Dr. Laura Hack is a Postdoctoral Fellow and Clinical Instructor under the mentorship of Drs. Leanne Williams, Alan Schatzberg, and Ruth O’Hara. She is a translational clinician with a research passion for integrating multiple types of biological and environmental data using advanced analytic techniques into a neuroscience-based taxonomy of mood, anxiety, and stressor-related disorders. Laura envisions herself as a ‘psychiatrist of the future,’ incorporating genetic information, brain imaging, blood-based markers, and data from wearable sensors into diagnostic and treatment decisions to help relieve the suffering that arises from our current trial-and-error approach.
Honors & Awards
Career Development Institute for Psychiatry, University of Pittsburgh and Stanford University (Jan 2020-Dec 2021)
Faculty Leadership and Professional Development Award, Department of Psychiatry and Behavioral Sciences, Stanford University (2020)
Research Colloquium for Junior Investigators, American Psychiatric Association (2019)
Young Investigator Poster Competition, 2nd Place, NEI Congress (2018)
Merit based Travel Fellowship Award, Society of Biological Psychiatry (2017)
New Investigator Award, American Society of Clinical Psychopharmacology (2017)
Psychiatry Resident Research Award, Emory University School of Medicine (2017)
Outstanding Resident Award Program, Honorable Mention, NIMH (2016)
Phi Kappa Phi Scholarship, Virginia Commonwealth University (2012)
Early Career Investigator Program Finalist, World Congress of Psychiatric Genetics (2011)
Merit based Alcohol Travel Award, International Society of Psychiatric Genetics (2009)
Magna Cum Laude, The College of William & Mary (2006)
Senior Thesis Honors in Neuroscience, The College of William & Mary (2006)
Summer Research Fellowship, Howard Hughes Medical Institute (2004)
James Monroe Scholarship, The College William & Mary (2002)
Postdoctoral Fellowship, MIRECC VA Palo Alto/Stanford University, Psychiatry (2021)
Psychiatry Residency, Emory University School of Medicine (2018)
Doctor of Philosophy, Virginia Commonwealth University (2014)
Doctor of Medicine, Virginia Commonwealth University (2014)
Bachelor of Science, College of William and Mary (2006)
Leanne Williams, Postdoctoral Faculty Sponsor
Identifying response and predictive biomarkers for Transcranial magnetic stimulation outcomes: protocol and rationale for a mechanistic study of functional neuroimaging and behavioral biomarkers in veterans with Pharmacoresistant depression.
2021; 21 (1): 35
BACKGROUND: Although repetitive transcranial magnetic stimulation ('TMS') is becoming a gold standard treatment for pharmacoresistant depression, we lack neural target biomarkers for identifying who is most likely to respond to TMS and why. To address this gap in knowledge we evaluate neural targets defined by activation and functional connectivity of the dorsolateral prefrontal cortex-anchored cognitive control circuit, regions of the default mode network and attention circuit, and interactions with the subgenual anterior cingulate. We evaluate whether these targets and interactions between them change in a dose-dependent manner, whether changes in these neural targets correspond to changes in cognitive behavioral performance, and whether baseline and early change in neural target and cognitive behavioral performance predict subsequent symptom severity, suicidality, and quality of life outcomes. This study is designed as a pragmatic, mechanistic trial partnering with the National Clinical TMS Program of the Veteran's Health Administration.METHODS: Target enrollment consists of 100 veterans with pharmacoresistant Major Depressive Disorder (MDD). All veterans will receive a clinical course of TMS and will be assessed at 'baseline' pre-TMS commencement, 'first week' after initiation of TMS (targeting five sessions) and 'post-treatment' at the completion of TMS (targeting 30 sessions). Veterans will be assessed using functional magnetic resonance imaging (fMRI), a cognitive behavioral performance battery, and established questionnaires. Multivariate linear mixed models will be used to assess whether neural targets change with TMS as a function of dose (Aim 1), whether extent and change of neural target relates to and predicts extent of behavioral performance (Aim 3), and whether extent of neural target change predicts improvement in symptom severity, suicidality, and quality of life (Aim 3). For all three aims, we will also assess the contribution of baseline moderators such as biological sex and age.DISCUSSION: To our knowledge, our study will be the first pragmatic, mechanistic observational trial to use fMRI imaging and cognitive-behavioral performance as biomarkers of TMS treatment response in pharmacoresistant MDD. The results of this trial will allow providers to select suitable candidates for TMS treatment and better predict treatment response by assessing circuit connectivity and cognitive-behavioral performance at baseline and during early treatment.TRIAL REGISTRATION: ClinicalTrials.gov NCT04663481 , December 5th, 2020, retrospectively registered. The first veteran was enrolled October 30th, 2020.
View details for DOI 10.1186/s12888-020-03030-z
View details for PubMedID 33435926
Epigenetic prediction of 17β-estradiol and relationship to trauma-related outcomes in women
View details for DOI 10.1016/j.cpnec.2021.100045
Ventral-Hippocampal Afferents to Nucleus Accumbens Encode Both Latent Vulnerability and Stress-Induced Susceptibility
SPRINGERNATURE. 2020: 312
View details for Web of Science ID 000596371000574
The Effect of Selective D3 Agonism on Anhedonia Symptoms and Reward Neurocircuitry in Subjects With MDD and Prominent Anhedonia
SPRINGERNATURE. 2020: 96–97
View details for Web of Science ID 000596371000193
Intrinsic reward circuit connectivity profiles underlying symptom and quality of life outcomes following antidepressant medication: a report from the iSPOT-D trial.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
There is a critical need to better understand the neural basis of antidepressant medication (ADM) response with respect to both symptom alleviation and quality of life (QoL) in major depressive disorder (MDD). Reward neurocircuitry has been implicated in QoL, the neural basis of MDD, and the mechanisms of ADM response. Yet, we do not know whether change in reward neurocircuitry as a function of ADM is associated with change in symptoms and QoL. To address this gap in knowledge, we analyzed data from 128 patients with MDD who participated in the iSPOT-D trial and were assessed with functional neuroimaging pre- and post-ADM treatment (randomized to sertraline, venlafaxine-XR, or escitalopram). 58 matched healthy controls were scanned at the same time points. We quantified functional connectivity (FC) of reward neurocircuitry using nucleus accumbens (NAc) seed regions of interest, and then characterized how changes in FC relate to symptom response (primary outcome) and QoL response (secondary outcome). Symptom responders showed an increase in NAc-dorsal anterior cingulate cortex (ACC) FC relative to non-responders (p<0.001) which was associated with improvement in physical QoL (p<0.0003), and a decrease in NAc-inferior parietal lobule FC relative to controls (p<0.001). QoL response was characterized by increases in FC between NAc-ventral ACC for environmental, NAc-thalamus for physical, and NAc-paracingulate gyrus for social domains (p<0.001). Symptom responders to sertraline were distinguished by a decrease in NAc-insula FC (p<0.001) and to venlafaxine-XR by an increase in NAc-inferior temporal gyrus FC (p<0.005). Findings suggest that change in reward neurocircuitry may underlie differential ADM response profiles with respect to symptoms and QoL in depression.
View details for DOI 10.1038/s41386-020-00905-3
View details for PubMedID 33230268
- A precision medicine-based, 'fast-fail' approach for psychiatry. Nature medicine 2020; 26 (5): 653–54
Functional Connectivity of Reward Circuitry is a Core Mechanistic Biomarker of Treatment Response and Quality of Life in Depression
ELSEVIER SCIENCE INC. 2020: S396–S397
View details for Web of Science ID 000535308201213
Mechanistic Trial Evaluating the Effect of Repetitive Transcranial Magnetic Stimulation on RDoC Constructs in Treatment-Resistant Depression
ELSEVIER SCIENCE INC. 2020: S412–S413
View details for Web of Science ID 000535308201252
Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.
To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z=-5.39, p=7.2*10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N>360,000) found association of this variant with propensity to use dietary supplements (p=1.68*10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR+AFR z=4.69, p=10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z=5.55, p=2.9*10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p=4.88*10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n=466,571) was positively associated with OD (OD vs. unexposed controls, p=8.1*10-5; OD cases vs. exposed controls, p=0.054) and OE (exposed vs. unexposed controls, p=3.6*10-5). A PRS based on a GWAS of neuroticism (n=390,278) was positively associated with OD (OD vs. unexposed controls, p=3.2*10-5; OD vs. exposed controls, p=0.002) but not with OE (p=0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.
View details for DOI 10.1038/s41380-020-0677-9
View details for PubMedID 32099098
Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.
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 between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
View details for DOI 10.1111/adb.12880
View details for PubMedID 32064741
Exploring Nonmotor Neuropsychiatric Manifestations of Parkinson Disease in a Comprehensive Care Setting.
Journal of geriatric psychiatry and neurology
Parkinson disease (PD) is a debilitating neurological condition that includes both motor symptoms and nonmotor symptoms (NMS). Psychiatric complaints comprise NMS and are collectively referred to as neuropsychiatric manifestations. Common findings include atypical depressive symptoms, anxiety, psychosis, impulse control disorder, deterioration of cognition, and sleep disturbances. Quality of life (QoL) of patients suffering from NMS is greatly impacted and many times can be more debilitating than motor symptoms of PD. We expand on knowledge gained from treatment models within a comprehensive care model that incorporates multidisciplinary specialists working alongside psychiatrists to treat PD. Insight into background, clinical presentations, and treatment options for patients suffering from neuropsychiatric manifestations of PD are discussed. Identifying symptoms early can help improve QoL, provide early symptom relief, and can assist tailoring treatment plans that limit neuropsychiatric manifestations.
View details for DOI 10.1177/0891988720915525
View details for PubMedID 32242493
A large-scale genome-wide association study meta-analysis of cannabis use disorder.
The lancet. Psychiatry
Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.
View details for DOI 10.1016/S2215-0366(20)30339-4
View details for PubMedID 33096046
Genes, Roommates, and Residence Halls: A Multidimensional Study of the Role of Peer Drinking on College Students' Alcohol Use.
Alcoholism, clinical and experimental research
2019; 43 (6): 1254–62
Peer drinking is one of the most robust predictors of college students' alcohol use and can moderate students' genetic risk for alcohol use. Peer effect research generally suffers from 2 problems: selection into peer groups and relying more on perceptions of peer alcohol use than peers' self-report. The goal of the present study was to overcome those limitations by capitalizing on a genetically informed sample of randomly assigned college roommates to examine multiple dimensions of peer influence and the interplay between peer effects and genetic predisposition on alcohol use, in the form of polygenic scores.We used a subsample (n = 755) of participants from a university-wide, longitudinal study at a large, diverse, urban university. Participants reported their own alcohol use during fall and spring and their perceptions of college peers' alcohol use in spring. We matched individuals into their rooms and residence halls to create a composite score of peer-reported alcohol use for each of those levels. We examined multiple dimensions of peer influence and whether peer influence moderated genetic predisposition to predict college students' alcohol use using multilevel models to account for clustering at the room and residence hall level.We found that polygenic scores (β = 0.12), perceptions of peer drinking (β = 0.37), and roommates' self-reported drinking (β = 0.10) predicted alcohol use (all ps < 0.001), while average alcohol use across residence hall did not (β = -0.01, p = 0.86). We found no evidence for interactions between peer influence and genome-wide polygenic scores for alcohol use.Our findings underscore the importance of genetic predisposition on individual alcohol use and support the potentially causal nature of the association between peer influence and alcohol use.
View details for DOI 10.1111/acer.14037
View details for PubMedID 31034622
View details for PubMedCentralID PMC6561118
Unpacking Genetic Risk Pathways for College Student Alcohol Consumption: The Mediating Role of Impulsivity.
Alcoholism, clinical and experimental research
The period of college represents a particularly risky developmental stage with regard to alcohol use, as college students engage in more risky drinking behaviors than their noncollege peers, and such problematic alcohol use is associated with far-reaching negative consequences. Existing findings from genome-wide association studies (GWAS) indicate that alcohol consumption has a complex polygenic etiology. Currently, there is a lack of studies examining genetic risk for alcohol consumption using polygenic risk scores (PRS) in college samples. In this study, we examined whether alcohol-specific and risky behavior-related PRS were longitudinally associated with alcohol consumption among college students and whether this effect might be partially mediated by impulsivity domains.The sample included n = 2,385 European ancestry (EA) and n = 1,153 African ancestry (AA) college students assessed over the course of 4 years. To indicate genetic risk, 2 PRS were created based on recent large-scale GWAS: alcohol consumption (Liu et al., 2019) -drinks per week (DPW)-PRS and risky behaviors (Linnér et al., 2019) -RISK-PRS. The main outcome was alcohol consumption, measured across 4 waves of follow-up data. The UPPS-P impulsivity subscales were examined as mediators of the genetic effect on alcohol consumption.The results from structural equation modeling showed that among EA students, both DPW-PRS and RISK-PRS had significant positive effects on alcohol consumption above and beyond UPPS dimensions and control variables. RISK-PRS explained larger portion of variance in alcohol consumption than DPW-PRS. RISK-PRS showed a significant indirect effect on alcohol consumption through sensation seeking and lack of perseverance; no significant indirect effect of DPW-PRS was found. No significant association of either PRS or alcohol consumption was found for AA participants.The current results found that PRS related to more broadly defined risky behaviors predicted alcohol consumption across college years and that this association was partially mediated via dimensions of impulsivity.
View details for DOI 10.1111/acer.14157
View details for PubMedID 31373688
Moving pharmacoepigenetics tools for depression toward clinical use.
Journal of affective disorders
2019; 249: 336–46
Major depressive disorder (MDD) is a leading cause of disability worldwide, and over half of patients do not achieve symptom remission following an initial antidepressant course. Despite evidence implicating a strong genetic basis for the pathophysiology of MDD, there are no adequately validated biomarkers of treatment response routinely used in clinical practice. Pharmacoepigenetics is an emerging field that has the potential to combine both genetic and environmental information into treatment selection and further the goal of precision psychiatry. However, this field is in its infancy compared to the more established pharmacogenetics approaches.We prepared a narrative review using literature searches of studies in English pertaining to pharmacoepigenetics and treatment of depressive disorders conducted in PubMed, Google Scholar, PsychINFO, and Ovid Medicine from inception through January 2019. We reviewed studies of DNA methylation and histone modifications in both humans and animal models of depression.Emerging evidence from human and animal work suggests a key role for epigenetic marks, including DNA methylation and histone modifications, in the prediction of antidepressant response. The challenges of heterogeneity of patient characteristics and loci studied as well as lack of replication that have impacted the field of pharmacogenetics also pose challenges to the development of pharmacoepigenetic tools. Additionally, given the tissue specific nature of epigenetic marks as well as their susceptibility to change in response to environmental factors and aging, pharmacoepigenetic tools face additional challenges to their development.This is a narrative and not systematic review of the literature on the pharmacoepigenetics of antidepressant response. We highlight key studies pertaining to pharmacoepigenetics and treatment of depressive disorders in humans and depressive-like behaviors in animal models, regardless of sample size or methodology. While we discuss DNA methylation and histone modifications, we do not cover microRNAs, which have been reviewed elsewhere recently.Utilization of genome-wide approaches and reproducible epigenetic assays, careful selection of the tissue assessed, and integration of genetic and clinical information into pharmacoepigenetic tools will improve the likelihood of developing clinically useful tests.
View details for PubMedID 30802699
Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders.
2018; 21 (12): 1656–69
Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n=46,568; African, n=6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P=9.8*10-13) and African ancestries (rs2066702; P=2.2*10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
View details for PubMedID 30482948
- Polyepigenetic Prediction of PTSD Physiology Based on Estrogen Status ELSEVIER SCIENCE INC. 2018: S141
- DNA Methylation Across the Genome Associates With Serum Estrogen Levels and PTSD ELSEVIER SCIENCE INC. 2018: S86–S87
Practical outpatient pharmacotherapy for alcohol use disorder.
Drugs in context
2018; 7: 212308
Alcohol use disorder (AUD) is commonly encountered in clinical practice. A combination of psychosocial intervention and pharmacotherapy is the cornerstone of AUD treatment. Despite their efficacy, safety and cost-effectiveness, clinicians are reluctant to prescribe medications to treat individuals with AUD. Given the high rate of relapse with psychosocial intervention alone, increasing patient access to this underutilized treatment has the potential to improve clinical outcome in this difficult-to-treat population. Herein, we provide practical pharmacotherapy strategies to improve treatment outcome for AUD. We review the efficacy and side effects of both on- and off-label agents with a particular focus on clinical applicability. Recommendations are supported by findings from randomized controlled trials (RCT) and meta-analyses selected to be representative, where possible, of current treatment guidelines. The goal of this paper is to help readers use pharmacotherapy with greater confidence when treating patients with AUD.
View details for DOI 10.7573/dic.212308
View details for PubMedID 29445407
View details for PubMedCentralID PMC5804871
- Data-Driven Subtypes of Depression in a Treatment Resistant Cohort 56th Annual Meeting of the American-College-of-Neuropsychopharmacology (ACNP) and Cognitive-Neuroscience-Society 2018
- Suicide Prediction Using Machine Learning Techniques in Screening and Clinician-Derived Data ELSEVIER SCIENCE INC. 2017: S361
Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms.
Alcoholism, clinical and experimental research
2017; 41 (5): 911–28
Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified.We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue.We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc).We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.
View details for PubMedID 28226201
Exposure to Glucocorticoids During Hippocampal Neurogenesis: Effects on DNA Hydroxymethylation
ELSEVIER SCIENCE INC. 2016: 94S
View details for Web of Science ID 000432440801069
Epigenetic mechanisms involved in the effects of stress exposure: focus on 5-hydroxymethylcytosine.
2016; 2 (3): dvw016
5-hydroxymethylcytosine (5hmC) is a recently re-discovered transient intermediate in the active demethylation pathway that also appears to play an independent role in modulating gene function. Epigenetic marks, particularly 5-methylcytosine, have been widely studied in relation to stress-related disorders given the long-lasting effect that stress has on these marks. 5hmC is a good candidate for involvement in the etiology of these disorders given its elevated concentration in mammalian neurons, its dynamic regulation during development of the central nervous system, and its high variability among individuals. Although we are unaware of any studies published to date examining 5 hmC profiles in human subjects who have developed a psychiatric disorder after a life stressor, there is emerging evidence from the animal literature that 5hmC profiles are altered in the context of fear-conditioning paradigms and stress exposure, suggesting a possible role for 5hmC in the biological underpinnings of stress-related disorders. In this review, the authors examine the available approaches for profiling 5hmC and describe their advantages and disadvantages as well as discuss the studies published thus far investigating 5hmC in the context of fear-related learning and stress exposure in animals. The authors also highlight the global versus locus-specific regulation of 5hmC in these studies. Finally, the limitations of the current studies and their implications are discussed.
View details for DOI 10.1093/eep/dvw016
View details for PubMedID 29492296
View details for PubMedCentralID PMC5804530
Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence.
2015; 10 (9): e0137671
Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.
View details for DOI 10.1371/journal.pone.0137671
View details for PubMedID 26381263
View details for PubMedCentralID PMC4575063
GENOMEWIDE ASSOCIATION STUDY OF ALCOHOL DEPENDENCE IN AN IRISH SAMPLE IDENTIFIES RISK LOCI SUPPORTED BY MODEL ORGANISM STUDIES AND CONVERGENT EVIDENCE
WILEY-BLACKWELL. 2014: 220A
View details for Web of Science ID 000337523701080
GENOMEWIDE ASSOCIATION STUDY OF ALCOHOL QUANTITATIVE TRAITS IN AN IRISH SAMPLE SUPPORTS THE USE OF PHENOTYPES BEYOND ALCOHOL DEPENDENCE DIAGNOSIS
WILEY-BLACKWELL. 2014: 309A
View details for Web of Science ID 000337523701435
- Summaries from the XIX World Congress of Psychiatric Genetics, Washington, DC, September 10-14, 2011. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2012; 159B (1): 128–29
The Effects of leptin on thermosensitive neurons in the anterior hypothalamus of the rat
FEDERATION AMER SOC EXP BIOL. 2011
View details for Web of Science ID 000310708400772
Limited associations of dopamine system genes with alcohol dependence and related traits in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD).
Alcoholism, clinical and experimental research
2011; 35 (2): 376–85
Over 50 years of evidence from research has established that the central dopaminergic reward pathway is likely involved in alcohol dependence (AD). Additional evidence supports a role for dopamine (DA) in other disinhibitory psychopathology, which is often comorbid with AD. Family and twin studies demonstrate that a common genetic component accounts for most of the genetic variance in these traits. Thus, DA-related genes represent putative candidates for the genetic risk that underlies not only AD but also behavioral disinhibition. Many linkage and association studies have examined these relationships with inconsistent results, possibly because of low power, poor marker coverage, and/or an inappropriate correction for multiple testing.We conducted an association study on the products encoded by 10 DA-related genes (DRD1-D5, SLC18A2, SLC6A3, DDC, TH, COMT) using a large, ethnically homogeneous sample with severe AD (n = 545) and screened controls (n = 509). We collected genotypes from linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) and employed a gene-based method of correction. We tested for association with AD diagnosis in cases and controls and with a variety of alcohol-related traits (including age-at-onset, initial sensitivity, tolerance, maximum daily drinks, and a withdrawal factor score), disinhibitory symptoms, and a disinhibitory factor score in cases only. A total of 135 SNPs were genotyped using the Illumina GoldenGate and Taqman Assays-on-Demand protocols.Of the 101 SNPs entered into standard analysis, 6 independent SNPs from 5 DA genes were associated with AD or a quantitative alcohol-related trait. Two SNPs across 2 genes were associated with a disinhibitory symptom count, while 1 SNP in DRD5 was positive for association with the general disinhibitory factor score.Our study provides evidence of modest associations between a small number of DA-related genes and AD as well as a range of alcohol-related traits and measures of behavioral disinhibition. While we did conduct gene-based correction for multiple testing, we did not correct for multiple traits because the traits are correlated. However, false-positive findings remain possible, so our results must be interpreted with caution.
View details for DOI 10.1111/j.1530-0277.2010.01353.x
View details for PubMedID 21083670
View details for PubMedCentralID PMC3443636
Effects of leptin on the firing rates of thermoregulatory neurons in the anterior hypothalamus
FEDERATION AMER SOC EXP BIOL. 2006: A1247
View details for Web of Science ID 000236326203449