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Recent findings in our lab demonstrated that the risk of cocaine relapse is closely linked to the hyperexcitability of cortical pyramidal neurons in the secondary motor cortex (M2), noticeable 45 days after cocaine intravenous self-administration (IVSA). The present study was designed to explore the underlying mechanisms of neuronal alterations in M2. Our hypothesis was that M2 neurons were affected directly by cocaine taking behaviors. This hypothesis was tested by monitoring individual neuronal activity in M2 using MiniScopes for in vivo Ca 2+ imaging in C57BL/6J mice when they had access to cocaine IVSA as a reinforcement (RNF) contingent to active lever press (ALP) but not to inactive lever press (ILP). With support of our established pipeline to processing Ca 2+ imaging data, the current study was designed to monitor M2 neuronal ensembles at the single-neuron level in real time with high temporal resolution and high throughput in each IVSA session and longitudinally among multiple IVSA sessions. Specifically, five consecutive 1-hr daily IVSA sessions were used to model the initial cocaine taking behaviors. Besides detailed analyses of IVSA events (ALP, ILP, and RNF), the data from Ca 2+ imaging recordings in M2 were analyzed by (1) comparing neuronal activation within a daily IVSA session (i.e., the first vs. the last 15 min) and between different daily sessions (i.e., the first vs. the last IVSA day), (2) associating Ca 2+ transients with individual IVSA events, and (3) correlating Ca 2+ transients with the cumulative effects of IVSA events. Our data demonstrated that M2 neurons are exquisitely sensitive to and significantly affected by concurrent operant behaviors and the history of drug exposure, which in turn sculpt the upcoming operant behaviors and the response to drugs. As critical nodes of the reward loop, M2 neurons appear to be the governing center orchestrating the establishment of addiction-like behaviors.

Research has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder (AUD), despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; mean age: 38). Within participants with an AUD diagnosis, we explored risk across other clinical conditions, polygenic scores (PGS) for comorbid psychiatric problems, and neurocognitive functioning for lifetime suicide attempt. Participants with an AUD who had attempted suicide had greater rates of trauma exposure, major depressive disorder, post-traumatic stress disorder, and other substance use disorders compared to those who had not attempted suicide. Polygenic scores for suicide attempt, depression, and PTSD were associated with reporting a suicide attempt (ORs = 1.22 - 1.44). Participants who reported a SA also had decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences relative to those who did not, but differences were small. Overall, individuals with an AUD who report a lifetime suicide attempt appear to experience greater levels of trauma, have more severe comorbidities, and carry polygenic risk for a variety of psychiatric problems. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders., Competing Interests: Disclosures The authors do not have any conflicts of interest to report.

Glucose-6-phosphate dehydrogenase (G6PD) protects red blood cells against oxidative damage through regeneration of NADPH. Individuals with G6PD polymorphisms (variants) that produce an impaired G6PD enzyme are usually asymptomatic, but at risk of hemolytic anemia from oxidative stressors, including certain drugs and foods. Prevention of G6PD deficiency-related hemolytic anemia is achievable through G6PD genetic testing or whole-genome sequencing (WGS) to identify affected individuals who should avoid hemolytic triggers. However, accurately predicting the clinical consequence of G6PD variants is limited by over 800 G6PD variants which remain of uncertain significance. There also remains significant variability in which deficiency-causing variants are included in pharmacogenomic testing arrays across institutions: many panels only include c.202G>A, even though dozens of other variants can also cause G6PD deficiency. Here, we seek to improve G6PD genotype interpretation using data available in the All of Us Research Program and using a yeast functional assay. We confirm that G6PD coding variants are the main contributor to decreased G6PD activity, and that 13% of individuals in the All of Us data with deficiency-causing variants would be missed if only the c.202G>A variant were tested for. We expand clinical interpretation for G6PD variants of uncertain significance; reporting that c.595A>G, known as G6PD Dagua or G6PD Açores, and the newly identified variant c.430C>G, reduce activity sufficiently to lead to G6PD deficiency. We also provide evidence that five missense variants of uncertain significance are unlikely to lead to G6PD deficiency, since they were seen in hemi- or homozygous individuals without a reduction in G6PD activity. We also applied the new WHO guidelines and were able to classify two synonymous variants as WHO class C. We anticipate these results will improve the accuracy, and prompt increased use, of G6PD genetic tests through a more complete clinical interpretation of G6PD variants. As the All of Us data increases from 245,000 to 1 million participants, and additional functional assays are carried out, we expect this research to serve as a template to enable complete characterization of G6PD deficiency genotypes. With an increased number of interpreted variants, genetic testing of G6PD will be more informative for preemptively identifying individuals at risk for drug- or food-induced hemolytic anemia.

Electronic health records, biobanks, and wearable biosensors contain multiple high-dimensional clinical data (HDCD) modalities (e.g., ECG, Photoplethysmography (PPG), and MRI) for each individual. Access to multimodal HDCD provides a unique opportunity for genetic studies of complex traits because different modalities relevant to a single physiological system (e.g., circulatory system) encode complementary and overlapping information. We propose a novel multimodal deep learning method, M-REGLE, for discovering genetic associations from a joint representation of multiple complementary HDCD modalities. We showcase the effectiveness of this model by applying it to several cardiovascular modalities. M-REGLE jointly learns a lower representation (i.e., latent factors) of multimodal HDCD using a convolutional variational autoencoder, performs genome wide association studies (GWAS) on each latent factor, then combines the results to study the genetics of the underlying system. To validate the advantages of M-REGLE and multimodal learning, we apply it to common cardiovascular modalities (PPG and ECG), and compare its results to unimodal learning methods in which representations are learned from each data modality separately, but the downstream genetic analyses are performed on the combined unimodal representations. M-REGLE identifies 19.3% more loci on the 12-lead ECG dataset, 13.0% more loci on the ECG lead I + PPG dataset, and its genetic risk score significantly outperforms the unimodal risk score at predicting cardiac phenotypes, such as atrial fibrillation (Afib), in multiple biobanks.

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6 , DALRD3 , CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder., Competing Interests: Chris German is employed by and hold stock or stock options in 23andMe, Inc. Erika L. Nurmi is on the Scientific Advisory Board for Myriad Genetics and Medical Advisory Board for Tourette Association of America and received Clinical trial funding from Emalex and Octapharma Pharmaceuticals. Jeremy Veenstra-VanderWeele has served on advisory boards or consulted with Roche, Novartis, and SynapDx; received research funding from Roche, Novartis, SynapDx, Seaside Therapeutics, Forest, Janssen, Acadia, Yamo, and MapLight; received stipends for editorial work from Wiley and Springer. Jens R. Wendland is a current employee and shareholder of Takeda Pharmaceuticals and a past employee and shareholder of F. Hoffmann-La Roche, Pfizer and Nestle Health Science. Cynthia M. Bulik reports: Pearson (author, royalty recipient).Peter Falkai reports no conflict of interest regarding this study and reports to have received financial support and Advisory Board: Richter, Recordati, Boehringer-Ingelheim, Otsuka, Janssen and Lundbeck. Hans J. Grabe has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. Ian B. Hickie is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney, Australia. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. Professor Hickie has previously led community-based and pharmaceutical industry-supported (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca, Janssen Cilag) projects focused on the identification and better management of anxiety and depression. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd which aims to transform mental health services through the use of innovative technologies. Benjamin M. Neale is a member of the scientific advisory board at Deep Genomics and Neumora. Christopher Pittenger consults and/or receives research support from Biohaven Pharmaceuticals, Freedom Biosciences, Ceruvia Lifesciences, Transcend Therapeutics, UCB BioPharma, and F-Prime Capital Partners. He owns equity in Alco Therapeutics. These relationships are not related to the current work. Dan J. Stein has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. Eric A. Storch reports receiving research funding to his institution from the Ream Foundation, International OCD Foundation, and NIH. He was formerly a consultant for Brainsway and Biohaven Pharmaceuticals in the past 12 months. He owns stock less than $5000 in NView/Proem for distribution related to the YBOCS scales. He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, Routledge, and Jessica Kingsley. Ole A. Andreasson reports to be a consultant to Cortechs.ai, Precision Health AS, speakers honorarium from Otsuka, Lundbeck, Sunovion, Janssen. Anders D. Børglum has received speaker fee from Lundbeck. David Mataix-Cols receives royalties for contributing articles to UpToDate, Wolters Kluwer Health, and personal fees for editorial work from Elsevier, all unrelated to the current work. Murray B. Stein has in the past 3 years received consulting income from Acadia Pharmaceuticals, BigHealth, Biogen, Bionomics, Boehringer Ingelheim, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, Otsuka, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). Joel Gelernter is paid for editorial work by the journal Complex Psychiatry. Pino Alonso has received funding from Biohaven, Boston Scientific, Medtronic. All other authors report no conflicts of interest.

Research has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder (AUD), despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; 17% Admixed African American ancestries; mean age: 38). We 1) conducted a genome-wide association study (GWAS) of SA and performed downstream analyses to determine whether we could identify specific biological pathways of risk, and 2) explored risk in aggregate across other clinical conditions, polygenic scores (PGS) for comorbid psychiatric problems, and neurocognitive functioning between those with AD who have and have not reported a lifetime suicide attempt. The GWAS and downstream analyses did not produce any significant associations. Participants with an AUD who had attempted suicide had greater rates of trauma exposure, major depressive disorder, post-traumatic stress disorder, and other substance use disorders compared to those who had not attempted suicide. Polygenic scores for suicide attempt, depression, and PTSD were associated with reporting a suicide attempt (ORs = 1.22-1.44). Participants who reported a SA also had decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences relative to those who did not, but differences were small. Overall, individuals with alcohol dependence who report SA appear to experience a variety of severe comorbidities and elevated polygenic risk for SA. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders., Competing Interests: Declarations Disclosures The authors do not have any conflicts of interest to report.

Although genome-wide association studies (GWAS) have identified loci associated with alcohol consumption and alcohol use disorder (AUD), they do not identify which variants are functional. To approach this, we evaluated the impact of variants in 3' untranslated regions (3'-UTRs) of genes in loci associated with substance use and neurological disorders using a massively parallel reporter assay (MPRA) in neuroblastoma and microglia cells. Functionally impactful variants explained a higher proportion of heritability of alcohol traits than non-functional variants. We identified genes whose 3'UTR activities are associated with AUD and alcohol consumption by combining variant effects from MPRA with GWAS results. We examined their effects by evaluating gene expression after CRISPR inhibition of neuronal cells and stratifying brain tissue samples by MPRA-derived 3'-UTR activity. A pathway analysis of differentially expressed genes identified inflammation response pathways. These analyses suggest that variation in response to inflammation contributes to the propensity to increase alcohol consumption., Competing Interests: Declaration of Interests The authors declare no competing interests.