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A high-resolution PheWAS approach to elucidate functional influences of alcohol-implicated variants from large-scale GWAS Wei Q. Deng1,2, Kyla Belisario1,2, Joshua Gray3, Emily Levitt1,2, Sandra Sanchez-Roige4, Abraham A. Palmer4, James MacKillop1,2,* 1. Peter Boris Centre for Addictions Research, St. Joseph’s Healthcare Hamilton, Hamilton, Ontario L8P 3R2, Canada; 2. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Canada; 3. Department of Medical and Clinical Psychology, Uniformed Services University, Bethesda, MD 20814, USA; 4. Department of Psychiatry, University of California San Diego, San Diego, CA, USA Methodology PRS-association Results Strategy: a high-resolution phenome-wide (PheWAS) approach, parsing GWAS findings derived from coarser phenotypes; Analytical units: 448 robustly-implicated risk variants for alcohol phenotypes and the polygenic risk scores (PRS) for sub-scales of the AUDIT (Consumption/Severity); Phenotypic outcomes: 41 curated phenotypes in 7 categories: alcohol use, alcohol reinforcing value, drinking motives, other addictive behaviors, commonly comorbid psychiatric syndromes, impulsivity, and personality; Study population: a community-based sample of 1,534 individuals of European ancestry; Conclusions: evidence of multifarious nature of genetic risk for alcohol consumption and problematic use, with genetic influences that act on both alcohol-specific and non-alcohol specific mechanisms. Abstract Materials Conclusion Population Assessment for Tomorrow’s Health (PATH) Registry - a community study by PBCAR on health behaviors - Participants completed psychological measures, a small number of cognitive tests, and provided DNA sample. - No clinical conditions were required - N = 1,534 samples with adequate genetic and phenotypic data A priori alcohol phenotype SNPs: - GWAS catalogue - Alcohol phenotype codes - Sample size > 10,000 in at least one homogenous population; - association p < 5E-8; - 448 (out of 546) SNP, RITM0024964, Strategy: a high-resolution phenome-wide (PheWAS) approach, parsing GWAS findings derived from coarser phenotypes; Analytical units: 448 robustly-implicated risk variants for alcohol phenotypes and the polygenic risk scores (PRS) for sub-scales of the AUDIT (Consumption/Severity); Phenotypic outcomes: 41 curated phenotypes in 7 categories: alcohol use, alcohol reinforcing value, drinking motives, other addictive behaviors, commonly comorbid psychiatric syndromes, impulsivity, and personality; Study population: a community-based sample of 1,534 individuals of European ancestry; Conclusions: evidence of multifarious nature of genetic risk for alcohol consumption and problematic use, with genetic influences that act on both alcohol-specific and non-alcohol specific mechanisms.

Whole Genome Sequence Analysis of Candidate Genes Identified Three Loci Potentially Related to Mefloquine Side Effects Monique Hollis-Perry1, Joshua Gray1, Dutchabong Shaw1,2, Daniel Hupalo1,2, Heidi Adams1,2, Xijun Zhang1,2, Matthew D. Wilkerson1, Lydia D. Hellwig1,2, Clifton Dalgard1, Jeffrey Livezey1, David Saunders1 1Uniformed Services University of Health Sciences Bethesda, MD; 2Henry Jackson Foundation for the Advancement of Military Medicine Bethesda, MD Gene Provided Data RSID Chr loc hg38 Site 1 ref/alt Site 2 ref/alt Site details ORM1 S rs17650,rs1126801 chr9 114323246. ; 114325132 G,G G,G ARG(CGG)20,VAL(GTG)156 ORM1 F1 rs17650,rs1126801 chr9 114323246. ; 114325132 G,A G,G GLN(CAG)20,VAL(GTG)156 ORM1 F2 rs17650,rs1126801 chr9 114323246. ; 114325132 G,A G,A GLN(CAG)20 MET(ATG)156 MTHFR A1298C rs1801131 chr1 11794419 A C p.Glu429Ala MTHFR C677T rs1801133 chr1 11796321 C T p.Ala222Val MDR1 C1236T rs1128503 chr7 87550285 A G p.Gly412Gly MDR1 G2677T rs2032582 chr7 87531302 A C p.Ala893Ser MDR1 C3435T rs1045642 chr7 87509329 A G p.Ile1145Ile PYK2 rs2883490 rs28834970 chr8 27337604 T C intronic HT2A rs7997012 rs7997012 chr13 46837850 A G intronic HT2A rs1928040 rs1928040 chr13 46873101 G A intronic HT2A rs6311 rs6311 chr13 46897343 C T intronic HT2A rs6313 rs6313 chr13 46895805 G A p.Ser34Ser ADA G22A rs73598374 chr20 44651586 C T p.Asp8Tyr ADORA2A (A2A) T1976C rs5751876 chr22 24441333 T C p.Tyr361Tyr ADORA2A (A2A) C2592T rs35320474 chr22 24441942 - T 3' UTR variant METHODS Volunteers with a history of exposure to mefloquine with or without adverse neuropsychiatric symptoms were invited to participate in this case-control cross-sectional study after interviews and medical records review. Investigators searched for potential associations within 7 candidate genes and 16 associated variants for study. Blood samples were collected in Paxgene RNA tubes from 50 volunteers. Mefloquine exposure was defined as: travel to an area with malaria prophylaxis recommendations; w, RITM0040216, Although mefloquine provides effective once-weekly antimalarial prophylaxis, this medication has fallen out of favor due to the risk of neuropsychiatric effects. These can appear after one or two doses, may be mild or severe and commonly include headaches, memory impairment, anxiety or depression, hallucinations, insomnia, and psychosis. Adverse events typically resolve after drug discontinuation, but some patients report long-term complications. While genetic susceptibilities have been identified, pharmacogenomic testing guidance for mefloquine use is not currently available.

RESEARCH POSTER PRESENTATION DESIGN © 2022 www.PosterPresentations.com 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% AUDIT-C severe Binge weekly+ Alcohol abuse/dependence DX PDHRA PTSD screen PTSDX PDHRA Depresion screen Depresion DX Adjustment Disorder DX Anxiety Disorder DX ADHDX SUDX Tobaco Use DX Curent tobaco use TBI DX Sleep DX Musculoskeletal pain Proabability of having diagnosis Latent Class Analysis Results 51.6% Relatively Healthy 17.3% Pain/Tobacco 13.1% Heavy Drinking/Pain/Tobacco 12.7% Mental Health/Pain/Tobacco/Sleep/TBI 5.4% Heavy Drinking/Mental Health/Pain/Tobacco/Sleep/TBI Military servicemembers drink at higher rates than their same-age civilian peers. Alcohol misuse is associated with increased rates of negative health outcomes including suicide and overdose. It also significantly impairs military readiness. At-risk alcohol use and alcohol use disorder (AUD) often co-occur with other psychological conditions. Such multimorbidity has been found to be associated with greater impairment and worse health outcomes than would be expected of individual conditions in isolation. Although multimorbidity itself is understood to occur at higher rates in individuals with at-risk drinking, specific types of multimorbidity (i.e., unique clinical profiles) remain poorly understood in this population. The purpose of this study is to understand multimorbidity clusters (i.e., co-occurring health conditions) among soldiers screening positive for post-deployment at-risk drinking. A better understanding of the mental and physical conditions that co-occur with at-risk drinking and AUD is necessary in order to better treat patients in an integrated fashion. INTRODUCTION METHODS RESULTS DISCUSSION Soldiers who screened positive for at-risk drinking during the postdeployment year are a heterogeneous group with varied multimorbidity clusters. The largest class, about half of the sample, was relatively healthy with few co-occurring conditions. Universal public health strategi, RITM0024966, Military servicemembers drink at higher rates than their same-age civilian peers. Alcohol misuse is associated with increased rates of negative health outcomes including suicide and overdose. It also significantly impairs military readiness. At-risk alcohol use and alcohol use disorder (AUD) often co-occur with other psychological conditions. Such multimorbidity has been found to be associated with greater impairment and worse health outcomes than would be expected of individual conditions in isolation. Although multimorbidity itself is understood to occur at higher rates in individuals with at-risk drinking, specific types of multimorbidity (i.e., unique clinical profiles) remain poorly understood in this population. The purpose of this study is to understand multimorbidity clusters (i.e., co-occurring health conditions) among soldiers screening positive for post-deployment at-risk drinking. A better understanding of the mental and physical conditions that co-occur with at-risk drinking and AUD is necessary in order to better treat patients in an integrated fashion.

Exploring the Feasibility of Digital Phenotyping in a Military Population Lauren S. Schultz1, Mikela A. Murphy1, Matthew F. Thompson1, Jonathan Knights2, Justin T. Baker2, Joshua C. Gray1 1Department of Medical and Clinical Psychology, Uniformed Services University, Bethesda, MD, 2Mindstrong Health, Inc., 303 Bryant Ave, Mountain View, CA 94041, USA INTRODUCTION • Mobile devices and wearable technology offer novel opportunities for researchers to collect moment-to-moment data points to estimate fluctuations in psychological and cognitive functioning (i.e., digital phenotyping) 1 • Studies utilizing passive data collection methods tend to experience greater sample retention and improved adherence and acceptance than studies utilizing active data collection due to less participant burden2 • Because of the presence of several help-seeking barriers in the military, data collection via digital phenotyping may provide valuable insight into mental health of military populations and offer a unique pathway to early intervention AIM: This study sought to investigate the feasibility of digital phenotyping in service members and veterans. RESULTS DISCUSSION • 100% of participants were willing to download and launch the app • All participants completed all 3 appointments, 0% attrition • Only one participant discontinued use of the app due to security concerns (i.e., concerns regarding what type of data would be collected from the app) • “The app has been a nuisance on the phone and I am not comfortable with the data collections portion of the app beyond surveys or task specific evaluation.” • While 3 participants complained of keyboard issues (e.g., different location of letter keys, typos), 2 participants discontinued use of the app due to keyboard issues after downloading the app • Keyboard issues were only reported by iOS users because the keys of the app’s keyboard are in a different location • There are unique security concerns related to data security within a military pop, RITM0016585, Mobile devices and wearable technology offer novel opportunities for researchers to collect moment-tomoment data points to estimate fluctuations in psychological and cognitive functioning (i.e., digital phenotyping) Studies utilizing passive data collection methods tend to experience greater sample retention and improved adherence and acceptance than studies utilizing active data collection due to less participant burden2 Because of the presence of several help-seeking barriers in the military, data collection via digital phenotyping may provide valuable insight into mental health of military populations and offer a unique pathway to early intervention AIM: This study sought to investigate the feasibility of digital phenotyping in service members and veterans.