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1.  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
2.  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
3.  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
4.  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
5.  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
6.  Genome-wide meta-analysis identifies new susceptibility loci for migraine 
Anttila, Verneri | Winsvold, Bendik S. | Gormley, Padhraig | Kurth, Tobias | Bettella, Francesco | McMahon, George | Kallela, Mikko | Malik, Rainer | de Vries, Boukje | Terwindt, Gisela | Medland, Sarah E. | Todt, Unda | McArdle, Wendy L. | Quaye, Lydia | Koiranen, Markku | Ikram, M. Arfan | Lehtimäki, Terho | Stam, Anine H. | Ligthart, Lannie | Wedenoja, Juho | Dunham, Ian | Neale, Benjamin M. | Palta, Priit | Hamalainen, Eija | Schürks, Markus | Rose, Lynda M | Buring, Julie E. | Ridker, Paul M. | Steinberg, Stacy | Stefansson, Hreinn | Jakobsson, Finnbogi | Lawlor, Debbie A. | Evans, David M. | Ring, Susan M. | Färkkilä, Markus | Artto, Ville | Kaunisto, Mari A | Freilinger, Tobias | Schoenen, Jean | Frants, Rune R. | Pelzer, Nadine | Weller, Claudia M. | Zielman, Ronald | Heath, Andrew C. | Madden, Pamela A.F. | Montgomery, Grant W. | Martin, Nicholas G. | Borck, Guntram | Göbel, Hartmut | Heinze, Axel | Heinze-Kuhn, Katja | Williams, Frances M.K. | Hartikainen, Anna-Liisa | Pouta, Anneli | van den Ende, Joyce | Uitterlinden, Andre G. | Hofman, Albert | Amin, Najaf | Hottenga, Jouke-Jan | Vink, Jacqueline M. | Heikkilä, Kauko | Alexander, Michael | Muller-Myhsok, Bertram | Schreiber, Stefan | Meitinger, Thomas | Wichmann, Heinz Erich | Aromaa, Arpo | Eriksson, Johan G. | Traynor, Bryan | Trabzuni, Daniah | Rossin, Elizabeth | Lage, Kasper | Jacobs, Suzanne B.R. | Gibbs, J. Raphael | Birney, Ewan | Kaprio, Jaakko | Penninx, Brenda W. | Boomsma, Dorret I. | van Duijn, Cornelia | Raitakari, Olli | Jarvelin, Marjo-Riitta | Zwart, John-Anker | Cherkas, Lynn | Strachan, David P. | Kubisch, Christian | Ferrari, Michel D. | van den Maagdenberg, Arn M.J.M. | Dichgans, Martin | Wessman, Maija | Smith, George Davey | Stefansson, Kari | Daly, Mark J. | Nyholt, Dale R. | Chasman, Daniel | Palotie, Aarno
Nature genetics  2013;45(8):912-917.
doi:10.1038/ng.2676
PMCID: PMC4041123  PMID: 23793025
7.  Childhood Sexual Abuse and Early Substance Use in Adolescent Girls: The Role of Familial Influences 
Addiction (Abingdon, England)  2013;108(5):993-1000.
Aim
To assess the extent to which the association between childhood sexual abuse (CSA) and early use of alcohol, cigarettes, and cannabis in adolescent girls is mediated by risk factors that tend to cluster in families where CSA occurs.
Design
An abridged version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) was administered by telephone. Participants: 3,761 female twins aged 18–29 (14.6% African American, 85.4% European American).
Measurements
CSA experiences and history of substance use were queried in the SSAGA-based interviews.
Findings
After controlling for familial influences on early substance use by including co-twin early use status in models, separate Cox proportional hazards regression analyses predicting onset of alcohol, cigarette, and cannabis use revealed a significant association with CSA. The effect was observed through age 19 for cigarettes and through age 21 for cannabis, but was limited to age 14 or younger for alcohol, with the most pronounced risk before age 10 (HR=4.59; CI: 1.96–10.74). CSA-associated risk for initiation of cigarette and cannabis use was also highest in the youngest age range, but the decline with age was much more gradual and the hazard ratios significantly lower (1.70; CI:1.13–2.56 for cigarettes and 2.34, CI:1.58–3.46 for cannabis).
Conclusions
Childhood sexual abuse history is a distinct risk factor for use of cigarettes and cannabis, and a very strong predictor of early age at first drink.
doi:10.1111/add.12115
PMCID: PMC3628962  PMID: 23316725
sexual abuse; alcohol; cigarettes; cannabis; women
8.  Genome-wide Association Study of a Quantitative Disordered Gambling Trait 
Addiction biology  2012;18(3):511-522.
Disordered gambling is a moderately heritable trait, but the underlying genetic basis is largely unknown. We performed a genome-wide association study (GWAS) for disordered gambling using a quantitative factor score in 1,312 twins from 894 Australian families. Association was conducted for 2,381,914 single nucleotide polymorphisms (SNPs) using the family-based association test in Merlin followed by gene and pathway enrichment analyses. Although no SNP reached genome-wide significance, six achieved P-values < 1 × 10−5 with variants in three genes (MT1X, ATXN1 and VLDLR) implicated in disordered gambling. Secondary case-control analyses found two SNPs on chromosome 9 (rs1106076 and rs12305135 near VLDLR) and rs10812227 near FZD10 on chromosome 12 to be significantly associated with lifetime DSM-IV pathological gambling and SOGS classified probable pathological gambling status. Furthermore, several addiction-related pathways were enriched for SNPs associated with disordered gambling. Finally, gene-based analysis of 24 candidate genes for dopamine agonist induced gambling in individuals with Parkinson’s disease suggested an enrichment of SNPs associated with disordered gambling. We report the first GWAS of disordered gambling. While further replication is required, the identification of susceptibility loci and biological pathways will be important in characterizing the biological mechanisms that underpin disordered gambling.
doi:10.1111/j.1369-1600.2012.00463.x
PMCID: PMC3470766  PMID: 22780124
association; disordered gambling; genomewide; MERLIN; quantitative
9.  Do Early Experiences with Cannabis vary in Cigarette Smokers? 
Drug and alcohol dependence  2012;128(3):255-259.
INTRODUCTION
We examine whether regular cigarette smokers were more likely to be exposed to and use cannabis at an earlier age, and further, upon initiation, whether their initial experiences with cannabis varied from those reported by never/non-regular cigarette smokers.
METHOD
A sample of 3797 Australian twins and siblings aged 21–46 years was used. Survival analyses examined whether cigarette smokers were at increased likelihood of early opportunity to use cannabis and early onset of cannabis use. Logistic regression examined whether cigarette smokers reported greater enjoyment of their cannabis experience, inhaling on the first try, differing positive and negative initial subjective reactions, smoked cigarettes with cannabis the first time and were more likely to try cannabis again within a week.
RESULTS
Regular cigarette smokers were more likely to report an earlier opportunity to use cannabis and early onset of cannabis use. Regular cigarette smokers were also considerably more likely to have enjoyed their first experience with cannabis and reported higher rates of positive initial reactions. They were more likely to report inhaling on the first try and smoking cigarettes with cannabis. Potentially negative subjective reactions were also elevated in regular cigarette smokers. Importantly, cigarette smokers were at 1.87 increased odds of smoking cannabis within a week of their initial use.
CONCLUSION
These findings indicate that the well-known overlap in cannabis and cigarette smoking behaviors may evolve as early as opportunity to use and extend through the course of the substance use trajectory.
doi:10.1016/j.drugalcdep.2012.09.002
PMCID: PMC3614406  PMID: 23010290
cannabis; cigarette; initial reaction; onset; opportunity
10.  ANKK1, TTC12, and NCAM1 Polymorphisms and Heroin Dependence – importance of considering drug exposure 
JAMA psychiatry (Chicago, Ill.)  2013;70(3):325-333.
Context
The genetic contribution to liability for opioid dependence is well-established; identification of the responsible genes has proved challenging.
Objective
To examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs) with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations.
Design
Case-control genetic association study that included two control groups (lacking an established optimal control group).
Setting
Semi-structured psychiatric interviews
Participants
Australian cases (N=1459) ascertained from opioid replacement therapy (ORT) clinics, neighborhood controls (N=531) ascertained from economically disadvantaged areas near opioid replacement therapy clinics, and unrelated Australian Twin Registry (ATR) controls (N=1495) not dependent on alcohol or illicit drugs selected from a twin and family sample.
Main Outcome Measure
Lifetime heroin dependence
Results
Comparison of cases with Australian Twin Registry controls found minimal evidence of association for all chromosome 11 cluster SNPs (p≥.01); a similar comparison to neighborhood controls revealed greater differences (p≥1.8 × 10−4). Comparing cases (N=1459) with the subgroup of neighborhood controls not dependent on illicit drugs (N=340), three SNPs were significantly associated (correcting for multiple testing): ANKK1 SNP rs877138 [most strongly associated; odds ratio 1.59; 95%CI (1.32–1.92); p=9.7 × 10−7], ANKK1 SNP rs4938013 and TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug-dependent (N=191) and non-dependent (N=340) neighborhood controls, suggesting that liability likely extends to non-opioid illicit drug dependence. Aggregate heroin dependence risk associated with two SNPs, rs877138 and rs4492854 (located in NCAM1), varied more than 4-fold (p= 2.74 × 10−9 for the risk-associated linear trend).
Conclusions
Our results provide further evidence of association for chromosome 11 gene cluster SNPs with substance dependence, including extension of liability to illicit drug dependence. Our findings highlight the necessity of considering drug exposure history when selecting control groups for genetic investigations of illicit drug dependence.
doi:10.1001/jamapsychiatry.2013.282
PMCID: PMC3789525  PMID: 23303482
11.  Examining the Association of NRXN3 SNPs with Borderline Personality Disorder Phenotypes in Heroin Dependent Cases and Socio-economically Disadvantaged Controls* 
Drug and alcohol dependence  2012;128(3):10.1016/j.drugalcdep.2012.11.011.
Background
Borderline personality disorder (BPD) and substance use disorders frequently cooccur; their dual presence predicts poor prognosis. The genetic underpinnings of BPD have not been well-characterized and could offer insight into comorbidity. The current report focuses on the association of Neurexin 3 (NRXN3) single nucleotide polymorphisms (SNPs) with BPD symptoms in heroin dependent cases and controls.
Methods
The sample of the Comorbidity and Trauma Study, a genetic association study of heroin dependence, consists of Australian heroin dependent cases ascertained from opioid replacement therapy clinics and controls ascertained in nearby economically-disadvantaged neighborhoods. The assessment included a screening instrument for BPD, used previously in Australian population surveys. Genotypic and BPD phenotypic data were available for 1439 cases and 507 controls. We examined the association of 1430 candidate gene SNPs with BPD phenotypes.
Results
One or more NRXN3 SNPs were nominally associated with all BPD phenotypes; however, none met the conservative significance threshold we employed to correct for multiple testing. The most strongly associated SNPs included rs10144398 with identity disturbance (p=4.9 × 10−5) and rs10151731 with affective instability (p=8.8 × 10−5). The strongest association with screening positive for BPD was found for the NRXN3 SNP, rs10083466 (p=.0013). Neither the correlation of BPD phenotypes nor the linkage disequilibrium relationships of the SNPs account for the number of observed associations involving NRXN3 SNPs.
Conclusions
Our findings provide intriguing preliminary evidence for the association of NRXN3 with BPD phenotypes. The strongest associations were found for traits (i.e., affective instability; identity disturbance) also observed with other disorders.
doi:10.1016/j.drugalcdep.2012.11.011
PMCID: PMC3832348  PMID: 23245376
borderline personality disorder; NRXN3; genetic association study; heroin dependence
12.  DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer landscape 
Nature genetics  2013;45(7):10.1038/ng.2649.
Introduction
Transposable element (TE) derived sequences comprise half of our genome and DNA methylome, and are presumed densely methylated and inactive. Examination of the genome-wide DNA methylation status within 928 TE subfamilies in human embryonic and adult tissues revealed unexpected tissue-specific and subfamily-specific hypomethylation signatures. Genes proximal to tissue-specific hypomethylated TE sequences were enriched for functions important for the tissue type and their expression correlated strongly with hypomethylation of the TEs. When hypomethylated, these TE sequences gained tissue-specific enhancer marks including H3K4me1 and occupancy by p300, and a majority exhibited enhancer activity in reporter gene assays. Many such TEs also harbored binding sites for transcription factors that are important for tissue-specific functions and exhibited evidence for evolutionary selection. These data suggest that sequences derived from TEs may be responsible for wiring tissue type-specific regulatory networks, and have acquired tissue-specific epigenetic regulation.
doi:10.1038/ng.2649
PMCID: PMC3695047  PMID: 23708189
14.  Cannabinoid receptor (CNR1) genotype moderates the effects of childhood physical abuse on anhedonia and depression 
Archives of general psychiatry  2012;69(7):732-740.
Context
The endocannabinoid system has been implicated in stress adaptation and the regulation of mood in rodent studies, but few human association studies have examined these links and replications are limited.
Objective
To examine whether a synonymous polymorphism, rs1049353, in exon 4 of the gene encoding the human endocannabinoid receptor (CNR1) moderates the effect of self-reported childhood physical abuse on lifetime anhedonia and depression and further, to replicate this interaction in an independent sample.
Design
Genetic association study in 1041 young adult U.S. women with replication in an independent Australian sample of 1428 heroin dependent cases and 506 neighborhood controls.
Main outcome measure
Self-reported anhedonia and depression (with anhedonia).
Results
In both samples, those who experienced childhood physical abuse were considerably more likely to report lifetime anhedonia. However, in those with one or more copies of the minor allele of rs1049353, this pathogenic effect of childhood physical abuse was attenuated. Thus, in those reporting childhood physical abuse, while 57% of those homozygous for the major allele reported anhedonia, only 29% of those who were carriers of the minor allele reported it (p < 0.02). rs1049353 also buffered the effects of childhood physical abuse on major depressive disorder, however this influence was largely attributable to anhedonic depression. These effects were also noted in an independent sample, where minor allele carriers were at decreased risk for anhedonia even when exposed to physical abuse.
Conclusions
Consistent with preclinical findings, a synonymous CNR1 polymorphism, rs1049353, is linked to the effects of stress attributable to childhood physical abuse on anhedonia and anhedonic depression. This polymorphism reportedly resides in the neighborhood of an exon splice enhancer and hence, future studies should carefully examine its impact on expression and conformational variation in CNR1, particularly in relation to stress adaptation.
doi:10.1001/archgenpsychiatry.2011.2273
PMCID: PMC3706194  PMID: 22393204
CNR1; endocannabinoid; physical abuse; rs1049353; GxE; anhedonia; major depression
15.  No association of candidate genes with cannabis use in a large sample of Australian twin families 
Addiction Biology  2011;17(3):687-690.
While there is solid evidence that cannabis use is heritable, attempts to identify genetic influences at the molecular level have yielded mixed results. Here, a large twin family sample (N=7452) was used to test for association between ten previously reported candidate genes and lifetime frequency of cannabis use using a gene-based association test. None of the candidate genes reached even nominal significance (p<.05). The lack of replication may point to our limited understanding of the neurobiology of cannabis involvement and also to potential publication bias and false-positive findings in previous studies.
doi:10.1111/j.1369-1600.2011.00320.x
PMCID: PMC3393887  PMID: 21507154
genes; cannabis; genetics; association
16.  Parent, sibling and peer influences on smoking initiation, regular smoking and nicotine dependence. Results from a genetically informative design 
Addictive Behaviors  2011;37(3):240-247.
We sought to determine whether parenting, sibling and peer influences are associated with offspring ever smoking, regular smoking and nicotine dependence (ND) after controlling for familial factors. We used a twin-family design and data from structured diagnostic surveys of 1,919 biological offspring (age 12–32 years), 1,107 twin fathers, and 1,023 mothers. Offspring were classified into one of four familial risk groups based on twin fathers' and their co-twins' history of DSM-III-R nicotine dependence. Multivariate multinomial logistic regression was used to model familial risk, paternal and maternal parenting behavior and substance use, sibling substance use, and friend and school peer smoking, alcohol and drug use. Ever smoking was associated with increasing offspring age, white race, high maternal pressure to succeed in school, sibling drug use, and friend smoking, alcohol and drug use. Offspring regular smoking was associated with these same factors with additional contribution from maternal ND. Offspring ND was associated with increasing offspring age, male gender, biological parents divorce, high genetic risk from father and mother ND, maternal problem drinking, maternal rule inconsistency and sibling drug use, and friend smoking, alcohol and drug use. Friend smoking had the largest magnitude of association with offspring smoking. This effect remains after accounting for familial liability and numerous parent and sibling level effects. Smoking interventions may have greatest impact by targeting smoking prevention among peer groups in adolescent and young adult populations.
doi:10.1016/j.addbeh.2011.10.005
PMCID: PMC3374497  PMID: 22094168
smoking; nicotine dependence; peers; gene and environment
17.  Longevity candidate genes and their association with personality traits in the elderly 
Human longevity and personality traits are both heritable and are consistently linked at the phenotypic level. We test the hypothesis that candidate genes influencing longevity in lower organisms are associated with variance in the five major dimensions of human personality (measured by the NEO-FFI and IPIP inventories) plus related mood states of anxiety and depression. Seventy single nucleotide polymorphisms (SNPs) in six brain expressed, longevity candidate genes (AFG3L2, FRAP1, MAT1A, MAT2A, SYNJ1 and SYNJ2) were typed in over one thousand 70-year old participants from the Lothian Birth Cohort of 1936 (LBC1936). No SNPs were associated with the personality and psychological distress traits at a Bonferroni corrected level of significance (p < 0.0002), but there was an over-representation of nominally significant (p < 0.05) SNPs in the synaptojanin-2 (SYNJ2) gene associated with agreeableness and symptoms of depression. Eight SNPs which showed nominally significant association across personality measurement instruments were tested in an extremely large replication sample of 17 106 participants. SNP rs350292, in SYNJ2, was significant: the minor allele was associated with an average decrease in NEO agreeableness scale scores of 0.25 points, and 0.67 points in the restricted analysis of elderly cohorts (most aged > 60 years). Because we selected a specific set of longevity genes based on functional genomics findings, further research on other longevity gene candidates is warranted to discover whether they are relevant candidates for personality and psychological distress traits.
doi:10.1002/ajmg.b.32013
PMCID: PMC3583011  PMID: 22213687
NEO personality; IPIP personality; anxiety; depressive symptoms; ageing; genetics
19.  Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations 
Human Molecular Genetics  2011;21(2):446-455.
Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 × 10−8; rs944002 in C14orf73 on chromosome 14, P = 4.7 × 10−13; rs340005 in RORA on chromosome 15, P = 2.4 × 10−8), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum PHET = 5.6 × 10−12 at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.
doi:10.1093/hmg/ddr478
PMCID: PMC3276286  PMID: 22010049
20.  Risk for Suicidal Thoughts and Behavior after Childhood Sexual Abuse in Women and Men 
Earlier studies have found an elevated risk for psychopathology and suicidal behavior associated with childhood sexual abuse (CSA); however the degree to which risk is mediated by depression and post-traumatic stress disorder (PTSD) in women and men remains unclear. We examined these issues in data from a family study of childhood maltreatment (N=2559). We found significant CSA-associated risk for depression, PTSD, and suicidal behavior for women and men. In survival analyses controlling for these disorders, we observed persistent, but somewhat reduced, CSA-associated risk for suicidal ideation and suicide attempt. Our findings thus suggest these disorders partially mediate CSA-associated risk.
doi:10.1111/j.1943-278X.2011.00040.x
PMCID: PMC3518050  PMID: 21599726
21.  Patterns of use, sequence of onsets and correlates of tobacco and cannabis 
Addictive behaviors  2011;36(12):1141-1147.
Background
While most individuals initiate their use of tobacco prior to onset of cannabis use, recent reports have identified a smaller subset of youth who report onset of cannabis use prior to tobacco use. In this study, we characterize patterns of cannabis and tobacco use (tobacco but not cannabis, cannabis but not tobacco or both) and compare the factors associated with onset of tobacco before cannabis and cannabis before tobacco.
Methods
Data on 1812 offspring aged 12–32 years, drawn from two related offspring of Vietnam Era twin studies, were used. Individuals were divided into tobacco but not cannabis (T), cannabis but not tobacco (C) and users of both substances (CT). Those who used both could be further classified by the timing of onset of tobacco and cannabis use. Multinomial logistic regression was used to characterize the groups using socio-demographic and psychiatric covariates. Furthermore, data on parental smoking and drug use was used to identify whether certain groups represented greater genetic or environmental vulnerability.
Results
22% (n=398) reported T, 3% (n=55) reported C and 44% reported CT (n=801). Of the 801 CT individuals, 72.8% (n=583), 9.9% (n=77) and 17.3% (n=139) reported onset of tobacco before cannabis, cannabis before tobacco and onsets at the same age. C users were as likely as CT users to report peer drug use and psychopathology, such as conduct problems while CT was associated with increased tobacco use relative to T. Onset of tobacco prior to cannabis, when compared onset of cannabis before tobacco or reporting initiation at the same age was associated with greater cigarettes smoked per day, however no distinct factors distinguished the group with onset of cannabis before tobacco from those with initiation at the same age.
Conclusion
A small subset of individuals report cannabis without tobacco use. Of those who use both cannabis and tobacco, a small group report cannabis use prior to tobacco use. Follow-up analyses that chart the trajectories of these individuals will be required to delineate their course of substance involvement.
doi:10.1016/j.addbeh.2011.07.005
PMCID: PMC3183489  PMID: 21820810
Cannabis; Tobacco; Reverse Gateways
22.  GWAS of butyrylcholinesterase activity identifies four novel loci, independent effects within BCHE and secondary associations with metabolic risk factors 
Human Molecular Genetics  2011;20(22):4504-4514.
Serum butyrylcholinesterase (BCHE) activity is associated with obesity, blood pressure and biomarkers of cardiovascular and diabetes risk. We have conducted a genome-wide association scan to discover genetic variants affecting BCHE activity, and to clarify whether the associations between BCHE activity and cardiometabolic risk factors are caused by variation in BCHE or whether BCHE variation is secondary to the metabolic abnormalities. We measured serum BCHE in adolescents and adults from three cohorts of Australian twin and family studies. The genotypes from ∼2.4 million single-nucleotide polymorphisms (SNPs) were available in 8791 participants with BCHE measurements. We detected significant associations with BCHE activity at three independent groups of SNPs at the BCHE locus (P = 5.8 × 10−262, 7.8 × 10−47, 2.9 × 10−12) and at four other loci: RNPEP (P = 9.4 × 10−16), RAPH1-ABI2 (P = 4.1 × 10−18), UGT1A1 (P = 4.0 × 10−8) and an intergenic region on chromosome 8 (P = 1.4 × 10−8). These loci affecting BCHE activity were not associated with metabolic risk factors. On the other hand, SNPs in genes previously associated with metabolic risk had effects on BCHE activity more often than can be explained by chance. In particular, SNPs within FTO and GCKR were associated with BCHE activity, but their effects were partly mediated by body mass index and triglycerides, respectively. We conclude that variation in BCHE activity is due to multiple variants across the spectrum from uncommon/large effect to common/small effect, and partly results from (rather than causes) metabolic abnormalities.
doi:10.1093/hmg/ddr375
PMCID: PMC3196893  PMID: 21862451
23.  Genome-wide association study identifies two loci strongly affecting transferrin glycosylation 
Human Molecular Genetics  2011;20(18):3710-3717.
Polysaccharide sidechains attached to proteins play important roles in cell–cell and receptor–ligand interactions. Variation in the carbohydrate component has been extensively studied for the iron transport protein transferrin, because serum levels of the transferrin isoforms asialotransferrin + disialotransferrin (carbohydrate-deficient transferrin, CDT) are used as biomarkers of excessive alcohol intake. We conducted a genome-wide association study to assess whether genetic factors affect CDT concentration in serum. CDT was measured in three population-based studies: one in Switzerland (CoLaus study, n = 5181) and two in Australia (n = 1509, n = 775). The first cohort was used as the discovery panel and the latter ones served as replication. Genome-wide single-nucleotide polymorphism (SNP) typing data were used to identify loci with significant associations with CDT as a percentage of total transferrin (CDT%). The top three SNPs in the discovery panel (rs2749097 near PGM1 on chromosome 1, and missense polymorphisms rs1049296, rs1799899 in TF on chromosome 3) were successfully replicated , yielding genome-wide significant combined association with CDT% (P = 1.9 × 10−9, 4 × 10−39, 5.5 × 10−43, respectively) and explain 5.8% of the variation in CDT%. These allelic effects are postulated to be caused by variation in availability of glucose-1-phosphate as a precursor of the glycan (PGM1), and variation in transferrin (TF) structure.
doi:10.1093/hmg/ddr272
PMCID: PMC3159549  PMID: 21665994
24.  A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications 
Biological psychiatry  2011;70(6):513-518.
Background
Given moderately strong genetic contributions to variation in alcoholism and heaviness of drinking (50–60% heritability), with high correlation of genetic influences, we have conducted a quantitative trait genomewide association study for phenotypes related to alcohol use and dependence.
Methods
Diagnostic interview and blood/buccal samples were obtained from sibships ascertained through the Australian Twin Registry. Genomewide SNP genotyping was performed with 8754 individuals [2062 alcohol dependent cases] selected for informativeness for alcohol use disorder and associated quantitative traits. Family-based association tests were performed for alcohol dependence, dependence factor score and heaviness of drinking factor score, with confirmatory case-population control comparisons using an unassessed population control series of 3393 Australians with genomewide SNP data.
Results
No findings reached genomewide significance (p=8.4×10−8 for this study), with lowest p-value for primary phenotypes of 1.2×10−7. Convergent findings for quantitative consumption and diagnostic and quantitative dependence measures suggest possible roles for a transmembrane protein gene (TMEM108) and for ANKS1A. The major finding, however, was small effect sizes estimated for individual SNPs, suggesting that hundreds of genetic variants make modest contributions (1/4% of variance or less) to alcohol dependence risk.
Conclusions
We conclude that (i) meta-analyses of consumption data may contribute usefully to gene-discovery; (ii) translation of human alcoholism GWAS results to drug discovery or clinically useful prediction of risk will be challenging; (iii) through accumulation across studies, GWAS data may become valuable for improved genetic risk differentiation in research in biological psychiatry (e.g. prospective high-risk or resilience studies).
doi:10.1016/j.biopsych.2011.02.028
PMCID: PMC3210694  PMID: 21529783
Alcoholism; genome-wide association; quantitative-trait; non-replication
25.  A 3p26-3p25 genetic linkage finding for DSM-IV major depression in heavy smoking families 
The American journal of psychiatry  2011;168(8):848-852.
Objective
The authors tested for genetic linkage of DSM-IV-diagnosed major depressive disorder in families that were ascertained for cigarette smoking.
Method
Within a study that targeted families characterized by a history of smoking, analyses derived a subset of 91 Australian families with two or more offspring with a history of DSM-IV major depressive disorder (affected sibling pairs, N=187) and 25 Finnish families (affected sibling pairs, N=33). Within this affected sibling pair design, the authors conducted nonparametric linkage analysis.
Results
In the Australian heavy smoking families, the authors found a genome-wide significant multipoint LOD score of 4.14 for major depressive disorder on chromosome 3 at 24.9 cM (3p26-3p25).
Conclusions
Genome-wide significant linkage was detected for major depressive disorder on chromosome 3p in a sample ascertained for smoking. A linkage peak at this location was also observed in an independent study of major depressive disorder.
doi:10.1176/appi.ajp.2011.10091319
PMCID: PMC3433250  PMID: 21572167

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