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1.  The role of conduct disorder in the relationship between alcohol, nicotine and cannabis use disorders 
Psychological medicine  2015;45(16):3505-3515.
Background
Genetic influences contribute significantly to comorbidity between conduct disorder and substance use disorders. Estimating the extent of overlap can assist in the development of phenotypes for genomic analyses.
Methods
Multivariate quantitative genetic analyses were conducted using data from 9577 individuals, including 3982 complete twin pairs and 1613 individuals whose cotwin was not interviewed (aged 24–37 years) from two Australian twin samples. Analyses examined the genetic correlation between alcohol dependence, nicotine dependence and cannabis abuse/dependence and the extent to which the correlations were attributable to genetic influences shared with conduct disorder.
Results
Additive genetic (a2=0.48 to 0.65) and nonshared environmental factors explained variance in substance use disorders. Familial effects on conduct disorder were due to additive genetic (a2=0.39) and shared environmental (c2=0.15) factors. All substance use disorders were influenced by shared genetic factors (rg=0.38–0.56), with all genetic overlap between substances attributable to genetic influences shared with conduct disorder. Genes influencing individual substance use disorders were also significant, explaining 40–73% of the genetic variance per substance.
Conclusions
Among substance users in this sample, the well-documented clinical comorbidity between conduct disorder and substance use disorders is primarily attributable to shared genetic liability. Interventions targeted at generally reducing deviant behaviors may address the risk posed by this shared genetic liability. However, there is also evidence for genetic and environmental influences specific to each substance. The identification of these substance-specific risk factors (as well as potential protective factors) is critical to the future development of targeted treatment protocols.
doi:10.1017/S0033291715001518
PMCID: PMC4730914  PMID: 26281760
conduct disorder; substance use disorders; alcohol; nicotine; cannabis; genetic overlap; twins
2.  Progression in Substance Use Initiation: A Multilevel Discordant Monozygotic Twin Design 
Journal of abnormal psychology  2015;124(3):596-605.
Considerable attention has been paid to the “gateway” pattern of drug use initiation in which individuals progress from tobacco and alcohol use to cannabis and other illicit drugs. The extent to which this sequence reflects a causal impact of licit substance use on illicit substance involvement remains unclear. Clarifying the mechanisms underlying substance use initiation may help inform our understanding of risk for psychopathology, as increasing research is demonstrating associations between initiation patterns and heavier involvement. This study examined patterns of substance use initiation using a discordant twin design. Participants were 3,476 monozygotic twins (37% male) from the Australian Twin Registry who reported on their ages of tobacco, alcohol, and cannabis initiation. Multilevel proportional hazard regression models were employed to (a) estimate within-twin-pair and between-twin-pair contributions to associations between the ages of onset of different drugs; and (b) examine whether the magnitude of effects differed as a function of the order of substance use initiation. Finding significant effects within twin pairs would support the hypothesis that the age of initiation of one substance causally influences the age of initiation of a subsequent substance. Finding significant effects between twin pairs would support the operation of familial influences that explain variation in the ages of initiation of multiple drugs. Within-twin-pair effects for typical patterns were modest. When initiation was atypical, however, larger within-twin-pair effects were observed and causal influences were more strongly implicated. Results support the utility of examining the timing and ordering of substance use initiation within sophisticated, genetically informative designs.
doi:10.1037/abn0000068
PMCID: PMC4573814  PMID: 26098047
Substance use initiation; discordant twins; multilevel modeling
3.  Meta-analysis of genome-wide association studies of anxiety disorders 
Molecular psychiatry  2016;21(10):1391-1399.
Anxiety disorders, namely generalized anxiety disorder, panic disorder, and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based upon clinical presentation, anxiety disorders likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based anxiety disorders, we applied two phenotypic approaches: (1) comparisons between categorical anxiety disorder cases and super-normal controls, and (2) quantitative phenotypic factor scores derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65×10−8); for factor scores, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86×10−9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of anxiety disorders.
doi:10.1038/mp.2015.197
PMCID: PMC4940340  PMID: 26754954
anxiety disorder; anxiety; genetics; genome-wide association study; meta-analysis
4.  Genome-wide association study of blood lead shows multiple associations near ALAD 
Human Molecular Genetics  2015;24(13):3871-3879.
Exposure to high levels of environmental lead, or biomarker evidence of high body lead content, is associated with anaemia, developmental and neurological deficits in children, and increased mortality in adults. Adverse effects of lead still occur despite substantial reduction in environmental exposure. There is genetic variation between individuals in blood lead concentration but the polymorphisms contributing to this have not been defined. We measured blood or erythrocyte lead content, and carried out genome-wide association analysis, on population-based cohorts of adult volunteers from Australia and UK (N = 5433). Samples from Australia were collected in two studies, in 1993–1996 and 2002–2005 and from UK in 1991–1992. One locus, at ALAD on chromosome 9, showed consistent association with blood lead across countries and evidence for multiple independent allelic effects. The most significant single nucleotide polymorphism (SNP), rs1805313 (P = 3.91 × 10−14 for lead concentration in a meta-analysis of all data), is known to have effects on ALAD expression in blood cells but other SNPs affecting ALAD expression did not affect blood lead. Variants at 12 other loci, including ABO, showed suggestive associations (5 × 10−6 > P > 5 × 10−8). Identification of genetic polymorphisms affecting blood lead reinforces the view that genetic factors, as well as environmental ones, are important in determining blood lead levels. The ways in which ALAD variation affects lead uptake or distribution are still to be determined.
doi:10.1093/hmg/ddv112
PMCID: PMC4459389  PMID: 25820613
5.  Associations Between Body Mass Index, Post-Traumatic Stress Disorder, and Child Maltreatment In Young Women 
Child abuse & neglect  2015;45:154-162.
The objective of this study was to examine interrelationships between child maltreatment, post-traumatic stress disorder (PTSD) and body mass index (BMI) in young women. We used multinomial logistic regression models to explore the possibility that PTSD statistically mediates or moderates the association between BMI category and self-reported childhood sexual abuse (CSA), physical abuse (CPA), or neglect among 3699 young women participating in a population-based twin study. Obese women had the highest prevalence of CSA, CPA, neglect, and PTSD (p<0.001 for all). Although all three forms of child maltreatment were significantly, positively associated with overweight and obesity in unadjusted models, only CSA was significantly associated with obesity after adjusting for other forms of maltreatment and covariates (OR = 2.21, 95% CI: 1.63, 3.00). CSA and neglect, but not CPA, were associated with underweight in unadjusted models; however, after adjusting for other forms of maltreatment and covariates, the associations were no longer statistically significant (OR = 1.43; 95% CI: 0.90-2.28 and OR = 2.16; 95% CI: 0.90-5.16 for CSA and neglect, respectively). Further adjustment for PTSD generally resulted in modest attenuation of effects across associations of child maltreatment forms with BMI categories, suggesting that PTSD may, at most, be only a weak partial mediator of these associations. Future longitudinal studies are needed to elucidate the mechanisms linking CSA and obesity and to further evaluate the role of PTSD in associations between child maltreatment and obesity.
doi:10.1016/j.chiabu.2015.02.007
PMCID: PMC4470860  PMID: 25770346
BMI; child maltreatment; obesity; PTSD
6.  Differences in childhood physical abuse reporting and the association between CPA and alcohol use disorder in European American and African American women 
The goal of the current study was to examine whether the magnitude of the association between childhood physical abuse (CPA) and alcohol use disorder (AUD) varies by type of CPA assessment and race of the respondents. Data are from the Missouri adolescent female twins study and the Missouri family study (N = 4508) where 21.2% identified as African American (AA) and 78.8% as European American (EA); mean age = 23.8. Data were collected using a structured comprehensive interview which assessed CPA experiences using behavioral questions about specific abusive behaviors and trauma checklist items. Cox proportional hazards regression analyses were conducted, adjusting for additional risk factors associated with AUD, including co-occurring psychiatric disorders (defined as time-varying) and parental alcohol misuse. Overall, CPA reporting patterns were highly correlated (tetrachoric rho = 0.73); although, only 25.8% of women who endorsed behaviorally defined CPA also endorsed checklist items whereas 72.2% of women who endorsed checklist items also endorsed behavioral questions. Racial disparities were evident, with behaviorally defined CPA increasing the hazard for AUD in EA but not AA women. Additional racial disparities in the risk for AUD were observed: increased hazard for AUD were associated with major depressive disorder in AA, and cannabis dependence and paternal alcohol problems in EA, women. Results demonstrate the relevance of the type of CPA measure in assessing CPA in studies of alcohol-related problems – behavioral items may be more inclusive of CPA exposure and more predictive of AUD– and highlight racial distinctions of AUD etiology in women.
doi:10.1037/adb0000174
PMCID: PMC4915219  PMID: 27322801
childhood physical abuse; alcohol use disorder; women; racial disparities
7.  Evidence of CNIH3 involvement in opioid dependence 
Molecular psychiatry  2015;21(5):608-614.
Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 SNPs, were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine, and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid dependent individuals. Meta-analyses found 5 genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective [p=4.30E-9; OR 0.64 (95%CI 0.55 – 0.74)]. Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP’s in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally-related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence complementing prior studies implicating the AMPA glutamate system.
doi:10.1038/mp.2015.102
PMCID: PMC4740268  PMID: 26239289
8.  Genome‐wide time‐to‐event analysis on smoking progression stages in a family‐based study 
Brain and Behavior  2016;e00462.
Abstract
Background
Various pivotal stages in smoking behavior can be identified, including initiation, conversion from experimenting to established use, development of tolerance, and cessation. Previous studies have shown high heritability for age of smoking initiation and cessation; however, time‐to‐event genome‐wide association studies aiming to identify underpinning genes that accelerate or delay these transitions are missing to date.
Methods
We investigated which single nucleotide polymorphisms (SNPs) across the whole genome contribute to the hazard ratio of transition between different stages of smoking behavior by performing time‐to‐event analyses within a large Finnish twin family cohort (N = 1962), and further conducted mediation analyses of plausible intermediate traits for significant SNPs.
Results
Genome‐wide significant signals were detected for three of the four transitions: (1) for smoking cessation on 10p14 (P = 4.47e‐08 for rs72779075 flanked by RP11‐575N15 and GATA3), (2) for tolerance on 11p13 (P = 1.29e‐08 for rs11031684 in RP1‐65P5.1), mediated by smoking quantity, and on 9q34.12 (P = 3.81e‐08 for rs2304808 in FUBP3), independent of smoking quantity, and (3) for smoking initiation on 19q13.33 (P = 3.37e‐08 for rs73050610 flanked by TRPM4 and SLC6A16) in analysis adjusted for first time sensations. Although our top SNPs did not replicate, another SNP in the TRPM4‐SLC6A16 gene region showed statistically significant association after region‐based multiple testing correction in an independent Australian twin family sample.
Conclusion
Our results suggest that the functional effect of the TRPM4‐SLC6A16 gene region deserves further investigation, and that complex neurotransmitter networks including dopamine and glutamate may play a critical role in smoking initiation. Moreover, comparison of these results implies that genetic contributions to the complex smoking behavioral phenotypes vary among the transitions.
doi:10.1002/brb3.462
PMCID: PMC4842934  PMID: 27134767
Cessation; genome‐wide association study; initiation; smoking behavior; time‐to‐event analysis
9.  Genome‐wide time‐to‐event analysis on smoking progression stages in a family‐based study 
Brain and Behavior  2016;6(5):e00462.
Abstract
Background
Various pivotal stages in smoking behavior can be identified, including initiation, conversion from experimenting to established use, development of tolerance, and cessation. Previous studies have shown high heritability for age of smoking initiation and cessation; however, time‐to‐event genome‐wide association studies aiming to identify underpinning genes that accelerate or delay these transitions are missing to date.
Methods
We investigated which single nucleotide polymorphisms (SNPs) across the whole genome contribute to the hazard ratio of transition between different stages of smoking behavior by performing time‐to‐event analyses within a large Finnish twin family cohort (N = 1962), and further conducted mediation analyses of plausible intermediate traits for significant SNPs.
Results
Genome‐wide significant signals were detected for three of the four transitions: (1) for smoking cessation on 10p14 (P = 4.47e‐08 for rs72779075 flanked by RP11‐575N15 and GATA3), (2) for tolerance on 11p13 (P = 1.29e‐08 for rs11031684 in RP1‐65P5.1), mediated by smoking quantity, and on 9q34.12 (P = 3.81e‐08 for rs2304808 in FUBP3), independent of smoking quantity, and (3) for smoking initiation on 19q13.33 (P = 3.37e‐08 for rs73050610 flanked by TRPM4 and SLC6A16) in analysis adjusted for first time sensations. Although our top SNPs did not replicate, another SNP in the TRPM4‐SLC6A16 gene region showed statistically significant association after region‐based multiple testing correction in an independent Australian twin family sample.
Conclusion
Our results suggest that the functional effect of the TRPM4‐SLC6A16 gene region deserves further investigation, and that complex neurotransmitter networks including dopamine and glutamate may play a critical role in smoking initiation. Moreover, comparison of these results implies that genetic contributions to the complex smoking behavioral phenotypes vary among the transitions.
doi:10.1002/brb3.462
PMCID: PMC4842934  PMID: 27134767
Cessation; genome‐wide association study; initiation; smoking behavior; time‐to‐event analysis
11.  Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior 
Thorgeirsson, Thorgeir E. | Gudbjartsson, Daniel F. | Surakka, Ida | Vink, Jacqueline M. | Amin, Najaf | Geller, Frank | Sulem, Patrick | Rafnar, Thorunn | Esko, Tõnu | Walter, Stefan | Gieger, Christian | Rawal, Rajesh | Mangino, Massimo | Prokopenko, Inga | Mägi, Reedik | Keskitalo, Kaisu | Gudjonsdottir, Iris H. | Gretarsdottir, Solveig | Stefansson, Hreinn | Thompson, John R. | Aulchenko, Yurii S. | Nelis, Mari | Aben, Katja K. | den Heijer, Martin | Dirksen, Asger | Ashraf, Haseem | Soranzo, Nicole | Valdes, Ana M | Steves, Claire | Uitterlinden, André G | Hofman, Albert | Tönjes, Anke | Kovacs, Peter | Hottenga, Jouke Jan | Willemsen, Gonneke | Vogelzangs, Nicole | Döring, Angela | Dahmen, Norbert | Nitz, Barbara | Pergadia, Michele L. | Saez, Berta | De Diego, Veronica | Lezcano, Victoria | Garcia-Prats, Maria D. | Ripatti, Samuli | Perola, Markus | Kettunen, Johannes | Hartikainen, Anna-Liisa | Pouta, Anneli | Laitinen, Jaana | Isohanni, Matti | Huei-Yi, Shen | Allen, Maxine | Krestyaninova, Maria | Hall, Alistair S | Jones, Gregory T. | van Rij, Andre M. | Mueller, Thomas | Dieplinger, Benjamin | Haltmayer, Meinhard | Jonsson, Steinn | Matthiasson, Stefan E. | Oskarsson, Hogni | Tyrfingsson, Thorarinn | Kiemeney, Lambertus A. | Mayordomo, Jose I. | Lindholt, Jes S | Pedersen, Jesper Holst | Franklin, Wilbur A. | Wolf, Holly | Montgomery, Grant W. | Heath, Andrew C. | Martin, Nicholas G. | Madden, Pamela A.F. | Giegling, Ina | Rujescu, Dan | Järvelin, Marjo-Riitta | Salomaa, Veikko | Stumvoll, Michael | Spector, Tim D | Wichmann, H-Erich | Metspalu, Andres | Samani, Nilesh J. | Penninx, Brenda W. | Oostra, Ben A. | Boomsma, Dorret I. | Tiemeier, Henning | van Duijn, Cornelia M. | Kaprio, Jaakko | Gulcher, Jeffrey R. | McCarthy, Mark I. | Peltonen, Leena | Thorsteinsdottir, Unnur | Stefansson, Kari
Nature genetics  2010;42(5):448-453.
Smoking is a risk factor for most of the diseases leading in mortality1. We conducted genome-wide association (GWA) meta-analyses of smoking data within the ENGAGE consortium to search for common alleles associating with the number of cigarettes smoked per day (CPD) in smokers (N=31,266) and smoking initiation (N=46,481). We tested selected SNPs in a second stage (N=45,691 smokers), and assessed some in a third sample (N=9,040). Variants in three genomic regions associated with CPD (P< 5·10−8), including previously identified SNPs at 15q25 represented by rs1051730-A (0.80 CPD,P=2.4·10−69), and SNPs at 19q13 and 8p11, represented by rs4105144-C (0.39 CPD, P=2.2·10−12) and rs6474412-T (0.29 CPD,P= 1.4·10−8), respectively. Among the genes at the two novel loci, are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6), and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6) highlighted in previous studies of nicotine dependence2-3. Nominal associations with lung cancer were observed at both 8p11 (rs6474412-T,OR=1.09,P=0.04) and 19q13 (rs4105144-C,OR=1.12,P=0.0006).
doi:10.1038/ng.573
PMCID: PMC3080600  PMID: 20418888
12.  The Nicotine Dependence Syndrome Scale in Finnish Smokers 
Drug and alcohol dependence  2006;89(1):42-51.
The Nicotine Dependence Syndrome Scale (NDSS) is a new multidimensional measure of nicotine dependence. The study aim was to examine the structure and heritability of the NDSS and its associations with nicotine dependence defined by FTND and DSM-IV criteria among Finnish smokers participating in an ongoing twin-family study. Adult twin pairs concordant for smoking from the Finnish Twin Cohort Study, and their siblings and parents were interviewed. Among 1370 smokers, the NDSS sum score (a summary measure of dependence) correlated moderately high with FTND score (r=0.62). Subjects in the highest NDSS sum score groups were more likely to be nicotine dependent according to DSM-IV criteria compared with those in the lowest quintile (odds ratio = 36.7, 95% Confidence interval 13.0–103). In exploratory factor analysis we derived three factors, named drive/priority, stereotypy/continuity and tolerance. The drive/priority factor correlated best with FTND (r=0.54). Genetic modelling showed no differences in the genetic architecture of NDSS or FTND by gender; the overall heritability estimate for NDSS was 0.30 (95% CI 0.06–0.47), and for FTND 0.40 (95% CI 0.23–0.55)
The NDSS sum score is moderately high associated with DSM-IV nicotine dependence as well as FTND. These analyses indicate that the NDSS functions well in a Finnish family-based sample and provide additional validation of a new scale developed to capture complex behavioral features of nicotine dependence.
doi:10.1016/j.drugalcdep.2006.11.017
PMCID: PMC1950147  PMID: 17174039
Tobacco use disorders; Nicotine dependence; DSM-IV; Validity and reliability; Twin study
13.  Genome-wide association study identifies novel locus for neuroticism and shows polygenic association with Major Depressive Disorder 
de Moor, Marleen H.M. | van den Berg, Stéphanie M. | Verweij, Karin J.H. | Krueger, Robert F. | Luciano, Michelle | Vasquez, Alejandro Arias | Matteson, Lindsay K. | Derringer, Jaime | Esko, Tõnu | Amin, Najaf | Gordon, Scott D. | Hansell, Narelle K. | Hart, Amy B. | Seppälä, Ilkka | Huffman, Jennifer E. | Konte, Bettina | Lahti, Jari | Lee, Minyoung | Miller, Mike | Nutile, Teresa | Tanaka, Toshiko | Teumer, Alexander | Viktorin, Alexander | Wedenoja, Juho | Abecasis, Goncalo R. | Adkins, Daniel E. | Agrawal, Arpana | Allik, Jüri | Appel, Katja | Bigdeli, Timothy B. | Busonero, Fabio | Campbell, Harry | Costa, Paul T. | Smith, George Davey | Davies, Gail | de Wit, Harriet | Ding, Jun | Engelhardt, Barbara E. | Eriksson, Johan G. | Fedko, Iryna O. | Ferrucci, Luigi | Franke, Barbara | Giegling, Ina | Grucza, Richard | Hartmann, Annette M. | Heath, Andrew C. | Heinonen, Kati | Henders, Anjali K. | Homuth, Georg | Hottenga, Jouke-Jan | Janzing, Joost | Jokela, Markus | Karlsson, Robert | Kemp, John P. | Kirkpatrick, Matthew G. | Latvala, Antti | Lehtimäki, Terho | Liewald, David C. | Madden, Pamela A.F. | Magri, Chiara | Magnusson, Patrik K.E. | Marten, Jonathan | Maschio, Andrea | Medland, Sarah E. | Mihailov, Evelin | Milaneschi, Yuri | Montgomery, Grant W. | Nauck, Matthias | Ouwens, Klaasjan G. | Palotie, Aarno | Pettersson, Erik | Polasek, Ozren | Qian, Yong | Pulkki-Råback, Laura | Raitakari, Olli T. | Realo, Anu | Rose, Richard J. | Ruggiero, Daniela | Schmidt, Carsten O. | Slutske, Wendy S. | Sorice, Rossella | Starr, John M. | Pourcain, Beate St | Sutin, Angelina R. | Timpson, Nicholas J. | Trochet, Holly | Vermeulen, Sita | Vuoksimaa, Eero | Widen, Elisabeth | Wouda, Jasper | Wright, Margaret J. | Zgaga, Lina | Scotland, Generation | Porteous, David | Minelli, Alessandra | Palmer, Abraham A. | Rujescu, Dan | Ciullo, Marina | Hayward, Caroline | Rudan, Igor | Metspalu, Andres | Kaprio, Jaakko | Deary, Ian J. | Räikkönen, Katri | Wilson, James F. | Keltikangas-Järvinen, Liisa | Bierut, Laura J. | Hettema, John M. | Grabe, Hans J. | van Duijn, Cornelia M. | Evans, David M. | Schlessinger, David | Pedersen, Nancy L. | Terracciano, Antonio | McGue, Matt | Penninx, Brenda W.J.H. | Martin, Nicholas G. | Boomsma, Dorret I.
JAMA psychiatry  2015;72(7):642-650.
Importance
Neuroticism is a personality trait that is briefly defined by emotional instability. It is a robust genetic risk factor for Major Depressive Disorder (MDD) and other psychiatric disorders. Hence, neuroticism is an important phenotype for psychiatric genetics. The Genetics of Personality Consortium (GPC) has created a resource for genome-wide association analyses of personality traits in over 63,000 participants (including MDD cases).
Objective
To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association (GWA) results based on 1000Genomes imputation, to evaluate if common genetic variants as assessed by Single Nucleotide Polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability, and to examine whether SNPs that predict neuroticism also predict MDD.
Setting
30 cohorts with genome-wide genotype, personality and MDD data from the GPC.
Participants
The study included 63,661 participants from 29 discovery cohorts and 9,786 participants from a replication cohort. Participants came from Europe, the United States or Australia.
Main outcome measure(s)
Neuroticism scores harmonized across all cohorts by Item Response Theory (IRT) analysis, and clinically assessed MDD case-control status.
Results
A genome-wide significant SNP was found in the MAGI1 gene (rs35855737; P=9.26 × 10−9 in the discovery meta-analysis, and P=2.38 × 10−8 in the meta-analysis of all 30 cohorts). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 of the discovery cohorts significantly predicted neuroticism in 2 independent cohorts. Importantly, polygenic scores also predicted MDD in these cohorts.
Conclusions and relevance
This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism, and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.
doi:10.1001/jamapsychiatry.2015.0554
PMCID: PMC4667957  PMID: 25993607
14.  Association between nicotine withdrawal and reward responsiveness in humans and rats 
JAMA psychiatry  2014;71(11):1238-1245.
Importance
Reward-related disturbances after withdrawal from nicotine are hypothesized to contribute to relapse to tobacco smoking, but mechanisms underlying and linking such processes remain largely unknown.
Objective
To determine whether withdrawal from nicotine affects reward responsiveness (i.e., the propensity to modulate behavior as a function of prior reinforcement experience) across species using translational behavioral assessments in humans and rats.
Design, Setting, Participants, and Main Outcomes and Measures
Analogous reward responsiveness tasks were used in both humans and rats to examine whether reward responsiveness varied in: 1) an ad libitum smoking condition compared to a 24-hour acute nicotine abstinence condition in 31 human smokers with (N=17) or without (N=14) a history of depression; 2) rats 24 hours after withdrawal from chronic nicotine (N=19) or saline (N=20); and 3) rats following acute nicotine exposure after withdrawal from either chronic nicotine or saline administration.
Results
In both human smokers and nicotine-treated rats, reward responsiveness was significantly reduced after 24-hour withdrawal from nicotine. In humans, withdrawal-induced deficits in reward responsiveness were greater in subjects with a history of depression. In rats previously exposed to chronic nicotine, acute nicotine re-exposure long after withdrawal potentiated reward responsiveness
Conclusions and Relevance
These findings across species converge in suggesting that organisms have diminished ability to modulate behavior as a function of reward during withdrawal of nicotine. This blunting may contribute to relapse to tobacco smoking, particularly in depression-vulnerable individuals, in order to re-instate responsiveness to natural rewards, and to experience potentiated nicotine-induced reward responsiveness. Moreover, demonstration of behavioral homology across humans and rodents provides a strong translational framework for the investigation and development of clinical treatments targeting reward responsiveness deficits during early withdrawal of nicotine.
doi:10.1001/jamapsychiatry.2014.1016
PMCID: PMC4353576  PMID: 25208057
15.  Human Mate Selection and Addiction: a Conceptual Critique 
Behavior genetics  2014;44(5):419-426.
The authors review past work on modeling human mate selection, and suggest, using illustrations from existing literature on the impact of alcoholism on relationship formation and dissolution and reproduction, that the challenges of adequately characterizing human mate selection have not yet been overcome. Some paths forwards are suggested.
doi:10.1007/s10519-014-9669-3
PMCID: PMC4195574  PMID: 25138372
mate selection; parental separation; reproductive timing
16.  GENETIC AND ENVIRONMENTAL RISK FOR MAJOR DEPRESSION IN AFRICAN-AMERICAN AND EUROPEAN-AMERICAN WOMEN 
It is unknown whether there are racial differences in the heritability of major depressive disorder (MDD) because most psychiatric genetic studies have been conducted in samples comprised largely of white non-Hispanics. To examine potential differences between African-American (AA) and European-American (EA) young adult women in (1) DSM-IV MDD prevalence, symptomatology and risk factors and (2) genetic and/or environmental liability to MDD, we analyzed data from a large, population representative sample of twins ascertained from birth records (n= 550 AA and n=3226 EA female twins) aged 18–28 years at the time of MDD assessment by semi-structured psychiatric interview. AA women were more likely to have MDD risk factors; however, there were no significant differences in lifetime MDD prevalence between AA and EA women after adjusting for covariates (Odds Ratio = 0.88, 95% confidence interval: 0.67–1.15 ). Most MDD risk factors identified among AAs were also associated with MDD at similar magnitudes among EAs. Although the MDD heritability point estimate was higher among AA than EA women in a model with paths estimated separately by race (56%, 95% CI: 29%–78% vs. 41%, 95% CI: 29%–52%), the best-fitting model was one in which additive genetic and nonshared environmental paths for AA and EA women were constrained to be equal (A = 43%, 33%–53% and E = 57%, 47%–67%). Despite a marked elevation in the prevalence of environmental risk exposures related to MDD among AA women, there were no significant differences in lifetime prevalence or heritability of MDD between AA and EA young women.
doi:10.1017/thg.2014.28
PMCID: PMC4222066  PMID: 24910290
depression; race; African-American; women; twins; heritability
17.  PTSD Risk Associated with a Functional DRD2 Polymorphism in Heroin Dependent Cases and Controls is Limited to Amphetamine Dependent Individuals 
Addiction biology  2013;19(4):700-707.
Posttraumatic stress disorder (PTSD), a pathologic response to severe stress, is a common comorbid disorder in substance dependent individuals. Evidence from twin studies suggests PTSD is moderately heritable. Genetic association studies to date have reported a limited number of replicated findings. We conducted a candidate gene association study in trauma-exposed individuals within the Comorbidity and Trauma Study’s sample (1343 heroin dependent cases and 406 controls from economically-disadvantaged neighborhoods). After data cleaning, the 1430 SNPs retained for analyses provided coverage of 72 candidate genes and included additional SNPs for which association was previously reported as well as 30 ancestry informative markers. We found a functional DRD2 promoter polymorphism (rs12364283) to be most highly associated with PTSD liability [OR 1.65 (1.27–2.15); p= 1.58 × 10−4]; however, this association was not significant with a stringent Bonferroni correction for multiple comparisons. The top hits include SNPs from other dopaminergic system genes: DRD2 DRD3, TH, and DBH. Additional analyses revealed the association involving rs12364283 is largely limited to amphetamine dependent individuals. Substantial risk is observed in amphetamine dependent individuals with at least one copy of this SNP [OR 2.86 (1.92–4.27); p=2.6 × 10−7]. Further analyses do not support extensive mediation of PTSD risk via self-reported impulsivity (BIS total score). These findings suggest roles for impairment in inhibitory control in the pathophysiology of PTSD and raise questions about stimulant use in certain populations (e.g., those in combat).
doi:10.1111/adb.12062
PMCID: PMC3883923  PMID: 23647975
amphetamine dependence; association study; DRD2; PTSD
18.  Different outcomes, same etiology? Shared genetic and environmental influences on non-suicidal self injury and suicidal ideation 
JAMA psychiatry  2014;71(6):699-705.
Importance
Non-suicidal and suicidal self-injury are very harmful behaviours and are associated with several psychiatric disorders. In the recently developed 5th version of the DSM, non-suicidal self-injury and suicidal behaviour disorder are for the first time introduced as conditions in their own right, instead of symptoms of other psychiatric disorders. It is unclear to what extent non-suicidal and suicidal self-injurious behaviours share the same underlying biological mechanisms and are influenced by the same environmental factors.
Objective
To determine the relative importance of genetic and environmental influences on the variation in non-suicidal self-injury and suicidal ideation and their covariation.
Design
Classical twin design, using population-based twin sample in which twins participated in semi-structured telephone interviews between 1996 and 2009 which primarily focused on psychiatric disorders.
Setting
General community.
Participants
10678 male and female Australian adult twins (mean age 32.8 years).
Main Outcome Measures
Lifetime presence of self-reported non-suicidal self-injury (NSSI) and suicidal ideation.
Results
The prevalence of NSSI and suicidal ideation was 4.7% and 26.5% and individuals that engaged in self-harm were much more likely to report suicidal ideation, OR(95%CIs)=8.4 (6.8–10.3). Results from a bivariate genetic model indicated that genetic factors explain a substantial part of the variance in both NSSI (37% for males and 59% for females) and suicidal ideation (41% and 55%, respectively), while residual influences (including nonshared environmental influences and measurement error) explain the remainder of the variance. Shared (family) environment did not seem to play a role. Moreover, both behaviours were strongly correlated (r=0.49 for males and 0.61 for females) and this correlation was largely explained by overlapping genetic influences (62% and 76% for males and females, respectively), whereas residual influences accounted for the remainder of the phenotypic correlation.
Conclusions and Relevance
Results indicated that the substantial correlation between NSSI and suicidal ideation is largely driven by overlapping genetic factors, suggesting that the two behaviours share similar biological underpinnings. Overlapping residual influences also explain part of the covariance between the two traits. Future research should further investigate which genetic and environmental influences underlie the vulnerability in NSSI and suicidal ideation.
doi:10.1001/jamapsychiatry.2014.89
PMCID: PMC4241464  PMID: 24760386
19.  Risks for Early Substance Involvement Associated with Parental Alcoholism and Parental Separation in an Adolescent Female Cohort* 
Drug and alcohol dependence  2014;138:130-136.
Background
We examined timing of substance involvement as a joint function of parental history of alcoholism and parental separation during childhood.
Method
Data were drawn from a large cohort of female like-sex twins [n = 613 African Ancestry (AA), n = 3550 European or other Ancestry (EA)]. Cox proportional hazards regression was conducted predicting age at first use of alcohol, first alcohol intoxication, first use and regular use of cigarettes, and first use of cannabis and other illicit drugs from dummy variables coding for parental alcoholism and parental separation. Propensity score analysis was also conducted comparing intact and separated families by predicted probability of parental separation.
Results
In EA families, increased risk of substance involvement was found in both alcoholic and separated families, particularly through ages 10 or 14 years, with risk to offspring from alcoholic separated families further increased. In AA families, associations with parental alcoholism and parental separation were weak and with few exceptions statistically nonsignificant. While propensity score findings confirmed unique risks observed in EA families, intact and separated AA families were poorly matched on risk-factors presumed to predate parental separation, especially parental alcoholism, requiring cautious interpretation of AA survival-analytic findings.
Conclusion
For offspring of European ancestry, parental separation predicts early substance involvement that is not explained by parental alcoholism nor associated family background characteristics. Additional research is needed to better characterize risks associated with parental separation in African American families.
doi:10.1016/j.drugalcdep.2014.02.020
PMCID: PMC4012919  PMID: 24647368
adolescent substance use; parental separation or divorce; parental alcoholism
20.  Genetic predisposition to schizophrenia associated with increased use of cannabis 
Molecular psychiatry  2014;19(11):1201-1204.
Cannabis is the most commonly used illicit drug worldwide. With debate surrounding the legalization and control of use, investigating its health risks has become a pressing area of research. One established association is that between cannabis use and schizophrenia, a debilitating psychiatric disorder affecting approximately 1% of the population over their lifetime. Although considerable evidence implicates cannabis use as a component cause of schizophrenia, it remains unclear whether this is entirely due to cannabis directly raising risk of psychosis, or whether the same genes that increases psychosis risk may also increase risk of cannabis use.
In a sample of 2,082 healthy individuals, we show an association between an individual’s burden of schizophrenia risk alleles and use of cannabis. This was significant both for comparing those who have ever vs. never used cannabis (p=2.6×10−4), and for quantity of use within users (p=3.0×10−3). While directly predicting only a small amount of the variance in cannabis use, these findings suggest that part of the association between schizophrenia and cannabis is due to a shared genetic aetiology. This form of gene-environment correlation is an important consideration when calculating the impact of environmental risk factors, including cannabis use.
doi:10.1038/mp.2014.51
PMCID: PMC4382963  PMID: 24957864
21.  Initial reactions to tobacco and cannabis smoking: A twin study 
Addiction (Abingdon, England)  2014;109(4):663-671.
Background and aims
Initial subjective reactions to cannabis and tobacco, broadly classified as positive or negative, have previously been explored for their associations with onset and maintenance of subsequent abuse/dependence. We examine (a) the factorial architecture of self-reported initial reactions to cannabis and tobacco; (b) whether these factors associate with concurrently reported age at onset of DSM-IV diagnosis of nicotine dependence and cannabis abuse/dependence; and (c) estimate heritable variation in and covariation between the factors.
Design
Factorial and exploratory structural equation modeling was conducted to examine the factor structure of initial reactions. Cox proportional hazards modeling was employed to examine their association with time to onset of diagnosis of DSM-IV nicotine dependence and cannabis abuse/dependence. Classical twin modeling, using univariate and multivariate models, was used to parse variance in each factor (and the covariance between factors) to their additive genetic, shared environmental and non-shared environmental sources.
Setting and Participants
General population sample of Caucasian female twins aged 18–32 years, with a lifetime history of tobacco [N=2393] and cannabis [N=1445] use.
Measurement
Self-report of initial subjective reactions to tobacco (cigarettes) and cannabis the first time they were used and time to onset of lifetime history of DSM-IV diagnosis of abuse (cannabis) and dependence (cannabis or nicotine).
Findings
Factors representing putatively positive and negative reactions to cannabis and tobacco emerged. Initial reactions to tobacco were associated with onset of DSM-IV diagnosis of nicotine dependence and cannabis abuse/dependence while initial reactions to cannabis were associated with onset of DSM-IV diagnosis of cannabis abuse/dependence alone. Genetic factors played a moderate role in each factor (heritability of 27–35%, p < 0.05) with the remaining variance attributed to individual-specific environment. Covariation across the factors indexing positive and negative initial reactions was attributable to genetic sources (0.18–0.58, p < 0.05), and to overlapping individual-specific environmental factors (−0.16–0.36, p < 0.05).
Conclusions
Initial subjective reactions to tobacco are associated with later onset of DSM-IV diagnosis of nicotine dependence and cannabis abuse/dependence while initial subjective reactions to cannabis are only associated with onset of diagnosis of DSM-IV cannabis abuse/dependence. Genetic and environmental factors underpin the overlap across the factors representing initial reactions, both positive and negative.
doi:10.1111/add.12449
PMCID: PMC3951663  PMID: 24325652
cannabis; tobacco; reactions; genetics; twin
22.  Association of OPRD1 Polymorphisms with Heroin Dependence in a Large Case-control Series 
Addiction biology  2012;19(1):10.1111/j.1369-1600.2012.00445.x.
Genes encoding the opioid receptors (OPRM1, OPRD1, and OPRK1) are obvious candidates for involvement in risk for heroin dependence. Prior association studies commonly had samples of modest size, included limited single nucleotide polymorphism (SNP) coverage of these genes, and yielded inconsistent results. Participants for the current investigation included 1459 heroin dependent cases ascertained from maintenance clinics in New South Wales, Australia, 1495 unrelated individuals selected from an Australian sample of twins and siblings as not meeting DSM-IV criteria for lifetime alcohol or illicit drug dependence (non-dependent controls), and 531 controls ascertained from economically-disadvantaged neighborhoods in proximity to the maintenance clinics. A total of 136 OPRM1, OPRD1, and OPRK1 SNPs were genotyped in this sample. After controlling for admixture with principal components analysis, our comparison of cases to non-dependent controls found 4 OPRD1 SNPs in fairly high linkage disequilibrium for which adjusted p values remained significant (e.g., rs2236857; OR 1.25; p=2.95 × 10−4) replicating a previously reported association. A post-hoc analysis revealed that the two-SNP (rs2236857 and rs581111) GA haplotype in OPRD1 is associated with greater risk (OR 1.68; p=1.41 × 10−5). No OPRM1 or OPRK1 SNPs reached more than nominal significance. Comparisons of cases to neighborhood controls reached only nominal significance. Our results replicate a prior report providing strong evidence implicating OPRD1 SNPs and, in particular, the two SNP (rs2236857 and rs581111) GA haplotype in liability for heroin dependence. Support was not found for similar association involving either OPRM1 or OPRK1 SNPs.
doi:10.1111/j.1369-1600.2012.00445.x
PMCID: PMC3867542  PMID: 22500942
association study; heroin dependence; OPRD1; OPRK1; OPRM1
23.  Are There Differences Between Young African-American and European-American Women in the Relative Influences of Genetics vs. Environment on Age at First Drink and Problem Alcohol Use? 
Alcoholism, clinical and experimental research  2013;37(11):10.1111/acer.12185.
Background
Differences in age at initiation of alcohol use and rates of problem drinking between African Americans (AA) and European Americans (EA) are well documented, but the association between early and problem use – and distinctions by ethnic group in this association - have yet to be examined in a genetically-informative framework.
Methods
Data were derived from a longitudinal study of female twins in Missouri. The sample was composed of 3,532 twins (13.6% AA, 86.4% EA) who participated in the fourth wave of data collection and reported consumption of at least one alcoholic drink over the lifetime. Mean age at Wave 4 was 21.7 (range=18–29) years. Twin modeling was conducted to estimate the relative contributions of additive genetic (A), shared environmental (C), and unique environmental (E) factors to variation in age at first drink and problem alcohol use and the cross-phenotype overlap in these influences.
Results
Early initiation of alcohol use predicted problem use in EA but not AA women. Separate AA and EA twin models produced substantially different estimates (but not statistically different models) of the relative contributions of A and C to problem alcohol use but similar genetic correlations between the phenotypes. Whereas 33% of the variance in the EA model of problem use was attributed to C, no evidence for C was found in the AA model. Heritability estimates for problem alcohol use were 41% in the AA model, 21% in the EA model. Evidence for A and C were found in both AA and EA models of age at first drink, but the A estimate was higher in the EA than AA model (44% vs. 26%).
Conclusions
Findings are suggestive of distinctions between AA vs. EA women in the relative contribution of genetic and environmental influences on the development of problem drinking.
doi:10.1111/acer.12185
PMCID: PMC3775995  PMID: 23763496
alcohol; African Americans; women; twins
24.  The genetic etiology of cannabis use initiation: a meta-analysis of genome-wide association studies and a SNP-based heritability estimation 
Addiction biology  2012;18(5):846-850.
While initiation of cannabis use is around 40% heritable, not much is known about the underlying genetic etiology. Here, we meta-analysed two genome-wide association studies of initiation of cannabis use with (>10,000 individuals). None of the genetic variants reached genome-wide significance. We also performed a gene-based association test, which also revealed no significant effects of individual genes. Finally, we estimated that only approximately 6.0% of the variation in cannabis initiation is due to common genetic variants. Future genetic studies using larger sample sizes and different methodologies (including sequencing) might provide more insight in the complex genetic etiology of cannabis use.
doi:10.1111/j.1369-1600.2012.00478.x
PMCID: PMC3548058  PMID: 22823124
genetics; cannabis; heritability; association
25.  DSM-IV defined conduct disorder and oppositional defiant disorder: An investigation of shared liability in female twins 
Psychological medicine  2014;44(5):1053-1064.
Background
DSM-IV specifies a hierarchal diagnostic structure such that an ODD diagnosis is applied only if criteria are not met for CD. Genetic studies of ODD and CD support a combination of shared genetic and environmental influences, but largely ignore the imposed diagnostic structure.
Methods
We examined whether ODD and CD share an underlying etiology while accounting for DSM-IV diagnostic specifications. Data from 1446 female twin pairs, aged 11–19, were fitted to two-stage models adhering to the DSM-IV diagnostic hierarchy.
Results
Models suggested that DSM-IV ODD-CD covariation is attributed largely to shared genetic influences.
Conclusions
This is the first study, to our knowledge, to examine genetic and environmental overlap among these disorders while maintaining DSM-IV hierarchical structure. Findings reflect primarily shared genetic influences and specific (i.e., uncorrelated) shared/familial environmental effects on these DSM-IV defined behaviors. These results have implications for how best to define CD and ODD for future genetically-informed analyses.
doi:10.1017/S0033291713001396
PMCID: PMC4024101  PMID: 23795654
adolescence; conduct disorder; genetics; oppositional defiant disorder; twins

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