatiotemporal variation during neurodevelopment remains poorly understood. Here, we explore the genetics of maturational...
Importance
Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.
Objective
To identify the most commo...
The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our da...
INTRODUCTION
The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers.
METHODS
Plasma Aβ40, Aβ42, t-Tau, and neurofilament light chain (NFL) were m...
Attention-deficit hyperactivity disorder (ADHD) is prevalent in children and associated with lower education performance. This association is often obtained from observational studies, which have limited ability to identify causal relationships. Knowledge of causes is useful, because it delineates intervention avenues more clearly, but research int...
Epigenome-wide association studies (EWAS) aim to identify differentially methylated loci associated with complex traits and disorders. EWAS of cigarette smoking shows some of the most widespread DNA methylation (DNAm) associations in blood. However, traditional EWAS cannot differentiate between causation and confounding, leading to ambiguity in eti...
Causal inference is inherently complex, often dependent on key assumptions that are sometimes overlooked. One such assumption is the potential for unidirectional or bidirectional causality, while another is population homogeneity, which suggests that the causal direction between two variables remains consistent across the study sample. Discerning t...
Importance
The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or “Long COVID”) in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults.
Observations
We describe the protoc...
Background
Plasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations.
Methods
W...
Internalizing (e.g., anxiety, depression) and disordered eating (DE; e.g., binge eating, dietary restraint) are highly comorbid, but the mechanisms underlying their comorbidity remain unknown. This was the first twin study to examine whether their co-occurrence may be driven by genetic and/or environmental influences on emotion regulation (ER; abil...
Cross-lagged panel models (CLPMs) are commonly used to estimate causal influences between two variables with repeated assessments. The lagged effects in a CLPM depend on the time interval between assessments, eventually becoming undetectable at longer intervals. To address this limitation, we incorporate instrumental variables (IVs) into the CLPM w...
Background
Trait‐level emotion regulation (ER) difficulties are associated with eating disorders (EDs) transdiagnostically. However, little research has examined whether within‐person fluctuations in ER longitudinally predict ED behaviors in daily life or the mechanisms of ER effects. Investigating daily ER could help us better understand why peopl...
Distinguishing those at risk of making a suicide attempt from those who experience only suicidal ideations remains a significant clinical challenge. Longitudinal studies during early adolescence may provide insight into altered brain and behavioral developmental trajectories among those who develop suicide behaviors (SB). Here, we applied linear mi...
Background
Predicted brain age difference (PBAD) scores are novel metrics which compare chronological age to age predicted from neuroimaging data. PBADs are highly relevant to Alzheimer’s disease (AD) and cognitive aging. Individuals with AD have predicted brain ages about 10 years older than their chronological age (Franke et al. 2010). Less is kn...
Background
Before onset of Alzheimer’s dementia, aggregation of amyloid‐beta (Aβ) is thought to drive accumulation of Tau, followed by neurodegeneration (indexed here by neurofilament light chain [NFL]). Why or how Aβ increases Tau accumulation remains unclear. Using genetically informative twins aged 61.4 to 73.3 years, we sought to: (1) identify...
Mendelian Randomization (MR) has become an important tool for causal inference in the health sciences. It takes advantage of the random segregation of alleles to control for background confounding factors. In brief, the method works by using genetic variants as instrumental variables, but it depends on the assumption of exclusion restriction, i.e.,...
INTRODUCTION
Despite their increased application, the heritability of Alzheimer's disease (AD)–related blood‐based biomarkers remains unexplored.
METHODS
Plasma amyloid beta 40 (Aβ40), Aβ42, the Aβ42/40 ratio, total tau (t‐tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (μ = 67.0, SD = 2.6). Twin models were used...
Background: Smoking-associated DNA methylation levels identified through epigenome-wide association studies (EWAS) are generally ascribed to smoking-reactive mechanisms, but the contribution of a shared genetic predisposition to smoking and DNA methylation levels is typically not accounted for.
Methods: We exploited a strong within-family design, i...
One type of genotype-environment interaction occurs when genetic effects on a phenotype are moderated by an environment; or when environmental effects on a phenotype are moderated by genes. Here we outline these types of genotype-environment interaction models, and propose a test of genotype-environment interaction based on the classical twin desig...
Importance
SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID . Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infect...
Importance:
Subjective memory concern has long been considered a state-related indicator of impending cognitive decline or dementia. The possibility that subjective memory concern may itself be a heritable trait is largely ignored, yet such an association would substantially confound its use in clinical or research settings.
Objective:
To assess...
Background
Previously, a study using a sample of the Adolescent Brain Cognitive Development (ABCD)® study from the earlier 1.0 release found differences in several resting state functional MRI (rsfMRI) brain connectivity measures associated with children reporting anhedonia. Here, we aim to reproduce, replicate, and extend the previous findings usi...
Some evidence suggests a biphasic pattern of changes in cortical thickness wherein higher, rather than lower, thickness is associated with very early Alzheimer's disease (AD) pathology. We examined whether integrating information from AD brain signatures based on mean diffusivity (MD) can aid in the interpretation of cortical thickness/volume as a...
Importance
The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or “Long COVID”) in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults.
Observations
We describe the protoc...
Twin and family studies have historically aimed to partition phenotypic variance into components corresponding to additive genetic effects (A), common environment (C), and unique environment (E). Here we present the ACE Model and several extensions in the Adolescent Brain Cognitive Development℠ Study (ABCD Study®), employed using the new Fast Effic...
Weighted least squares (WLS) estimation has tremendous utility for structural equation models (SEMs) that include ordered categorical data. However, some common statistical programs for fitting these models lack full flexibility in specification. Moreover, the popular approach toward model identification of ordinal variables arbitrarily constrains...
A general method is introduced in which variables that are products of other variables in the context of a structural equation model (SEM) can be decomposed into the sources of variance due to the multiplicands. The result is a new category of SEM which we call a Products of Variables Model (PoV). Some useful and practical features of PoV models in...
Objective:
Using Swedish nationwide registry data, we investigated the contribution of genetic and environmental risk factors to the etiology of alcohol use disorders by extended twin pedigree modeling.
Methods:
Alcohol use disorder (AUD) was defined using public inpatient, outpatient, prescription and criminal records. Three-generational pedigr...
Composite scores of MRI‐based brain regions associated with Alzheimer’s disease (AD) pathology, commonly termed ‘AD signatures,' are tools developed to identify brain changes specific to mild AD. In recent work from our group, we found that a novel diffusion‐based cortical mean diffusivity (MD) signature among cognitively normal adults in their 50s...
Composite scores of MRI‐based brain regions associated with Alzheimer’s disease (AD) pathology, commonly termed ‘AD signatures’, are tools developed to identify brain changes specific to mild AD. We found that a novel diffusion‐based cortical mean diffusivity (MD) signature among cognitively normal adults in their 50s aided prediction of 12‐year pr...
Background
Blood-based neurofilament light chain (NfL) is a promising biomarker of neurodegeneration across multiple neurodegenerative diseases. However, blood-based NfL is highly associated with renal function in older adults, which leads to the concern that blood-based NfL levels may be influenced by renal function, rather than neurodegeneration...
Background
The amyloid‐tau‐neurodegeneration (ATN) framework has led to an increased focus on Alzheimer’s disease (AD) biomarkers. The costs and invasiveness of methods relying on cerebrospinal fluid or positron emission tomography imaging have led to efforts to develop sensitive blood‐based biomarkers. Although AD is highly heritable, the biometri...
Twin studies yield valuable insights into the sources of variation, covariation and causation in human traits. The ABCD Study® (abcdstudy.org) was designed to take advantage of four universities known for their twin research, neuroimaging, population-based sampling, and expertise in genetic epidemiology so that representative twin studies could be...
Establishing causality is an essential step towards developing interventions for psychiatric disorders, substance use and many other conditions. While randomized controlled trials (RCTs) are considered the gold standard for causal inference, they are unethical in many scenarios. Mendelian randomization (MR) can be used in such cases, but importantl...
Twin and family studies have historically aimed to partition phenotypic variance into components corresponding to additive genetic effects (A), common environment (C), and unique environment (E). Here we present the ACE Model and several extensions in the Adolescent Brain Cognitive Development SM ; Study (ABCD Study ® ), employed using the new Fast...
Background
Previously, a study using a sample of the Adolescent Brain Cognitive Development (ABCD)® study from the earlier 1.0 release found differences in several resting state functional MRI (rsfMRI) brain connectivity measures associated with children reporting anhedonia. Here, we aim to reproduce, replicate, and extend the previous findings usi...
Cross-lagged panel models (CLPMs) are commonly used to estimate causal influences between two variables with repeated measurements. In a CLPM, the magnitude and significance of the lagged effects depend on the time interval between measurement occasions, and these effects usually become undetectable at longer intervals. To address this limitation,...
Background:
COVID-19 was associated with significant financial hardship and increased binge eating (BE). However, it is largely unknown whether financial stressors contributed to BE during the pandemic. We used a longitudinal, cotwin control design that controls for genetic/environmental confounds by comparing twins in the same family to examine w...
Genotype-environment (GxE) interaction occurs when genetic effects on an outcome (phenotype) are moderated by an environment, or when environmental effects on a phenotype are moderated by genes. Our aim is to present an overview of GxE interaction models, and to propose a test of GxE interaction, which includes observed genetic variables (polygenic...
Smoking-associated DNA methylation levels identified through epigenome-wide association studies (EWAS) are generally ascribed to smoking-reactive mechanisms, but the contribution of a shared genetic predisposition to smoking and DNA methylation levels is typically not accounted for. We exploited a strong within-family design, i.e., the discordant m...
The amyloid-tau-neurodegeneration (ATN) framework has led to an increased focus on Alzheimers disease (AD) biomarkers. The cost and invasiveness of obtaining biomarkers via cerebrospinal fluid has motivated efforts to develop sensitive blood-based biomarkers. Although AD is highly heritable, the biometric genetic and environmental etiology of blood...
INTRODUCTION
Genetic influences on the stability of subjective memory concerns (SMC) may confound its interpretation as a state-related risk indicator.
METHODS
We estimated genetic influences on SMC and SMC change from average ages 38 to 67, genetic correlations of SMC with memory and depressive symptoms at average ages 56, 62, and 67, and correla...
Background
Stress is associated with binge eating and emotional eating (EE) cross-sectionally. However, few studies have examined stress longitudinally, limiting understanding of how within-person fluctuations in stress influence EE over time and whether stress is a risk factor or consequence of EE. Additionally, little is known regarding how the b...
Longitudinal data are needed to examine effects of the COVID-19 pandemic on disordered eating. We capitalized on an ongoing, longitudinal study collecting daily data to examine changes in disordered eating symptoms in women across 49 days that spanned the time before and during the COVID-19 outbreak in the United States. Women from the Michigan Sta...
The classical twin design is used to decompose phenotypic variance into genetic and environmental variance components. In practice, for reasons of identification, either an ADE or an ACE twin model is fitted, i.e., models with three variance components. Jöreskog proposed to use the Moore-Penrose inverse to estimate the four genetic and environmenta...
Background:
While negative affect (NA) typically increases risk for binge eating, the ultimate impact of NA may depend on a person's ability to regulate their emotions. In this daily, longitudinal study, we examined whether emotion regulation (ER) modified the strength of NA-dysregulated eating associations.
Methods:
Women (N = 311) from the Mic...
Background
Composite scores of MRI-derived metrics in brain regions associated with Alzheimer’s disease (AD), commonly termed ‘AD signatures,’ have been developed to distinguish early AD-related atrophy from normal age-associated changes. Diffusion-based gray matter signatures may be more sensitive to early AD-related changes compared to thickness/...
Objective
To determine associations of alcohol use with cognitive aging among middle-aged men.
Method
1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003–2007 to 2016–2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, form...
Magnetic resonance imaging data are being used in statistical models to predicted brain ageing (PBA) and as biomarkers for neurodegenerative diseases such as Alzheimer’s Disease. Despite their increasing application, the genetic and environmental etiology of global PBA indices is unknown. Likewise, the degree to which genetic influences in PBA are...
The advent of molecular genetics might seem to have reduced the importance of twin studies, but in many ways, their utility has greatly increased instead. We first clarify the motivations for twin studies – to identify the origins of individual differences, with a view to using this information to better understand complex traits, and to improve th...
Establishing causal associations is an essential step towards developing interventions for psychiatric, substance use and many other disorders. While randomized controlled trials (RCTs) are considered the gold standard for causal inference, they are unethical in many scenarios. Mendelian randomization (MR) can instead be used, but both methods focu...
Reduced volumes in brain regions of interest (ROIs), primarily from adult samples, are associated with posttraumatic stress disorder (PTSD). We extended this work to children using data from the Adolescent Brain Cognitive Development (ABCD) Study® (N = 11,848; M age = 9.92). Structural equation modeling and an elastic-net (EN) machine-learning appr...
Objective
Alzheimer’s disease (AD) is highly heritable, and AD polygenic risk scores (AD-PRSs) have been derived from genome-wide association studies. However, the nature of genetic influences very early in the disease process is still not well known. Here we tested the hypothesis that an AD-PRSs would be associated with changes in episodic memory...
Background
Composite scores of MRI‐based brain morphometry, commonly termed ‘Alzheimer’s disease (AD) signatures,’ have demonstrated associations with AD symptom severity and progression to AD. Our group recently showed that two AD signatures, a cortical thickness/volume and mean diffusivity (MD) signature, aid prediction of progression to mild cog...
Background
Concerns abound regarding childhood smartphone use, but studies to date have largely relied on self-reported screen use. Self-reporting of screen use is known to be misreported by pediatric samples and their parents, limiting the accurate determination of the impact of screen use on social, emotional, and cognitive development. Thus, a m...
Background and aims
Smoking is associated with increased risk for brain aging/atrophy and dementia. Few studies have examined early associations with brain aging. This study aimed to measure whether adult men with a history of heavier smoking in early midlife would have older than predicted brain age 16 to 28 years later.
Design
Prospective cohort...