Publications by authors named "Daniel E Adkins"

53 Publications

Genetic association study of childhood aggression across raters, instruments, and age.

Transl Psychiatry 2021 07 30;11(1):413. Epub 2021 Jul 30.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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http://dx.doi.org/10.1038/s41398-021-01480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324785PMC
July 2021

A large-scale genome-wide association study meta-analysis of cannabis use disorder.

Lancet Psychiatry 2020 12 20;7(12):1032-1045. Epub 2020 Oct 20.

Stanford University Graduate School of Education, Stanford University, Stanford, CA, USA.

Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.

Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.

Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10). Cannabis use disorder and cannabis use were genetically correlated (r 0·50, p=1·50 × 10), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.

Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.

Funding: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.
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http://dx.doi.org/10.1016/S2215-0366(20)30339-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674631PMC
December 2020

A large-scale genome-wide association study meta-analysis of cannabis use disorder.

Lancet Psychiatry 2020 12 20;7(12):1032-1045. Epub 2020 Oct 20.

Stanford University Graduate School of Education, Stanford University, Stanford, CA, USA.

Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.

Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.

Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10). Cannabis use disorder and cannabis use were genetically correlated (r 0·50, p=1·50 × 10), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.

Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.

Funding: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.
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http://dx.doi.org/10.1016/S2215-0366(20)30339-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674631PMC
December 2020

Early external-environmental and internal-health predictors of risky sexual and aggressive behavior in adolescence: An integrative approach.

Dev Psychobiol 2021 Apr 31;63(3):556-571. Epub 2020 Aug 31.

Center for the Study of Children at Risk, Alpert Medical School of Brown University and Women and Infants Hospital of Rhode Island, Providence, RI, USA.

External predictive adaptive response (PAR) models assume that developmental exposures to stress carry predictive information about the future state of the environment, and that development of a faster life history (LH) strategy in this context functions to match the individual to this expected harsh state. More recently internal PAR models have proposed that early somatic condition (i.e., physical health) critically regulates development of LH strategies to match expected future somatic condition. Here we test the integrative hypothesis that poor physical health mediates the relation between early adversity and faster LH strategies. Data were drawn from a longitudinal study (birth to age 16; N = 1,388) of mostly African American participants with prenatal substance exposure. Results demonstrated that both external environmental conditions early in life (prenatal substance exposure, socioeconomic adversity, caregiver distress/depression, and adverse family functioning) and internal somatic condition during preadolescence (birthweight/gestational age, physical illness) uniquely predicted the development of faster LH strategies in adolescence (as indicated by more risky sexual and aggressive behavior). Consistent with the integrative hypothesis, the effect of caregiver distress/depression on LH strategy was mostly mediated by worse physical health. Discussion highlights the implications of these findings for theory and research on stress, development, and health.
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http://dx.doi.org/10.1002/dev.22029DOI Listing
April 2021

Illness, Social Disadvantage, and Sexual Risk Behavior in Adolescence and the Transition to Adulthood.

Arch Sex Behav 2021 01 27;50(1):205-217. Epub 2020 May 27.

Consortium for Families and Health Research, University of Utah, 380 S 1530 E, Salt Lake City, UT, 84112, USA.

This study investigated the influence of illness on sexual risk behavior in adolescence and the transition to adulthood, both directly and through moderation of the impact of social disadvantage. We hypothesized positive effects for social disadvantages and illness on sexual risk behavior, consistent with the development of faster life history strategies among young people facing greater life adversity. Using the first two waves of the National Longitudinal Study of Adolescent to Adult Health, we developed a mixed-effects multinomial logistic regression model predicting sexual risk behavior in three comparisons: risky nonmonogamous sex versus safer nonmonogamous sex, versus monogamous sex, and versus being sexually inactive, by social characteristics, illness, interactions thereof, and control covariates. Multiple imputation was used to address a modest amount of missing data. Subjects reporting higher levels of illness had lower odds of having safer nonmonogamous sex (OR = 0.84, p < .001), monogamous sex (OR = 0.82, p < .001), and being sexually inactive (OR = 0.74, p < .001) versus risky nonmonogamous sex, relative to subjects in better health. Illness significantly moderated the sex (OR = 0.88, p < .01), race/ethnicity (e.g., OR = 1.21, p < .001), and childhood SES (OR = 0.94; p < .01) effects for the sexually inactive versus risky nonmonogamous sex comparison. Substantive findings were generally robust across waves and in sensitivity analyses. These findings offer general support for the predictions of life history theory. Illness and various social disadvantages are associated with increased sexual risk behavior in adolescence and the transition to adulthood. Further, analyses indicate that the buffering effects of several protective social statuses against sexual risk-taking are substantially eroded by illness.
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http://dx.doi.org/10.1007/s10508-020-01747-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791890PMC
January 2021

Transition preparation activities among families of youth on the autism spectrum: Preliminary study using repeated assessments across a school year.

PLoS One 2020 16;15(4):e0231551. Epub 2020 Apr 16.

Department of Family and Consumer Studies, College of Social and Behavioral Science, University of Utah, Salt Lake City, UT, United States of America.

Much is still unknown about the transition to adulthood for youth with autism spectrum disorder (ASD), including what preparation activities best support positive adult outcomes. Parents play a crucial role in the transition planning and preparation process, yet the existing literature lacks detailed information about parent perceptions about transition preparation activities. To examine family transition preparation activities, we conducted a ten-month study of the transition preparation process of 15 families of youth with ASD across an academic year. Youth were ages 14-17 and 93% male. We collected data on transition preparation activity time spent and parent satisfaction over twenty data collection points. We used multi-level modeling to determine longitudinal trajectories of parent-reported preparation for the transition to adulthood based on endorsed transition preparation activities. Findings from this preliminary study revealed that discussions about the future were the most commonly endorsed activities, while social activities were most associated with increased parental perception of transition preparation over time. This study expands understanding of various transition preparation activities engaged in by families of youth with ASD during high school, though research with a larger and more diverse sample is needed to extend findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231551PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161970PMC
July 2020

Molecular Genetic Risk for Psychosis Is Associated With Psychosis Risk Symptoms in a Population-Based UK Cohort: Findings From Generation Scotland.

Schizophr Bull 2020 Mar 27. Epub 2020 Mar 27.

Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA.

Objective: Subthreshold psychosis risk symptoms in the general population may be associated with molecular genetic risk for psychosis. This study sought to optimize the association of risk symptoms with genetic risk for psychosis in a large population-based cohort in the UK (N = 9104 individuals 18-65 years of age) by properly accounting for population stratification, factor structure, and sex.

Methods: The newly expanded Generation Scotland: Scottish Family Health Study includes 5391 females and 3713 males with age M [SD] = 45.2 [13] with both risk symptom data and genetic data. Subthreshold psychosis symptoms were measured using the Schizotypal Personality Questionnaire-Brief (SPQ-B) and calculation of polygenic risk for schizophrenia was based on 11 425 349 imputed common genetic variants passing quality control. Follow-up examination of other genetic risks included attention-deficit hyperactivity disorder (ADHD), autism, bipolar disorder, major depression, and neuroticism.

Results: Empirically derived symptom factor scores reflected interpersonal/negative symptoms and were positively associated with polygenic risk for schizophrenia. This signal was largely sex specific and limited to males. Across both sexes, scores were positively associated with neuroticism and major depressive disorder.

Conclusions: A data-driven phenotypic analysis enabled detection of association with genetic risk for schizophrenia in a population-based sample. Multiple polygenic risk signals and important sex differences suggest that genetic data may be useful in improving future phenotypic risk assessment.
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http://dx.doi.org/10.1093/schbul/sbaa042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505177PMC
March 2020

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

Mol Psychiatry 2020 08 26;25(8):1673-1687. Epub 2020 Feb 26.

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.
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http://dx.doi.org/10.1038/s41380-020-0677-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392789PMC
August 2020

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

Hazardous air pollutants are associated with worse performance in reading, math, and science among US primary schoolchildren.

Environ Res 2020 02 15;181:108925. Epub 2019 Nov 15.

Departments of Sociology and Psychiatry, University of Utah, 390 1530 E #301, Salt Lake City, UT, 84112, USA. Electronic address:

Emerging evidence demonstrates that chronic exposure to air pollution may negatively impact children's cognitive processing and memory. Little is currently known about how air pollution impacts individual children's academic performance through time. Academic performance is practically important, given its linkage to children's future life course trajectories. Individual-level, longitudinal data from 16,000 US primary school students are combined with a tract-level hazardous air pollutant (HAP) measure to assess how kindergarten exposures are associated with competencies in reading, math and science through third grade. We employed linear mixed models with repeated measures within children (e.g., five math tests across four years), clustering within census tracts, and random effects specified at the child- and census tract-levels. Controlling for a comprehensive list of time variant and time invariant covariates, we found statistically significant associations between higher levels of HAPs and lower reading (b = -0.02; p < 0.05), math (b = -0.02; p < 0.001), and science (b = -0.05; p < 0.001) scores. These negative effects of pollution on academic competency in the early primary school years add to the weight of evidence that air pollution harms children's academic potential.
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http://dx.doi.org/10.1016/j.envres.2019.108925DOI Listing
February 2020

Pathway-based polygene risk for severe depression implicates drug metabolism in CONVERGE.

Psychol Med 2020 04 2;50(5):793-798. Epub 2019 Apr 2.

Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.

Background: The Psychiatric Genomics Consortium (PGC) has made major advances in the molecular etiology of MDD, confirming that MDD is highly polygenic. Pathway enrichment results from PGC meta-analyses can also be used to help inform molecular drug targets. Prior to any knowledge of molecular biomarkers for MDD, drugs targeting molecular pathways (MPs) proved successful in treating MDD. It is possible that examining polygenicity within specific MPs implicated in MDD can further refine molecular drug targets.

Methods: Using a large case-control GWAS based on low-coverage whole genome sequencing (N = 10 640) in Han Chinese women, we derived polygenic risk scores (PRS) for MDD and for MDD specific to each of over 300 MPs previously shown to be relevant to psychiatric diagnoses. We then identified sets of PRSs, accounting for critical covariates, significantly predictive of case status.

Results: Over and above global MDD polygenic risk, polygenic risk within the GO: 0017144 drug metabolism pathway significantly predicted recurrent depression after multiple testing correction. Secondary transcriptomic analysis suggests that among genes in this pathway, CYP2C19 (family of Cytochrome P450) and CBR1 (Carbonyl Reductase 1) might be most relevant to MDD. Within the cases, pathway-based risk was additionally associated with age at onset of MDD.

Conclusions: Results indicate that pathway-based risk might inform etiology of recurrent major depression. Future research should examine whether polygenicity of the drug metabolism gene pathway has any association with clinical presentation or treatment response. We discuss limitations to the generalizability of these preliminary findings, and urge replication in future research.
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http://dx.doi.org/10.1017/S0033291719000618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774907PMC
April 2020

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders.

Nat Neurosci 2018 12 26;21(12):1656-1669. Epub 2018 Nov 26.

NIH/NIAAA, Laboratory of Neurogenetics, Bethesda, MD, USA.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10) and African ancestries (rs2066702; P = 2.2 × 10). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
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http://dx.doi.org/10.1038/s41593-018-0275-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430207PMC
December 2018

Bleeding, cramping, and satisfaction among new copper IUD users: A prospective study.

PLoS One 2018 7;13(11):e0199724. Epub 2018 Nov 7.

Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, United States of America.

Objective: We assess change in bleeding, cramping, and IUD satisfaction among new copper (Cu) IUD users during the first six months of use, and evaluate the impact of bleeding and cramping on method satisfaction.

Methods: We recruited 77 women ages 18-45 for this prospective longitudinal observational cohort study. Eligible women reported regular menses, had no exposure to hormonal contraception in the last three months, and desired a Cu IUD for contraception. We collected data prospectively for 180 days following IUD insertion. Monthly, participants reported bleeding scores using the validated pictorial blood loss assessment chart (PBAC), IUD satisfaction using a five-point Likert scale, and cramping using a six-level ordinal scale. We used multiple imputation to address nonrandom attrition. Structural equation models for count and ordered outcomes were used to model bleeding, cramping, and IUD satisfaction growth curves over the six monthly repeated assessments.

Results: Bleeding significantly decreased (approximately 23%) over the course of the study from an estimated PBAC = 195 at one month post-insertion to PBAC = 151 at six months (t = -2.38, p<0.05). Additionally, IUD satisfaction improved over time (t = 2.65, p<0.01), increasing from between "Neutral" and "Satisfied" to "Satisfied" over the six month study. Cramping decreased notably over the six month study from between biweekly and weekly, to once or twice a month (t = -4.38, p<0.001). Finally, bleeding, but not cramping, was associated with IUD satisfaction across the study (t = -2.31, p<0.05) and at study end (t = -2.81, p<0.01).

Conclusions: New Cu IUD users reported decreasing bleeding and cramping, and increasing IUD satisfaction, over the first six months. Method satisfaction was negatively associated with bleeding.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199724PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221252PMC
April 2019

The Impact of Sexual Satisfaction, Functioning, and Perceived Contraceptive Effects on Sex Life on IUD and Implant Continuation at 1 Year.

Womens Health Issues 2018 Sep - Oct;28(5):401-407. Epub 2018 Aug 18.

Department of Obstetrics and Gynecology, The University of Utah, Salt Lake City, Utah.

Introduction: Contraceptives improve women's lives and public health, but many women discontinue their contraceptive method owing to dissatisfaction. An underexamined aspect of contraceptive discontinuation is sexual acceptability, or how contraception affects sexual experiences. Investigators' aims were two-fold: 1) to document changes in multiple domains of women's sexual experiences with their intrauterine device (IUD) or contraceptive implant over time and 2) to examine whether these sexuality factors were associated with method continuation at 12 months.

Methods: We enrolled 200 eligible family planning clients and collected data at baseline and at 1, 3, 6, and 12 months. Sexual acceptability measures included the Female Sexual Function Index-6, the New Sexual Satisfaction Scale, and participants' perceptions of whether their contraceptive method had had a neutral, positive, or negative effect on their sex life. Survival analysis and Cox regression with time-varying covariates related sexuality measures to method continuation over time while controlling for other relevant factors.

Results: Among 193 women who received an IUD or implant, 20% selected the copper IUD, 46% the levonorgestrel IUD, and 34% the etonogestrel implant. Ten percent discontinued their method during the year. Although changes in Female Sexual Function Index-6 and New Sexual Satisfaction Scale scores were not associated with discontinuation, individuals who perceived that their method detracted from their sexual experience had significantly higher removal rates than those who reported no sexual changes or positive sexual changes (adjusted hazard ratio, 8.04; 95% CI, 1.53-42.24), even when controlling for method type, bleeding changes, and a variety of covariates and controls.

Conclusions: Although limited by the small sample of discontinuers, we found that women's perceptions of how their method affects their sex life were associated with contraceptive continuation over time. Sexual acceptability should receive more attention in both contraceptive research and counseling.
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http://dx.doi.org/10.1016/j.whi.2018.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281294PMC
November 2018

Cross-validation of the Inventory of Callous-Unemotional Traits across reporters and genders in a sample of detained youth.

Psychol Assess 2019 Jan 6;31(1):15-26. Epub 2018 Aug 6.

Department of Sociology.

The development of the Inventory of Callous-Unemotional Traits (ICU) has contributed importantly to research on the role of callous-unemotional traits in youth offending. However, findings from recent studies have raised questions about the measure's psychometric properties by yielding discrepant findings about how best to optimize the ICU for capturing meaningful variability in callous-unemotional traits across genders, reporters, and samples. The present study drew data from a sample of justice-involved adolescents and examined the psychometric properties of the ICU across caregiver- and youth self-report versions as well as across genders. Findings suggested that the ICU functioned differently across caregiver- and youth self-report versions and, thus, that different scale variations may better optimize the use of the ICU for caregiver versus youth self-reports. Specifically, findings from the current study supported the use of a youth self-reported ICU scale excluding reverse-coded items and the caregiver-reported full scale. Minimal gender differences emerged. Continued efforts to optimize the psychometric qualities and functional significance of the ICU, particularly the youth self-report form, may enhance efforts both to identify and intervene with the subgroup of youth at particular risk for recidivism. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0000636DOI Listing
January 2019

An epigenetic pathway approach to investigating associations between prenatal exposure to maternal mood disorder and newborn neurobehavior.

Dev Psychopathol 2018 08;30(3):881-890

University of British Columbia.

Following recent advances in behavioral and psychiatric epigenetics, researchers are increasingly using epigenetic methods to study prenatal exposure to maternal mood disorder and its effects on fetal and newborn neurobehavior. Despite notable progress, various methodological limitations continue to obscure our understanding of the epigenetic mechanisms underpinning prenatal exposure to maternal mood disorder on newborn neurobehavioral development. Here we detail this problem, discussing limitations of the currently dominant analytical approaches (i.e., candidate epigenetic and epigenome-wide association studies), then present a solution that retains many benefits of existing methods while minimizing their shortcomings: epigenetic pathway analysis. We argue that the application of pathway-based epigenetic approaches that target DNA methylation at transcription factor binding sites could substantially deepen our mechanistic understanding of how prenatal exposures influence newborn neurobehavior.
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http://dx.doi.org/10.1017/S0954579418000688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074043PMC
August 2018

Incorporating epigenetic mechanisms to advance fetal programming theories.

Dev Psychopathol 2018 08;30(3):807-824

University of Utah.

Decades of fetal programming research indicates that we may be able to map the origins of many physical, psychological, and medical variations and morbidities before the birth of the child. While great strides have been made in identifying associations between prenatal insults, such as undernutrition or psychosocial stress, and negative developmental outcomes, far less is known about how adaptive responses to adversity regulate the developing phenotype to match stressful conditions. As the application of epigenetic methods to human behavior has exploded in the last decade, research has begun to shed light on the role of epigenetic mechanisms in explaining how prenatal conditions shape later susceptibilities to mental and physical health problems. In this review, we describe and attempt to integrate two dominant fetal programming models: the cumulative stress model (a disease-focused approach) and the match-mismatch model (an evolutionary-developmental approach). In conjunction with biological sensitivity to context theory, we employ these two models to generate new hypotheses regarding epigenetic mechanisms through which prenatal and postnatal experiences program child stress reactivity and, in turn, promote development of adaptive versus maladaptive phenotypic outcomes. We conclude by outlining priority questions and future directions for the fetal programming field.
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http://dx.doi.org/10.1017/S0954579418000469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079515PMC
August 2018

Sexual Orientation Disparities in Pregnancy and Infant Outcomes.

Matern Child Health J 2019 Jan;23(1):72-81

School of Nursing, Columbia University, New York, NY, USA.

Objectives Little is known about maternal and infant health among sexual minority women (SMW), despite the large body of research documenting their multiple preconception risk factors. This study used data from the 2006-2015 National Survey of Family Growth (NSFG) to investigate sexual orientation inequities in pregnancy and birth outcomes, including miscarriage, stillbirth, preterm birth, and birth weight. Methods Women reported 19,955 study eligible pregnancies and 15,996 singleton live births. Sexual orientation was measured using self-reported identity and histories of same-sex sexual experiences (heterosexual-WSM [women who only report sex with men]; heterosexual-WSW [women who report sex with women]; bisexual, and lesbian). Logistic regression models were used that adjusted for several maternal characteristics. Results Compared to heterosexual-WSM, heterosexual-WSW (OR 1.25, 95% CI 1.00-1.58) and bisexual and lesbian women (OR 1.77, 95% CI 1.34-2.35) were more likely to report miscarriage, and bisexual and lesbian women were more likely to report a pregnancy ending in stillbirth (OR 2.85, 95% CI 1.40-5.83). Lesbian women were more likely to report low birth weight infants (OR 2.64, 95% CI 1.38-5.07) and bisexual and lesbian women were more likely to report very preterm births (OR 1.84, 95% CI 1.11-3.04) compared to heterosexual-WSM. Conclusions for Practice This study documents significant sexual orientation inequities in pregnancy and birth outcomes. More research is needed to understand the mechanisms that underlie disparate outcomes and to develop interventions to improve sexual minority women's maternal and infant health.
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http://dx.doi.org/10.1007/s10995-018-2595-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501574PMC
January 2019

Enhancing Psychosis-Spectrum Nosology Through an International Data Sharing Initiative.

Schizophr Bull 2018 10;44(suppl_2):S460-S467

Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT.

The latent structure of schizotypy and psychosis-spectrum symptoms remains poorly understood. Furthermore, molecular genetic substrates are poorly defined, largely due to the substantial resources required to collect rich phenotypic data across diverse populations. Sample sizes of phenotypic studies are often insufficient for advanced structural equation modeling approaches. In the last 50 years, efforts in both psychiatry and psychological science have moved toward (1) a dimensional model of psychopathology (eg, the current Hierarchical Taxonomy of Psychopathology [HiTOP] initiative), (2) an integration of methods and measures across traits and units of analysis (eg, the RDoC initiative), and (3) powerful, impactful study designs maximizing sample size to detect subtle genomic variation relating to complex traits (the Psychiatric Genomics Consortium [PGC]). These movements are important to the future study of the psychosis spectrum, and to resolving heterogeneity with respect to instrument and population. The International Consortium of Schizotypy Research is composed of over 40 laboratories in 12 countries, and to date, members have compiled a body of schizotypy- and psychosis-related phenotype data from more than 30000 individuals. It has become apparent that compiling data into a protected, relational database and crowdsourcing analytic and data science expertise will result in significant enhancement of current research on the structure and biological substrates of the psychosis spectrum. The authors present a data-sharing infrastructure similar to that of the PGC, and a resource-sharing infrastructure similar to that of HiTOP. This report details the rationale and benefits of the phenotypic data collective and presents an open invitation for participation.
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http://dx.doi.org/10.1093/schbul/sby059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188505PMC
October 2018

Polygenic prediction of the phenome, across ancestry, in emerging adulthood.

Psychol Med 2018 08 27;48(11):1814-1823. Epub 2017 Nov 27.

Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

Background: Identifying genetic relationships between complex traits in emerging adulthood can provide useful etiological insights into risk for psychopathology. College-age individuals are under-represented in genomic analyses thus far, and the majority of work has focused on the clinical disorder or cognitive abilities rather than normal-range behavioral outcomes.

Methods: This study examined a sample of emerging adults 18-22 years of age (N = 5947) to construct an atlas of polygenic risk for 33 traits predicting relevant phenotypic outcomes. Twenty-eight hypotheses were tested based on the previous literature on samples of European ancestry, and the availability of rich assessment data allowed for polygenic predictions across 55 psychological and medical phenotypes.

Results: Polygenic risk for schizophrenia (SZ) in emerging adults predicted anxiety, depression, nicotine use, trauma, and family history of psychological disorders. Polygenic risk for neuroticism predicted anxiety, depression, phobia, panic, neuroticism, and was correlated with polygenic risk for cardiovascular disease.

Conclusions: These results demonstrate the extensive impact of genetic risk for SZ, neuroticism, and major depression on a range of health outcomes in early adulthood. Minimal cross-ancestry replication of these phenomic patterns of polygenic influence underscores the need for more genome-wide association studies of non-European populations.
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http://dx.doi.org/10.1017/S0033291717003312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971142PMC
August 2018

Opportunities for an enhanced integration of neuroscience and genomics.

Brain Imaging Behav 2018 Aug;12(4):1211-1219

Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23220, USA.

Neuroimaging and genetics are two rapidly expanding fields of research. Thoughtful integration of these areas is critical for ongoing large-scale research into the genetic mechanisms underlying brain structure, function, and development. Neuroimaging genetics has been slow to evolve relative to psychiatric genetics research, and some may be unaware that new statistical methods allow for the genomic analysis of more modestly-sized imaging samples. We present a broad overview of the extant imaging genetics literature, provide an interpretation of the major problems surrounding the integration of neuroimaging and genetics, discuss the influence and impact of genetics consortia, and suggest statistical genetic analyses that expand the repertoire of imaging researchers amassing rich behavioral data in modestly-sized samples. Specific attention is paid to the creative use of polygenic risk scoring in imaging genetic analyses, with primers on the most current risk scoring applications.
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http://dx.doi.org/10.1007/s11682-017-9780-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912999PMC
August 2018

Enrichment methods provide a feasible approach to comprehensive and adequately powered investigations of the brain methylome.

Nucleic Acids Res 2017 Jun;45(11):e97

Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.

Methylome-wide association studies are typically performed using microarray technologies that only assay a very small fraction of the CG methylome and entirely miss two forms of methylation that are common in brain and likely of particular relevance for neuroscience and psychiatric disorders. The alternative is to use whole genome bisulfite (WGB) sequencing but this approach is not yet practically feasible with sample sizes required for adequate statistical power. We argue for revisiting methylation enrichment methods that, provided optimal protocols are used, enable comprehensive, adequately powered and cost-effective genome-wide investigations of the brain methylome. To support our claim we use data showing that enrichment methods approximate the sensitivity obtained with WGB methods and with slightly better specificity. However, this performance is achieved at <5% of the reagent costs. Furthermore, because many more samples can be sequenced simultaneously, projects can be completed about 15 times faster. Currently the only viable option available for comprehensive brain methylome studies, enrichment methods may be critical for moving the field forward.
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http://dx.doi.org/10.1093/nar/gkx143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499761PMC
June 2017

Deep Sequencing of 71 Candidate Genes to Characterize Variation Associated with Alcohol Dependence.

Alcohol Clin Exp Res 2017 04 24;41(4):711-718. Epub 2017 Mar 24.

Center for Biomarker Research and Precision Medicine , School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia.

Background: Previous genomewide association studies (GWASs) have identified a number of putative risk loci for alcohol dependence (AD). However, only a few loci have replicated and these replicated variants only explain a small proportion of AD risk. Using an innovative approach, the goal of this study was to generate hypotheses about potentially causal variants for AD that can be explored further through functional studies.

Methods: We employed targeted capture of 71 candidate loci and flanking regions followed by next-generation deep sequencing (mean coverage 78X) in 806 European Americans. Regions included in our targeted capture library were genes identified through published GWAS of alcohol, all human alcohol and aldehyde dehydrogenases, reward system genes including dopaminergic and opioid receptors, prioritized candidate genes based on previous associations, and genes involved in the absorption, distribution, metabolism, and excretion of drugs. We performed single-locus tests to determine if any single variant was associated with AD symptom count. Sets of variants that overlapped with biologically meaningful annotations were tested for association in aggregate.

Results: No single, common variant was significantly associated with AD in our study. We did, however, find evidence for association with several variant sets. Two variant sets were significant at the q-value <0.10 level: a genic enhancer for ADHFE1 (p = 1.47 × 10 ; q = 0.019), an alcohol dehydrogenase, and ADORA1 (p = 5.29 × 10 ; q = 0.035), an adenosine receptor that belongs to a G-protein-coupled receptor gene family.

Conclusions: To our knowledge, this is the first sequencing study of AD to examine variants in entire genes, including flanking and regulatory regions. We found that in addition to protein coding variant sets, regulatory variant sets may play a role in AD. From these findings, we have generated initial functional hypotheses about how these sets may influence AD.
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http://dx.doi.org/10.1111/acer.13352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378639PMC
April 2017

Age of onset and family history as indicators of polygenic risk for major depression.

Depress Anxiety 2017 05 2;34(5):446-452. Epub 2017 Feb 2.

Virginia Institute for Psychiatric & Behavioral Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

Background: The extent to which earlier age of onset (AO) is a reflection of increased genetic risk for major depression (MD) is still unknown. Previous biometrical research has provided mixed empirical evidence for the genetic overlap of AO with MD. If AO is demonstrated to be relevant to molecular polygenic risk for MD, incorporation of AO as a phenotype could enhance future genetic studies.

Methods: This research estimated the SNP-based heritability of AO in the China, Oxford and VCU Experimental Research on Genetic Epidemiology (CONVERGE) case-control sample (N = 9,854; MD case, n = 4,927). Common single nucleotide polymorphism heritability of MD was also examined across both high and low median-split AO groups, and best linear unbiased predictor (BLUP) scores of polygenic risk, in split-halves, were used to predict AO. Distributions of genetic risk across early and late AO were compared, and presence of self-reported family history (FH) of MD was also examined as a predictor of AO.

Results: AO was not significantly heritable and polygenic risk derived from the aggregated effects of common genetic variants did not significantly predict AO in any analysis. AO was modestly but significantly lower in cases with a first-degree genetic FH of MD.

Conclusions: Findings indicate that AO is associated with greater self-reported genetic risk for MD in cases, yet not associated with common variant polygenic risk for MD. Future studies of early MD may benefit more from the examination of important moderating variables such as early life events.
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http://dx.doi.org/10.1002/da.22607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501985PMC
May 2017

Machine Learning and Electronic Health Records: A Paradigm Shift.

Authors:
Daniel E Adkins

Am J Psychiatry 2017 02;174(2):93-94

From the Departments of Psychiatry and Sociology, University of Utah, Salt Lake City, Utah.

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http://dx.doi.org/10.1176/appi.ajp.2016.16101169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807064PMC
February 2017

The Rate of Change in Alcohol Misuse Across Adolescence is Heritable.

Alcohol Clin Exp Res 2017 01 28;41(1):57-64. Epub 2016 Nov 28.

Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia.

Background: Alcohol use typically begins during adolescence and escalates into young adulthood. This represents an important period for the establishment of alcohol use and misuse patterns, which can have psychosocial and medical consequences. Although changes in alcohol use during this time have been phenotypically characterized, their genetic nature is poorly understood.

Methods: Participants of the Avon Longitudinal Study of Parents and Children completed the Alcohol Use Disorders Identification Test (AUDIT) 4 times from age 16 to 20. We used Mplus to construct a growth model characterizing changes in AUDIT scores across time (N = 4,545, where data were available for at least 2 time points). The slope of the model was used as the phenotype in a genomewide association study (N = 3,380), followed by secondary genetic analyses.

Results: No individual marker met genomewide significance criteria. Top markers mapped to biologically plausible candidate genes. The slope term was moderately heritable (h = 0.26, p = 0.009), and replication attempts using a meta-analysis of independent samples provided support for implicated variants at the aggregate level. Nominally significant (p < 0.00001) markers mapped to putatively active genomic regions in brain tissue more frequently than expected by chance.

Conclusions: These results build on prior studies by demonstrating that common genetic variation impacts alcohol misuse trajectories. Influential loci map to genes that merit additional research, as well as to intergenic regions with regulatory functions in the central nervous system. These findings underscore the complex biological nature of alcohol misuse across development.
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http://dx.doi.org/10.1111/acer.13262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5205550PMC
January 2017

High density methylation QTL analysis in human blood via next-generation sequencing of the methylated genomic DNA fraction.

Genome Biol 2015 Dec 23;16:291. Epub 2015 Dec 23.

Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA, 23298, USA.

Background: Genetic influence on DNA methylation is potentially an important mechanism affecting individual differences in humans. We use next-generation sequencing to assay blood DNA methylation at approximately 4.5 million loci, each comprising 2.9 CpGs on average, in 697 normal subjects. Methylation measures at each locus are tested for association with approximately 4.5 million single nucleotide polymorphisms (SNPs) to exhaustively screen for methylation quantitative trait loci (meQTLs).

Results: Using stringent false discovery rate control, 15 % of methylation sites show genetic influence. Most meQTLs are local, where the associated SNP and methylation site are in close genomic proximity. Distant meQTLs and those spanning different chromosomes are less common. Most local meQTLs encompass common SNPs that alter CpG sites (CpG-SNPs). Local meQTLs encompassing CpG-SNPs are enriched in regions of inactive chromatin in blood cells. In contrast, local meQTLs lacking CpG-SNPs are enriched in regions of active chromatin and transcription factor binding sites. Of 393 local meQTLs that overlap disease-associated regions from genome-wide studies, a high percentage encompass common CpG-SNPs. These meQTLs overlap active enhancers, differentiating them from CpG-SNP meQTLs in inactive chromatin.

Conclusions: Genetic influence on the human blood methylome is common, involves several heterogeneous processes and is predominantly dependent on local sequence context at the meQTL site. Most meQTLs involve CpG-SNPs, while sequence-dependent effects on chromatin binding are also important in regions of active chromatin. An abundance of local meQTLs resulting from methylation of CpG-SNPs in inactive chromatin suggests that many meQTLs lack functional consequence. Integrating meQTL and Roadmap Epigenomics data could assist fine-mapping efforts.
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http://dx.doi.org/10.1186/s13059-015-0842-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699364PMC
December 2015

Psychometric modeling of abuse and dependence symptoms across six illicit substances indicates novel dimensions of misuse.

Addict Behav 2016 Feb 17;53:132-40. Epub 2015 Oct 17.

Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Brisbane, Australia.

Aims: This study explored the factor structure of DSM III-R/IV symptoms for substance abuse and dependence across six illicit substance categories in a population-based sample of males.

Method: DSM III-R/IV drug abuse and dependence symptoms for cannabis, sedatives, stimulants, cocaine, opioids and hallucinogens from 4179 males born 1940-1970 from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders were analyzed. Confirmatory factor analyses tested specific hypotheses regarding the latent structure of substance misuse for a comprehensive battery of 13 misuse symptoms measured across six illicit substance categories (78 items).

Results: Among the models fit, the latent structure of substance misuse was best represented by a combination of substance-specific factors and misuse symptom-specific factors. We found no support for a general liability factor to illicit substance misuse.

Conclusions: Results indicate that liability to misuse illicit substances is drug class specific, with little evidence for a general liability factor. Additionally, unique dimensions capturing propensity toward specific misuse symptoms (e.g., tolerance, withdrawal) across substances were identified. While this finding requires independent replication, the possibility of symptom-specific misuse factors, present in multiple substances, raises the prospect of genetic, neurobiological and behavioral predispositions toward distinct, narrowly defined features of drug abuse and dependence.
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http://dx.doi.org/10.1016/j.addbeh.2015.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679450PMC
February 2016

Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium.

Behav Genet 2016 Mar 11;46(2):170-82. Epub 2015 Sep 11.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.

Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.
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http://dx.doi.org/10.1007/s10519-015-9735-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751159PMC
March 2016

Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses.

Nicotine Tob Res 2016 May 17;18(5):626-31. Epub 2015 Aug 17.

Center for Biomarker Research and Precision Medicine, School of Pharmacy, Virginia Commonwealth University, Richmond, VA;

Introduction: Genome-wide association study meta-analyses have robustly implicated three loci that affect susceptibility for smoking: CHRNA5\CHRNA3\CHRNB4, CHRNB3\CHRNA6 and EGLN2\CYP2A6. Functional follow-up studies of these loci are needed to provide insight into biological mechanisms. However, these efforts have been hampered by a lack of knowledge about the specific causal variant(s) involved. In this study, we prioritized variants in terms of the likelihood they account for the reported associations.

Methods: We employed targeted capture of the CHRNA5\CHRNA3\CHRNB4, CHRNB3\CHRNA6, and EGLN2\CYP2A6 loci and flanking regions followed by next-generation deep sequencing (mean coverage 78×) to capture genomic variation in 363 individuals. We performed single locus tests to determine if any single variant accounts for the association, and examined if sets of (rare) variants that overlapped with biologically meaningful annotations account for the associations.

Results: In total, we investigated 963 variants, of which 71.1% were rare (minor allele frequency < 0.01), 6.02% were insertion/deletions, and 51.7% were catalogued in dbSNP141. The single variant results showed that no variant fully accounts for the association in any region. In the variant set results, CHRNB4 accounts for most of the signal with significant sets consisting of directly damaging variants. CHRNA6 explains most of the signal in the CHRNB3\CHRNA6 locus with significant sets indicating a regulatory role for CHRNA6. Significant sets in CYP2A6 involved directly damaging variants while the significant variant sets suggested a regulatory role for EGLN2.

Conclusions: We found that multiple variants implicating multiple processes explain the signal. Some variants can be prioritized for functional follow-up.
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http://dx.doi.org/10.1093/ntr/ntv166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942610PMC
May 2016
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