Browsing by Author "Miller, Alex P."

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    A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency
    (Springer, 2024) Thomas, Nathaniel S.; Gillespie, Nathan A.; Chan, Grace; Edenberg, Howard J.; Kamarajan, Chella; I-Chun Kuo, Sally; Miller, Alex P.; Nurnberger, John I., Jr.; Tischfield, Jay; Dick, Danielle M.; Salvatore, Jessica E.; Medical and Molecular Genetics, School of Medicine
    Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.
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    Binge drinking trajectories across adolescence and early adulthood: Associations with genetic influences for dual-systems impulsive personality traits, alcohol consumption, and alcohol use disorder
    (medRxiv, 2024-10-16) Miller, Alex P.; Spychala, Kellyn M.; Slutske, Wendy S.; Fromme, Kim; Gizer, Ian R.; Psychiatry, School of Medicine
    Binge drinking is a relatively common pattern of alcohol use among youth with normative frequency trajectories peaking in emerging and early adulthood. Frequent binge drinking is a critical risk factor for not only the development of alcohol use disorders (AUDs) but also increased odds of alcohol-related injury and death, and thus constitutes a significant public health concern. Changes in binge drinking across development are strongly associated with changes in impulsive personality traits (IPTs) which have been hypothesized as intermediate phenotypes associated with genetic risk for heavy alcohol use and AUD. The current study sought to examine the extent to which longitudinal changes in binge drinking and intoxication frequency across adolescence and early adulthood are associated with genetic influences underlying dual-systems IPTs (i.e., top-down [lack of self-control] and bottom-up [sensation seeking and urgency] constructs) alongside genetic risk for alcohol consumption and AUD. Associations were tested using conditional latent growth curve polygenic score (PGS) models in three independent longitudinal samples (N=10,554). Results suggested consistent significant and independent associations across all samples between sensation seeking PGSs and model intercepts (i.e., higher frequency of binge drinking at first measurement occasion) and alcohol consumption PGSs and model slopes (i.e., steeper increases toward peak binge drinking frequency). Urgency PGSs were not significantly associated with changes in binge drinking or intoxication frequency. Collectively, these findings highlight the role of unique but correlated IPT and alcohol-specific genetic factors in the emergence and escalation of binge drinking during adolescence and early adulthood.
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    Correlates of attendance in mental health services for individuals with psychotic disorders: A critical review
    (Taylor & Francis, 2016) Bonfils, Kelsey A.; Bouchard, Lauren; Kukla, Marina; Miller, Alex P.; McGuire, Alan B.; Department of Psychology, School of Science
    Low attendance to mental health care results in loss of time, money, and treatment gains. No prior review in this area has taken into account the quality of studies or varying definitions of attendance. The current review provides a critical evaluation of variables associated with attendance in consumers with psychotic symptoms participating in outpatient mental health services, with a focus on study quality and operationalization of attendance. EMBASE, MEDLINE, PsycINFO, CINAHL, and the Cochrane Library were searched for empirical articles relevant to attendance to mental health services by individuals diagnosed with a psychotic disorder. Eligible articles were rated for quality by two coauthors; high-quality articles were reviewed in-depth. Twenty-eight articles were eligible; 11 articles qualified for in-depth review. Four attendance outcome types were identified, including the prediction of dropout, time engaged, categorical attendance, and continuous attendance. Ongoing substance use during treatment was consistently associated with lower attendance in high-quality articles. More high-quality research using systematically defined outcome types is needed to identify reliable associations with attendance. Commonly tested variables such as demographics show little utility in predicting attendance. Future research in this area should expand upon current findings focusing on clinically and theoretically relevant variables.
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    Genetic Risk for Alcohol Use Disorder in Relation to Individual Symptom Criteria: Do Polygenic Indices Provide Unique Information for Understanding Severity and Heterogeneity?
    (medRxiv, 2024-09-23) Kim, Yongguk; Lane, Sean P.; Miller, Alex P.; Wilhelmsen, Kirk C.; Gizer, Ian R.; Psychiatry, School of Medicine
    Alcohol Use Disorder (AUD) is a heterogenous category with many unique configurations of symptoms. Previous investigations of AUD heterogeneity using molecular genetics methods studied the association between genetic liability and individual AUD symptoms at the latent level or focusing on a small number of genetic variants. Notably, these studies did not investigate potential severity differences between symptoms in their genetic analyses. Therefore, the current study aimed to examine the genetic risk for individual AUD symptom criteria by using a polygenic risk score (PRS) approach to assess the relative severity of each AUD symptom and test for associates with AUD symptoms above and beyond a unidimensional AUD construct. An AUD PRS was created using summary statistics obtained from published genome-wide association studies (GWAS), and Multiple Indicators Multiple Causes (MIMIC) models were employed to examine the effect of the PRS on overall AUD severity as well as on individual symptoms after accounting for this overall effect. The phenotypic severity of AUD symptoms was highly correlated with the genetic severity of AUD symptoms (r = 0.78). Results of MIMIC models indicated that the AUD PRS significantly predicted the AUD factor. Regression paths testing the unique, direct effects of the PRS on individual AUD symptoms, independent of the latent AUD factor, were not significant. These results imply that PRSs derived from GWAS of AUD influence symptom expression through a single genetic factor that is highly correlated with the relative severity of individual symptoms when measured at the phenotypic level. Item-level GWAS of AUD symptoms are needed to further parse heterogeneous symptom expression and allow for more nuanced tests of these conclusions.
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    Managing physical and mental health conditions: Consumer perspectives on integrated care
    (Taylor & Francis, 2017) Rollins, Angela L.; Wright-Berryman, Jennifer; Henry, Nancy H.; Quash, Alicia M.; Benbow, Kyle; Bonfils, Kelsey A.; Hedrick, Heidi; Miller, Alex P.; Firmin, Ruth L.; Salyers, Michelle P.; Department of Psychology, School of Science
    Despite the growing trend of integrating primary care and mental health services, little research has documented how consumers with severe mental illnesses (SMI) manage comorbid conditions or view integrated services. We sought to better understand how consumers perceive and manage both mental and physical health conditions and their views of integrated services. We conducted semi-structured interviews with consumers receiving primary care services integrated in a community mental health setting. Consumers described a range of strategies to deal with physical health conditions and generally viewed mental and physical health conditions as impacting one another. Consumers viewed integration of primary care and mental health services favorably, specifically its convenience, friendliness, and knowledge of providers, and collaboration between providers. Although integration was viewed positively, consumers with SMI may need a myriad of strategies and supports to both initiate and sustain lifestyle changes that address common physical health problems.
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    Multi-ancestral genome-wide association study of clinically defined nicotine dependence reveals strong genetic correlations with other substance use disorders and health-related traits
    (medRxiv, 2025-02-03) Johnson, Emma C.; Lai, Dongbing; Miller, Alex P.; Hatoum, Alexander S.; Deak, Joseph D.; Balbona, Jared V.; Baranger, David A. A.; Galimberti, Marco; Sanichwankul, Kittipong; Thorgeirsson, Thorgeir; McColbert, Sarah; Sanchez-Roige, Sandra; Adhikari, Keyrun; Docherty, Anna; Degenhardt, Louisa; Edwards, Tobias; Fox, Louis; Giannelis, Alexandros; Jeffries, Paul; Korhonen, Tellervo; Morrison, Claire; Nunez, Yaira Z.; Palviainen, Teemu; Su, Mei-Hsin; Romero Villela, Pamela N.; Wetherill, Leah; Willoughby, Emily A.; Zellers, Stephanie; Bierut, Laura; Buchwald, Jadwiga; Copeland, William; Corley, Robin; Friedman, Naomi P.; Foroud, Tatiana M.; Gillespie, Nathan A.; Gizer, Ian R.; Heath, Andrew C.; Hickie, Ian B.; Kaprio, Jaakko A.; Keller, Matthew C.; Lee, James L.; Lind, Penelope A.; Madden, Pamela A.; Maes, Hermine H. M.; Martin, Nicholas G.; McGue, Matt; Medland, Sarah E.; Nelson, Elliot C.; Pearson, John V.; Porjesz, Bernice; Stallings, Michael; Vrieze, Scott; Wilhelmsen, Kirk C.; Walters, Raymond K.; Polimanti, Renato; Malison, Robert T.; Zhou, Hang; Stefansson, Kari; Potenza, Marc N.; Mutirangura, Apiwat; Shotelersuk, Vorasuk; Kalayasiri, Rasmon; Edenberg, Howard J.; Gelernter, Joel; Agrawal, Arpana; Medical and Molecular Genetics, School of Medicine
    Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement. We conducted a genome-wide association study of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry, 10,231 of African ancestry, 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes. We replicated the well-known association at the CHRNA5 locus (lead SNP: rs147144681, p =1.27E-11 in European ancestry; lead SNP = rs2036527, p = 6.49e-13 in cross-ancestry analysis). DSM-NicDep showed strong positive genetic correlations with cannabis use disorder, opioid use disorder, problematic alcohol use, lung cancer, material deprivation, and several psychiatric disorders, and negative correlations with respiratory function and educational attainment. A polygenic score of DSM-NicDep predicted DSM-5 tobacco use disorder and 6 of 11 individual diagnostic criteria, but none of the Fagerström Test for Nicotine Dependence (FTND) items, in the independent NESARC-III sample. In genomic structural equation models, DSM-NicDep loaded more strongly on a previously identified factor of general addiction liability than did a "problematic tobacco use" factor (a combination of cigarettes per day and nicotine dependence defined by the FTND). Finally, DSM-NicDep was strongly genetically correlated with a GWAS of tobacco use disorder as defined in electronic health records, suggesting that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics of this disorder.
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    Neuroanatomical Variability and Substance Use Initiation in Late Childhood and Early Adolescence
    (American Medical Association, 2024-12-02) Miller, Alex P.; Baranger, David A. A.; Paul, Sarah E.; Garavan, Hugh; Mackey, Scott; Tapert, Susan F.; LeBlanc, Kimberly H.; Agrawal, Arpana; Bogdan, Ryan; Psychiatry, School of Medicine
    Importance: The extent to which neuroanatomical variability associated with early substance involvement, which is associated with subsequent risk for substance use disorder development, reflects preexisting risk and/or consequences of substance exposure remains poorly understood. Objective: To examine neuroanatomical features associated with early substance use initiation and to what extent associations may reflect preexisting vulnerability. Design, setting, and participants: Cohort study using data from baseline through 3-year follow-up assessments of the ongoing longitudinal Adolescent Brain Cognitive Development Study. Children aged 9 to 11 years at baseline were recruited from 22 sites across the US between June 1, 2016, and October 15, 2018. Data were analyzed from February to September 2024. Exposures: Substance use initiation through 3-year follow-up (ie, age <15 years). Main outcomes and measures: Self-reported alcohol, nicotine, cannabis, and other substance use initiation and baseline magnetic resonance imaging (MRI)-derived estimates of brain structure (ie, global and regional cortical volume, thickness, surface area, sulcal depth, and subcortical volume). Covariates included family (eg, familial relationships), pregnancy (eg, prenatal exposure to substances), child (eg, sex and pubertal status), and MRI (eg, scanner model) variables. Results: Among 9804 children (mean [SD] baseline age, 9.9 [0.6] years; 5160 boys [52.6%]; 213 Asian [2.2%], 1474 Black [15.0%], 514 Hispanic/Latino [5.2%], 29 American Indian [0.3%], 10 Pacific Islander [0.1%], 7463 White [76.1%], and 75 other [0.7%]) with nonmissing baseline neuroimaging and covariate data, 3460 (35.3%) reported substance use initiation before age 15. Initiation of any substance or alcohol use was associated with thinner cortex in prefrontal regions (eg, rostral middle frontal gyrus, β = -0.03; 95% CI, -0.02 to -0.05; P = 6.99 × 10-6) but thicker cortex in all other lobes, larger globus pallidus and hippocampal volumes, as well as greater global indices of brain structure (eg, larger whole brain volume, β = 0.05; 95% CI, 0.03 to 0.06; P = 2.80 × 10-8) following Bonferroni or false discovery rate multiple testing correction. Cannabis use initiation was associated with lower right caudate volume (β = -0.03; 95% CI, -0.01 to -0.05; P = .002). Post hoc examinations restricting to postbaseline initiation suggested that the majority of associations, including thinner prefrontal cortex and greater whole brain volume, preceded initiation. Conclusions and relevance: In this cohort study of children, preexisting neuroanatomical variability was associated with substance use initiation. In addition to putative neurotoxic effects of substance exposure, brain structure variability may reflect predispositional risk for initiating substance use earlier in life with potential cascading implications for development of later problems.
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    Still rethinking the J‐shaped curve: A commentary on Kember et al., 2024
    (Wiley, 2025) Miller, Alex P.; Psychiatry, School of Medicine