John I Nurnberger

John I Nurnberger
Indiana University School of Medicine | IUSOM · Psychiatry, Medical and Molecular Genetics, and Medical Neuroscience

MD PhD

About

734
Publications
83,653
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54,692
Citations
Citations since 2017
143 Research Items
16904 Citations
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201720182019202020212022202305001,0001,5002,0002,5003,000
201720182019202020212022202305001,0001,5002,0002,5003,000

Publications

Publications (734)
Article
Introduction: Suicidal thoughts and behaviors have partially distinct genetic etiologies. Methods: We used PRS-CS to create polygenic risk scores (PRS) from GWAS of non-suicidal self-injury, broad sense self-harm ideation, non-fatal suicide attempt, death by suicide, and depression. Using mixed-effect models, we estimated whether these PRS were ass...
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Background and hypothesis: Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs....
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Alcohol use disorders (AUDs) and related electrophysiological endophenotypes have been associated with the GABRA2 gene. However, the causal variants in GABRA2 and their mechanisms of influence on AUD and its correlates have not been established. Here we investigate the phenotypic spectrum of a GABRA2 coding variant (rs279858) through a phenome-wide...
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Introduction: Alcohol use disorder (AUD) is on the ascendancy in the US older adult population. The association between AUD and adverse brain outcomes remains inconclusive. Method: In a retrospective cohort design using US insurance claim data (2007-2020), 129,182 individuals with AUD were matched with 129,182 controls by age, sex, race, and cli...
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The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the ge...
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Some styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater ri...
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Bipolar disorder (BD) is characterized by mood episodes, disrupted circadian rhythms and gray matter reduction in the brain. Lithium is an effective pharmacotherapy for BD, but not all patients respond to treatment. Lithium has neuroprotective properties and beneficial effects on circadian rhythms that may distinguish lithium responders (Li-R) from...
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Background: Researchers have identified genetic and neural risk factors for externalizing behaviors. However, it has not yet been determined if genetic risk is conferred in part through associations with more proximal neurophysiological risk markers. Methods: Participants from the Collaborative Study on the Genetics of Alcoholism, a large, family-b...
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Suicidal thoughts and behaviors have partially distinct genetic etiologies. We used PRS-CS to create polygenic risk scores (PRS) from GWAS of non-suicidal self-injury, broad sense self-harm ideation, non-fatal suicide attempt, death by suicide, and depression. Using mixed-effect models, we estimated whether these PRS were associated with a range of...
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Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk for BD in young people at high familial risk (HR) of BD. Peri...
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Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located wi...
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Bipolar disorder is an often-severe mental health condition characterized by alternation between extreme mood states of mania and depression. Despite strong heritability and the recent identification of 64 common variant risk loci of small effect, pathophysiological mechanisms remain unknown. Here, we analyzed genome sequences from 41 multiply-affe...
Preprint
Alcohol use disorder (AUD) is on the ascendancy in the US older adult population, while the association between AUD and adverse brain outcomes remains inconclusive. The objective of this work is to investigate the associations between AUD with the onset of Alzheimer’s disease and Parkinson’s disease. In a retrospective cohort design using US insura...
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We investigated gene–environment effects on structural brain endophenotype in bipolar disorder (BD) using a novel method of combining polygenic risk scores with epigenetic signatures since traditional methods of examining the family history and trauma effects have significant limitations. The study enrolled 119 subjects, including 55 BD spectrum (B...
Article
Bipolar disorder (BD) is a complex and dynamic condition with a typical onset in late adolescence or early adulthood followed by an episodic course with intervening periods of subthreshold symptoms or euthymia. It is complicated by the accumulation of comorbid medical and psychiatric disorders. The etiology of BD remains unknown and no reliable bio...
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Full-text available
Genome-wide association studies (GWAS) in admixed populations such as African American (AA) have limited sample sizes, resulting poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within...
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Full-text available
Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study...
Article
Cover image: The cover image is based on the Research Article Effects of polygenic risk for suicide attempt and risky behavior on brain structure in young people with familial risk of bipolar disorder by Bronwyn Overs, Janice Fullerton et al., https://doi.org/10.1002/ajmg.b.32879. The cover image, by Overs et al., depicts right hemisphere cortical...
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Background Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essentia...
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Background Genome-wide association studies (GWAS) have been conducted in Alcohol Use Disorder (AUD) and they permit the use of polygenic risk scores (PRS), in combination with clinical variables, to predict the onset of AUD in vulnerable populations. Methods 2794 adolescent/young adult subjects from the Collaborative Study on the Genetics of Alcoh...
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Bipolar disorder (BD) is associated with a 20–30‐fold increased suicide risk compared to the general population. First‐degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide‐related polygenic risk score...
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Bipolar disorder is typified by episodes of manic/hypomanic and depressive symptoms, either distinctly or concurrently as mixed symptoms. While depressive symptoms are the major driver of risk, it is unclear whether specific combinations of manic and anxiety symptoms contribute differentially to suicidal ideation and behavior in individuals with bi...
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Objective This work was undertaken to define and characterize the role of currently available somatic treatments in psychiatry in either increasing or reducing the risk for suicide. Methods Members of the Suicide Prevention Task Group of the National Network of Depression Centers performed a literature review of somatic treatments known to increas...
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Aims: Bipolar Disorder (BD) is associated with a 20-30 fold increased suicide risk compared to the general population. First-degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide-related polygenic risk...
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Genetic predispositions and environmental influences both play an important role in adolescent externalizing behavior; however, they are not always independent. To elucidate gene–environment interplay, we examined the interrelationships between externalizing polygenic risk scores, parental knowledge, and peer substance use in impacting adolescent e...
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Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we...
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Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association an...
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Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30–40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of “clock genes” and that lithium...
Preprint
Full-text available
Bipolar disorder is an often-severe mental health disorder characterized by alternation between extreme mood states of mania and depression. Despite strong heritability and the recent identification of 64 loci of small effect, pathophysiological mechanisms and much of the genetic risk remain unknown. Here, through genome sequencing and linkage and...
Article
Background: Suicidal thoughts and behaviors (STBs) and nonsuicidal self-injury (NSSI) behaviors are moderately heritable and may reflect an underlying predisposition to depression, impulsivity, and cognitive vulnerabilities to varying degrees. Objectives: We aimed to estimate the degrees of association between genetic liability to depression, im...
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Background Lithium is regarded as a first line treatment for bipolar disorder (BD), but partial response and non‐response commonly occurs. There exists a need to identify lithium non‐responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. Methods The P...
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Predictive models for recovering from alcohol use disorder (AUD) and identifying related predisposition biomarkers can have a tremendous impact on addiction treatment outcomes and cost reduction. Our sample (N = 1376) included individuals of European (EA) and African (AA) ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA) wh...
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A recent article by Franklin and Dwyer¹ analyzes genes identified in two previous genome‐wide association studies (GWAS) of bipolar disorder2,3. They establish that the 230 genes identified in the two studies are evolutionarily conserved (in C elegans and zebrafish but not in drosophila), that they contain regions of homology and are highly interac...
Preprint
Bipolar disorder (BD) is a neuropsychiatric disorder with genetic risk factors defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. While lithium is an effective drug for BD, 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of c...
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Background : It has not been established that suicide risk with mixed symptoms is any greater than the depressive component or if there is synergy between depressive and manic symptoms in conveying suicide risk. Methods : The National Network of Depression Centers Mood Outcomes Program collected data from measurement-based care for 17,179 visits f...
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Significance Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understanding the biology of alcohol use disorder (AUD). Methods Integration of “multi-omics” data is often necessary to nominate candidate causal variants and genes and prioritize them for follow up studies. Here, we used...
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Bipolar disorder is often comorbid with anxiety, which is itself associated with poorer clinical outcomes, including suicide. A better etiologic understanding of this comorbidity could inform diagnosis and treatment. The present study aims to test whether comorbid anxiety in bipolar disorder reflects shared genetic risk factors. We also sought to a...
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Background Aggression often occurs alongside alcohol and drug misuse. However, it is not clear whether the latent and manifest relations among alcohol‐related, drug‐related, and non–substance‐related aggression are separate manifestations of a single construct or instead are 3 distinct constructs. Methods To examine these associations, we conducte...
Preprint
BACKGROUND: Aggression often occurs alongside alcohol and drug misuse. However, it is not clear whether the latent and manifest relations among alcohol-related, drug-related, and non-substance-related aggression are separate manifestations of a single construct or instead are three distinct constructs. METHODS: To examine these associations, we con...
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Many studies demonstrate that marriage protects against risky alcohol use and moderates genetic influences on alcohol outcomes; however, previous work has not considered these effects from a developmental perspective or in high-risk individuals. These represent important gaps, as it cannot be assumed that marriage has uniform effects across develop...
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African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response to alcohol than European Americans. Genome‐wide association studies (GWAS) have identified genes/variants associated with alcohol dependence specifically in AA; however, the sample sizes are still not large enough to detect variants with small effects....
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Genome-wide, polygenic risk scores (PRS) have emerged as a useful way to characterize genetic liability. There is growing evidence that PRS may prove useful for early identification of those at increased risk for certain diseases. The current potential of PRS for alcohol use disorders (AUD) remains an open question. Using data from both a populatio...
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Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were t...
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The National Institute of Mental Health (NIMH) ‘fast-fail’ approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for...
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Shared genetic factors contribute to the high degree of comorbidity among externalizing problems (e.g. substance use and antisocial behavior). We leverage this common genetic etiology to identify genetic influences externalizing problems in participants from the Collaborative Study on the Genetics of Alcoholism (European ancestry = 7568; African an...
Article
Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest sing...
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Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity...
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Lithium (Li) is a medication long-used to treat bipolar disorder. It is currently under investigation for multiple nervous system disorders, including Alzheimer’s disease (AD). While perturbation of RNA levels by Li has been previously reported, its effects on the whole transcriptome has been given little attention. We, therefore, sought to determi...
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Background: Suicidality is a leading cause of death among adolescents. In addition to other psychiatric conditions, youths with attention-deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders (DBDs) are at heightened risk for suicide. Decision-making deficits are a hallmark symptom of ADHD and DBDs and are also implicated in suic...
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Background: As part of the ongoing Collaborative Study of the Genetics of Alcoholism, we performed a longitudinal study of a high risk cohort of adolescents/young adults from families with a proband with an alcohol use disorder, along with a comparison group of age-matched controls. The intent was to compare the development of alcohol problems in...
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Differences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Depende...
Preprint
Full-text available
Genome-wide, polygenic risk scores (PRS) have emerged as a useful way to characterize genetic liability using genotypic data. There is growing evidence that PRS may prove useful to identify those at increased risk for developing certain diseases. The current utility of PRS in relation to alcohol use disorders (AUD) remains an open question. Using d...
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Full-text available
Major psychiatric disorders are heritable but they are genetically complex. This means that, with certain exceptions, single gene markers will not be helpful for diagnosis. However, we are learning more about the large number of gene variants that, in combination, are associated with risk for disorders such as schizophrenia, bipolar disorder, and o...
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The level of response (LR) to alcohol as measured with the Self-Report of the Effects of Alcohol Retrospective Questionnaire (SRE) evaluates the number of standard drinks usually required for up to four effects. The need for a higher number of drinks for effects is genetically influenced and predicts higher risks for heavy drinking and alcohol prob...
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Genetic influences on alcohol and drug dependence partially overlap, however specific loci underlying this overlap remain unclear. We conducted a genome‐wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7,291 European‐Americans (EA; 2,927 cases) and 3,132 African‐Americans (AA: 1,315 cases)...
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Children's perceptions are important to understanding family environment in the bipolar disorder (BD)high-risk context. Our objectives were to empirically derive patterns of offspring-perceived family environment, and to test the association of family environment with maternal or paternal BD accounting for offspring BD and demographic characteristi...
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Genome‐wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (e.g., ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWASs of DSM‐IV AD (primary analysis), DSM‐IV AD criter...
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Background: Alcohol consumption and problems are increasing among older adults, who are at elevated risk for alcohol-related accidents and medical problems. This paper describes a pilot follow-up of older adults with a history of alcohol dependence that was designed to determine the feasibility of conducting a more extensive investigation. Method...
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Background Genome‐wide association studies (GWAS) have begun to identify loci related to alcohol consumption, but little is known about whether this genetic propensity overlaps with specific indices of problem drinking in ascertained samples. Methods In 6,731 European‐Americans who had been exposed to alcohol, we examined whether polygenic risk sc...
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Bipolar disorder (BD) is characterized by recurrent mood episodes, and circadian rhythm disturbances. Past studies have identified calcium channel genes as risk loci for BD. CACNA1C encodes an L-type calcium channel (LTCC) involved in the entrainment of circadian rhythms to light. Another calcium channel, i.e., the ryanodine receptor (RYR), is invo...
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Alcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially express...