About

Henry R Kranzler, MD, is the Karl E. Rickels Professor of Psychiatry at the University of Pennsylvania's Perelman School of Medicine. He serves as Co-Associate Director of Research at the VISN 4 Mental Illness Research, Education, and Clinical Center (VAMC) and is the Director of the Center for Studies of Addiction at PSOM. His professional focus is on addiction research, with particular emphasis on alcohol use disorder, opioid use, and nicotine dependence. Dr. Kranzler's work involves investigating the genetic and biological underpinnings of substance use disorders, including conducting large-scale meta-analyses and genome-wide association studies. His research aims to understand the genetic contributions to addiction and related traits, contributing to the development of targeted treatments and interventions.

Research topics

• Biology
• Medicine
• Genetics
• Psychiatry
• Psychology
• Computer Science
• Clinical psychology
• Internal medicine
• Neuroscience
• Computational biology
• Pharmacology
• Physical therapy
• Medical emergency
• Developmental psychology

Selected publications

• Mu-opioid receptor availability in patients with opioid use disorder treated with either methadone or buprenorphine

  medRxiv · 2025-10-08

  preprintOpen accessSenior author

  Abstract Methadone (MET) and buprenorphine (BUP)—mu-opioid receptor (MOR) agonists—are efficacious treatments for opioid use disorder (OUD). Using high-sensitivity, long axial field-of-view PET imaging with [ 11 C]carfentanil, we compared MOR availability in 5 MET and 5 BUP patients and 13 healthy controls (HCs) in five brain regions: ventral tegmentum, thalamus, caudate, putamen, and amygdala. MOR availability differed across groups (F 10,34 =5.6, p<0.001) and was lower in BUP patients than HCs across all brain regions (mean reduction=39.1±15.2%; p<0.001), lower in MET patients than HCs in the ventral tegmentum and amygdala (p’s<0.05), and lower in BUP than MET patients in four of five regions (p’s<0.05). MOR availability was inversely related to serum drug levels, linear for MET (R²=0.83, linear) and logarithmic for BUP (R²=0.96). [ 11 C]carfentanil PET may be useful in guiding personalized OUD treatment based on receptor engagement, which differs significantly between the two opioid agonist treatments. Studies are needed to link MOR availability with specific clinical characteristics (e.g., hedonic capacity, MOR agonist-associated weight gain) and OUD treatment outcomes.

  PublisherOA PDFDOI

• Disaggregating the Genetic Overlap Between Educational Attainment and Substance Use Phenotypes

  medRxiv · 2025-07-18

  preprintOpen accessSenior author

  Abstract Background Educational attainment (EA) is positively genetically correlated with alcohol and cannabis use, but negatively correlated with alcohol and cannabis use disorders. These opposing associations suggest that shared genetic influences differ by level of substance involvement and for the cognitive (CogEA) and non-cognitive (NonCogEA) components of EA. Methods To test this, we examined the shared genetic architecture of EA, CogEA, and NonCogEA with alcohol consumption (AC), alcohol use disorder (AUD), lifetime cannabis use (CanUse), and cannabis use disorder (CUD). We used bivariate causal mixture models, local genetic correlation analyses, and conditional/conjunctional false discovery rate analyses to identify polygenic, regional, and variant-level overlap. Results For variants shared with AC, 48.12% and 52.86% showed concordant effects with CogEA and NonCogEA, respectively, compared to 38.40% and 41.02% for AUD. For CanUse, 71.42% and 65.56% of shared variants were concordant with CogEA and NonCogEA, respectively, versus 37.97% and 42.23% for CUD. Jointly associated loci were identified for each substance-EA pair. AUD and CogEA variants were enriched for expression in the basal ganglia, CUD and CogEA in the substantia nigra, and CanUse and NonCogEA in the cerebellum and its hemispheres. Conclusions Although EA is associated with greater substance use and lower risk for disorder, this pattern reflects a complex mix of concordant and discordant variant effects. CogEA and NonCogEA show partially distinct patterns, particularly for cannabis-related traits, highlighting the importance of disaggregating EA to clarify the genetic architecture underlying its paradoxical associations with substance-related traits.

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• T23. MULTIVARIATE, MULTIOMIC ANALYSIS IN 799,429 INDIVIDUALS IDENTIFIES 134 LOCI ASSOCIATED WITH SOMATOFORM TRAITS

  European Neuropsychopharmacology · 2025-10-01

  articleOpen accessSenior author

  Somatoform traits, which manifest as persistent physical symptoms without a clear medical cause, are prevalent and pose significant challenges to clinical practice. Persistent physical symptoms have complex etiologies and often co-occur with one another and with psychiatric disorders. Their co-occurrence with psychiatric disorders has led to their inclusion in empirically based models of psychopathology, including the Hierarchical Taxonomy of Psychopathology (HiTOP). Understanding the genetic basis of these traits could improve diagnostic and therapeutic approaches and inform psychiatric nosology models. With publicly available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multiomic analysis of four somatoform traits—fatigue, irritable bowel syndrome, pain intensity, and health satisfaction—in an effective sample size of 799,429 individuals genetically similar to European reference panels. Additionally, we conducted drug repurposing analyses to identify potential druggable targets and Mendelian randomization analyses to identify potential causal effects of gut microbiota abundance on somatoform traits. Using genomic structural equation modeling, GWAS identified 134 loci significantly associated with a somatoform common factor, including 44 loci not significant in the input GWAS and 8 novel loci for somatoform traits. Gene-property analyses highlighted an enrichment of genes involved in synaptic transmission and enriched gene expression in 12 brain tissues. Six genes, including members of the CD300 family, had putatively causal effects mediated by protein abundance. There was substantial polygenic overlap (76-83%) between the somatoform and externalizing, internalizing, and general psychopathology factors. Somatoform polygenic scores were associated most strongly with obesity, Type 2 diabetes, tobacco use disorder, and mood/anxiety disorders in independent biobanks. Drug repurposing analyses suggested potential therapeutic targets, including MEK inhibitors. Mendelian randomization indicated potentially protective effects of gut microbiota, including Ruminococcus bromii. Consistent with emerging medical and genetic knowledge, somatoform traits have a shared etiology and considerable polygenic overlap with psychopathology. Given the high polygenic and phenotypic overlap with psychopathology, our results support the inclusion of a proposed somatoform spectrum in the HiTOP framework. These findings underscore the need for treatment approaches that recognize the interconnectedness of physical and mental health. The biological insights from drug repurposing and Mendelian randomization analyses could provide promising avenues for treatment development.

  PublisherDOI

• W90. MAJOR DEPRESSIVE DISORDER AMPLIFIES THE COMBINED EFFECT OF POLYGENIC RISK AND CHILDHOOD TRAUMA ON RISK OF LIFETIME SUICIDE ATTEMPT

  European Neuropsychopharmacology · 2025-10-01

  articleOpen access

  Suicidal behavior emerges from a complex interplay of genetic and environmental risk factors. Prior findings show that cumulative childhood trauma (CT) moderates the effect of suicide attempt (SA) polygenic risk score (SA PRS), with genetic risk more strongly associated with SA among individuals exposed to greater trauma. However, it is unclear whether this relationship varies by history of major depressive disorder (MDD), another key risk factor for suicidal behavior. MDD may reflect or exacerbate the expression of genetically influenced traits and may intensify the influence of genetic risk for suicide, particularly when combined with early-life trauma. This study examined whether lifetime MDD status moderates the interaction between SA PRS and CT in predicting lifetime SA using a PRS derived from the largest GWAS meta-analysis of SA to date (N = 958,896; present analyses restricted to European (EUR) ancestry participants [35,311 cases/777,575 controls]). Data were analyzed from 3,176 EUR adults who participated in the Yale-Penn study, which was designed for genetic research on psychiatric and substance use disorders. PRS-CS software was used to generate the PRS. Logistic regression tested associations between PRS and lifetime suicide attempt, adjusting for age, sex, the top 10 genetic principal components, lifetime MDD, and CT. Two- and three-way interactions between SA PRS, CT, and MDD were also included. Twelve percent of the sample (N=379) reported a suicide attempt, and 16.7% (N=519) reported MDD. Higher SA PRS (OR=1.46, 95%CI=1.29-1.65), cumulative CT (OR=1.82, 95%CI=1.62-2.03), and MDD diagnosis (OR=2.39, 95%CI=1.82-3.13) were each independently associated with suicide attempt. A three-way interaction also emerged (SA PRS × cumulative CT × MDD; OR=1.48, 95%CI=1.14–1.89), suggesting MDD modifies the joint effect of genetic risk and childhood trauma on suicide attempt. Among individuals with MDD (Figure 1), the predicted probability of suicide attempt increased from 12% (low PRS, no trauma) to 61% (high PRS, high trauma), compared to a smaller increase—from 2% to 32%—in those without MDD (Figure 2). MDD shapes how polygenic risk and early-life adversity interact to influence suicide risk. The combined effect of genetic liability and childhood trauma was substantially greater among individuals with MDD than those without, indicating MDD may amplify the impact of this gene-environment interaction. MDD may reflect underlying vulnerabilities—such as heightened stress reactivity—that increase susceptibility to suicide attempts. Incorporating polygenic risk information alongside diagnostic and trauma history may enhance risk stratification and support more precise prevention efforts.

  PublisherDOI

• Etiological basis for chronic pain genetic variation in brain and dorsal root ganglia cell types

  medRxiv · 2025-07-03 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Chronic pain is a complex clinical problem comprising multiple conditions that may share a common genetic profile. Genome-wide association studies (GWAS) have identified many risk loci whose cell-type context remains unclear. Here, we integrated GWAS data on chronic pain ( N = 1,235,695) with single-cell RNA sequencing (scRNA-seq) data from human brain and dorsal root ganglia (hDRG), and single-cell chromatin accessibility data from human brain and mouse dorsal horn. Pain-associated variants were enriched in glutamatergic neurons; mainly in prefrontal cortex, hippocampal CA1-3, and amygdala. In hDRG, the hPEP.TRPV1/A1.2 neuronal subtype showed robust enrichment. Chromatin accessibility analyses revealed variant enrichment in excitatory and inhibitory neocortical neurons in brain and in midventral neurons and oligodendrocyte precursor cells in the mouse dorsal horn. Gene-level heritability in the brain highlighted roles for kinase activity, GABAergic synapses, axon guidance, and neuron projection development. In hDRG, implicated genes related to glutamatergic signaling and neuronal projection. In cervical DRG of patients with acute or chronic pain ( N = 12), scRNA-seq data from neuronal or non-neuronal cells were enriched for chronic pain-associated genes (e.g., EFNB2 , GABBR1 , NCAM1 , SCN11A ). This cell-type-specific genetic architecture of chronic pain across central and peripheral nervous system circuits provides a foundation for targeted translational research.

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• Robust inference and widespread genetic correlates from a large-scale genetic association study of human personality

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-20 · 12 citations

  preprintOpen access

  Personality traits describe stable differences in how individuals think, feel, and behave and how they interact with and experience their social and physical environments. We assemble data from 46 cohorts including 611K-1.14M participants with European-like and African-like genomes for genome-wide association studies (GWAS) of the Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness to experience), and data from 51K participants for within-family GWAS. We identify 1,257 lead genetic variants associated with personality, including 823 novel variants. Common genetic variants explain 4.8%-9.3% of the variance in each trait, and 10.5%-16.2% accounting for measurement unreliability. Genetic effects on personality are highly consistent across geography, reporter (self vs. close other), age group, and measurement instrument, and we find minimal spousal assortment for personality in recent history. In stark contrast to many other social and behavioral traits, within-family GWAS and polygenic index analyses indicate little to no shared environmental confounding in genetic associations with personality. Polygenic prediction, genetic correlation, and Mendelian randomization analyses indicate that personality genetics have widespread, potentially causal associations with a wide range of consequential behaviors and life outcomes. The genetic architecture of personality is robust and fundamental to being a human.

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• Effect of smartphone breathalyzer feedback on willingness to drive in moderately intoxicated individuals: A randomized trial.

  Psychology of Addictive Behaviors · 2025-08-14

  articleOpen access

  OBJECTIVE: The present study examined the impact of smartphone breathalyzer feedback on individuals' decisions to drive when they are moderately intoxicated. Although the legal driving limit for blood alcohol concentration (BAC) in the United States is < 0.08%, crash risk begins to increase at moderate BACs ≥ 0.04%. METHOD: We conducted a laboratory-based, randomized controlled trial in 20 adult drivers aged 21-39 with a history of binge drinking. Participants were given sex- and weight-based doses of alcohol over 90 min with a target peak BAC of 0.10%. Smartphone breathalyzer measurements were taken every 15 min until the participant's BAC declined to 0.03%. Ten participants received feedback on their BAC readings, while the other 10 were blinded to BAC readings. After each measurement, participants were asked to rate on 10-point scales how much they were intoxicated, able to drive, and willing to drive. RESULTS: s < .001. CONCLUSIONS: Being aware of their BAC may make drinkers more willing to drive up to the legal BAC limit of 0.08%, despite being in a range associated with increased crash risk. We recommend that breathalyzer apps provide salient feedback about the risks of driving with a BAC in the moderately intoxicated range. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

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• Moderation of treatment outcomes by polygenic risk for alcohol‐related traits in placebo‐controlled trials of topiramate

  Alcohol Clinical and Experimental Research · 2025-05-30 · 1 citations

  articleOpen access1st authorCorresponding

  BACKGROUND: In two 12-week, randomized, placebo-controlled trials (RCTs) in individuals with alcohol use disorder (AUD), topiramate significantly reduced heavy drinking days (HDDs), and alcohol-related problems. In a secondary analysis of those findings, we examined four broad measures of genetic risk-polygenic scores (PGS)-of problematic alcohol use (PAU), drinks per week (DPW), and time to relapse to any drinking (TR) and heavy drinking (THR) as moderators of topiramate's effect on HDDs and alcohol-related problems. METHODS: We analyzed data from 285 individuals with AUD (65.6% male) of European-like ancestry, who were treated with either topiramate (49.1%) or placebo (50.9%). All patients underwent genome-wide array genotyping, and PGS were calculated using summary statistics from genome-wide association studies of PAU, DPW, and TR and THR (two time-to-event outcomes among patients treated in AUD pharmacotherapy trials). We hypothesized an interaction effect in which greater genetic risk-particularly for PAU-would be associated with a greater therapeutic response to topiramate than placebo. RESULTS: As shown previously, topiramate significantly reduced both HDDs (odds ratio [OR] = 0.50, p < 0.001) and Short Index of Problems (SIP) scores (b = -3.04, p < 0.001) more than placebo. There were nonsignificant associations of higher PGS with more HDDs (OR = 1.17, 95% CI = 0.98-1.41, p = 0.091) and a greater reduction in HDDs in the topiramate group (OR = 0.80, 95% CI = 0.62-1.03, p = 0.089). There were also significant interaction effects with treatment on SIP score by PGS for PAU (b = -1.64, SE = 0.78, p = 0.033), TR (b = -2.16, SE = 0.72, p = 0.003), and TRH (b = -2.17, SE = 0.72, p = 0.003). CONCLUSIONS: These findings provide proof of principle for the use of alcohol-related PGS as moderators of the effects of topiramate for treating AUD. Larger RCTs of topiramate are needed to provide adequate statistical power to validate this pharmacogenetic approach to precision AUD treatment.

  PublisherOA PDFDOI

• Genotype‐by‐sex interaction analyses for alcohol use disorder across biobanks

  Alcohol Clinical and Experimental Research · 2025-09-29 · 1 citations

  articleOpen access

  Abstract Background Alcohol use and alcohol use disorder (AUD) are significant contributors to morbidity and mortality, with different prevalences between males and females. Despite the established genetic contribution to AUD, sex as a biological variable and the interplay with genetic factors in the disorder remain largely unexplored. This study aimed to address the key question as to how genetic variations interact with biological sex to influence the AUD risk. Methods We conducted genome‐wide genotype‐by‐sex (G × S) interaction analyses using multiancestry datasets from the Million Veteran Program (MVP) and UK Biobank (UKB). In total, 1,039,476 participants were analyzed, comprising 150,429 AUD cases and 889,046 controls. AUD cases were defined using ICD‐9/10 codes in the MVP and using ICD‐10 codes (field ID 41270) along with self‐reported history of alcohol addiction (field ID 20406) in the UKB. Results In single‐ancestry analyses, we identified two loci in African ancestry samples with lead single‐nucleotide polymorphisms (SNPs) rs2183020 ( p = 1.82 × 10 −8 ) and rs9304803 ( p = 4.66 × 10 −8 ), and one locus in Admixed American ancestry samples with lead SNP rs9527196 ( p = 2.83 × 10 −8 ). The cross‐ancestry meta‐analysis identified one additional locus with lead SNP rs62446539 ( p = 3.95 × 10 −8 ). The deep learning method predicted that rs9304803 has B‐cell type‐specific enhancer activity. Rs2183020 and rs9304803 exhibited expression quantitative trait locus (eQTL) effects on multiple genes across various tissues, including the brain. Further experiments in ethanol‐exposed human neurons confirmed expression changes in several of these genes. Phenome‐wide association analyses revealed significant associations between rs2183020 and weight/body mass index, and between rs9304803 and prothrombin time (measured as international normalized ratio). Conclusions We believe this is the first genome‐wide G × S study of AUD, providing novel insights into the genetic basis of sex differences in AUD and advancing our understanding of its biological underpinnings.

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• [ ¹¹ C]Carfentanil PET Whole-Body Imaging of μ-Opioid Receptors: A First in-Human Study

  Journal of Nuclear Medicine · 2025-05-08

  articleSenior author

  μ-opioid receptors (MORs) are G-coupled receptors widely expressed in the brain and body. MORs have a high affinity for both endogenous opioids such as β-endorphins and exogenous opioids such as fentanyl. They mediate pain and reward and have been implicated in the pathophysiology of opioid, cocaine, and other substance use disorders. Using an instrument with a long axial field of view and the MOR-selective radioligand [¹¹C]carfentanil, we measured the whole-body distribution of MORs in 13 healthy humans. We also examined sex differences in MOR distribution at baseline and after pretreatment with the MOR antagonist naloxone. <b>Methods:</b> Six female and 7 male healthy subjects underwent 2 [¹¹C]carfentanil PET imaging sessions—one at baseline and one immediately after pretreatment with the MOR antagonist naloxone (13 μg/kg). Whole-body PET imaging was performed on an instrument with a 142-cm axial bore. [¹¹C]carfentanil brain distribution volume ratios were determined using the occipital cortex and the visual cortex within it as reference regions. For peripheral organ distribution volume ratios, the descending aorta and proximal-extremity muscle (biceps/triceps) were used as reference regions. <b>Results:</b> Naloxone blockade reduced MOR availability by 40%–50% in the caudate, putamen, thalamus, amygdala, and ventral tegmentum, brain regions known to express high levels of MORs. Women showed greater receptor occupancy in the thalamus, amygdala, hippocampus, and frontal and temporal lobes and a greater naloxone-induced reduction in thalamic MOR availability than men (<i>P</i> &lt; 0.05). For determining brain MOR availability, there was less variance in the visual cortex than in the occipital cortex reference region. For peripheral MOR determination, the descending aorta reference region showed less variance than the extremity muscle, but both showed blocking effects of naloxone. <b>Conclusion:</b> [¹¹C]carfentanil whole-body PET scans are useful for understanding MOR physiology under both baseline and blocking conditions. Extra–central nervous system reference regions may be useful for quantifying radiotracers when a region devoid of binding in the central nervous system is unavailable. The long axial field of view was useful for measuring changes in the short-lived radiotracer [¹¹C]carfentanil, with and without naloxone blocking. Further research is needed to evaluate the behavioral and clinical relevance of sex differences in naloxone–MOR interactions.

  PublisherDOI

Recent grants

• Penn PET Addiction Center of Excellence (Penn PACE)

  NIH · $19.1M · 2019–2025

• NIH Grant R01AA011062

  NIH · $1.4M · 2002

• NIH Grant R01DA018432

  NIH · $3.5M · 2012

• NIH Grant I01BX003341

  NIH · 2017

• NIH Grant M01RR006192

  NIH · $5.1M · 2011

Frequent coauthors

• Joel Gelernter

  1809 shared

• Lindsay A. Farrer

  Framingham Heart Study

  532 shared

• Jonathan Covault

  University of Connecticut

  391 shared

• Raymond F. Anton

  Medical University of South Carolina

  331 shared

• Renato Polimanti

  330 shared

• Rachel L. Kember

  305 shared

• Hongyu Zhao

  Jilin Academy of Traditional Chinese Medicine

  271 shared

• Hang Zhou

  Sun Yat-sen University

  231 shared

Labs

• Kranzler LabPI

Education

• Psychiatric Residency, Psychiatry

  University of Connecticut School of Medicine

  1986

• M.D.

  Rutgers Robert Wood Johnson Medical School

  1982

Awards & honors

• Karl E. Rickels Professor of Psychiatry
• Director, Center for Studies of Addiction (PSOM)