Genetic and Depressive Traits Moderate the Reward-Enhancing Effects of Acute Nicotine in Young Light Smokers.

INTRODUCTION: Rates of light smoking have increased in recent years and are associated with adverse health outcomes. Reducing light smoking is a challenge because it is unclear why some but not others, progress to heavier smoking. Nicotine has profound effects on brain reward systems and individual differences in nicotine's reward-enhancing effects may drive variability in smoking trajectories. Therefore, we examined whether a genetic risk factor and personality traits known to moderate reward processing, also moderate the reward-enhancing effects of nicotine. METHODS: Light smokers (n = 116) performed a Probabilistic Reward Task to assess reward responsiveness after receiving nicotine or placebo (order counterbalanced). Individuals were classified as nicotine dependence 'risk' allele carriers (rs16969968 A-allele carriers) or non-carriers (non-A-allele carriers), and self-reported negative affective traits were also measured. RESULTS: Across the sample, reward responsiveness was greater following nicotine compared to placebo (p = 0.045). For Caucasian A-allele carriers but not non-A-allele carriers, nicotine enhanced reward responsiveness compared to placebo for those who received placebo first (p = 0.010). Furthermore, for A-allele carriers but not non-A-allele carriers who received nicotine first, the enhanced reward responsiveness in the nicotine condition carried over to the placebo condition (p < 0.001). Depressive traits also moderated the reward-enhancing effects of nicotine (p = 0.010) and were associated with blunted reward responsiveness following placebo but enhanced reward responsiveness following nicotine. CONCLUSION: These findings suggest that individual differences in a genetic risk factor and depressive traits alter nicotine's effect on reward responsiveness in light smokers and may be important factors underpinning variability in smoking trajectories in this growing population. IMPLICATIONS: Individuals carrying genetic risk factors associated with nicotine dependence(rs16969968 A-allele carriers) and those with higher levels of depressive personality traits, showmore pronounced increases in reward learning following acute nicotine exposure. These findingssuggest that genetic and personality factors may drive individual differences in smoking trajectoriesin young light smokers by altering the degree to which nicotine enhances reward processing. CLINICAL TRIAL REGISTRATION: NCT02129387 (pre-registered hypothesis: www.clinicaltrials.gov).

Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders.

Migraine and major depressive disorder (MDD) are comorbid, moderately heritable and to some extent influenced by the same genes. In a previous paper, we suggested the possibility of causality (one trait causing the other) underlying this comorbidity. We present a new application of polygenic (genetic risk) score analysis to investigate the mechanisms underlying the genetic overlap of migraine and MDD. Genetic risk scores were constructed based on data from two discovery samples in which genome-wide association analyses (GWA) were performed for migraine and MDD, respectively. The Australian Twin Migraine GWA study (N = 6,350) included 2,825 migraine cases and 3,525 controls, 805 of whom met the diagnostic criteria for MDD. The RADIANT GWA study (N = 3,230) included 1,636 MDD cases and 1,594 controls. Genetic risk scores for migraine and for MDD were used to predict pure and comorbid forms of migraine and MDD in an independent Dutch target sample (NTR-NESDA, N = 2,966), which included 1,476 MDD cases and 1,058 migraine cases (723 of these individuals had both disorders concurrently). The observed patterns of prediction suggest that the 'pure' forms of migraine and MDD are genetically distinct disorders. The subgroup of individuals with comorbid MDD and migraine were genetically most similar to MDD patients. These results indicate that in at least a subset of migraine patients with MDD, migraine may be a symptom or consequence of MDD.

A mega-analysis of genome-wide association studies for major depressive disorder.

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

Applying polygenic risk scores to postpartum depression.

The etiology of major depressive disorder (MDD) is likely to be heterogeneous, but postpartum depression (PPD) is hypothesized to represent a more homogenous subset of MDD. We use genome-wide SNP data to explore this hypothesis. We assembled a total cohort of 1,420 self-report cases of PPD and 9,473 controls with genome-wide genotypes from Australia, The Netherlands, Sweden and the UK. We estimated the total variance attributable to genotyped variants. We used association results from the Psychiatric Genomics Consortia (PGC) of bipolar disorder (BPD) and MDD to create polygenic scores in PPD and related MDD data sets to estimate the genetic overlap between the disorders. We estimated that the percentage of variance on the liability scale explained by common genetic variants to be 0.22 with a standard error of 0.12, p = 0.02. The proportion of variance (R (2)) from a logistic regression of PPD case/control status in all four cohorts on a SNP profile score weighted by PGC-BPD association results was small (0.1 %) but significant (p = 0.004) indicating a genetic overlap between BPD and PPD. The results were highly significant in the Australian and Dutch cohorts (R (2) > 1.1 %, p < 0.008), where the majority of cases met criteria for MDD. The genetic overlap between BPD and MDD was not significant in larger Australian and Dutch MDD case/control cohorts after excluding PPD cases (R (2) = 0.06 %, p = 0.08), despite the larger MDD group affording more power. Our results suggest an empirical genetic evidence for a more important shared genetic etiology between BPD and PPD than between BPD and MDD.

Testing the role of circadian genes in conferring risk for psychiatric disorders.

Disturbed sleep and disrupted circadian rhythms are a common feature of psychiatric disorders, and many groups have postulated an association between genetic variants in circadian clock genes and psychiatric disorders. Using summary data from the association analyses of the Psychiatric Genomics Consortia (PGC) for schizophrenia, bipolar disorder and major depressive disorder, we evaluated the evidence that common SNPs in genes encoding components of the molecular clock influence risk to psychiatric disorders. Initially, gene-based and SNP P-values were analyzed for 21 core circadian genes. Subsequently, an expanded list of genes linked to control of circadian rhythms was analyzed. After correcting for multiple comparisons, none of the circadian genes were significantly associated with any of the three disorders. Several genes previously implicated in the etiology of psychiatric disorders harbored no SNPs significant at the nominal level of P < 0.05, and none of the the variants identified in candidate studies of clock genes that were included in the PGC datasets were significant after correction for multiple testing. There was no evidence of an enrichment of associations in genes linked to control of circadian rhythms in human cells. Our results suggest that genes encoding components of the molecular clock are not good candidates for harboring common variants that increase risk to bipolar disorder, schizophrenia, or major depressive disorder.

Metabolic and biochemical effects of low-to-moderate alcohol consumption.

BACKGROUND: Alcohol consumption has multiple biochemical consequences. Only a few of these are useful as diagnostic markers, but many reflect potentially harmful or beneficial effects of alcohol. Average consumption of 2 to 4 drinks per day is associated with lower overall or cardiovascular mortality risk than either lower or higher intake. We have analyzed the dose-response relationships between reported alcohol consumption and 17 biomarkers, with emphasis on intake of up to 3 drinks per day. METHODS: Biochemical tests were performed on serum from 8,396 study participants (3,750 men and 4,646 women, aged 51 ± 13 years, range 18 to 93) who had provided information on alcohol consumption in the week preceding blood collection. RESULTS: Gamma glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, carbohydrate-deficient transferrin, urate, ferritin, and bilirubin showed little or no change with alcohol consumption below 2 to 3 drinks per day, but increased with higher intake. High-density lipoprotein cholesterol and albumin showed increasing results, and insulin showed decreasing results, across the entire range of alcohol use. Biphasic responses, where subjects reporting 1 to 2 drinks per day had lower results than those reporting either more or less alcohol use, occurred for triglycerides, glucose, C-reactive protein, alkaline phosphatase, and butyrylcholinesterase. Increasing alcohol use was associated with decreasing low-density lipoprotein cholesterol (LDL-C) in younger women, but higher LDL-C in older men. CONCLUSIONS: Some markers show threshold relationships with alcohol, others show continuous ones, and a third group show biphasic or U-shaped relationships. Overall, the biochemical sequelae of low-to-moderate alcohol use are consistent with the epidemiological evidence on morbidity and mortality.

Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD.

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10(-35) and <10(-8) respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10(-6)). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10(-20)) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.

Chromosome 20 shows linkage with DSM-IV nicotine dependence in Finnish adult smokers.

INTRODUCTION: Chromosome 20 has previously been associated with nicotine dependence (ND) and smoking cessation. Our aim was to replicate and extend these findings. METHODS: First, a total of 759 subjects belonging to 206 Finnish families were genotyped with 18 microsatellite markers residing on chromosome 20, in order to replicate previous linkage findings. Then, the replication data were combined to an existing whole-genome linkage data resulting in a total of 1,302 genotyped subjects from 357 families. ND diagnosed by DSM-IV criteria, the Fagerström Test for Nicotine Dependence (FTND) score, and the lifetime maximum number of cigarettes smoked within a 24-hr period (MaxCigs24) were used as phenotypes in the nonparametric linkage analyses. RESULTS: We replicated previously reported linkage to DSM-IV ND, with a maximum logarithm of odd (LOD) score of 3.8 on 20p11, with females contributing more (maximum LOD [MLOD] score 3.4 on 20q11) than males (MLOD score 2.6 on 20p11). With the combined sample, a suggestive LOD score of 2.3 was observed for DSM-IV ND on 20p11. Sex-specific analyses revealed that the signal was driven by females with a maximum LOD score of 3.3 (on 20q11) versus LOD score of 1.3 in males (on 20q13) in the combined sample. No significant linkage signals were obtained for FTND or MaxCigs24. CONCLUSIONS: Our results provide further evidence that chromosome 20 harbors genetic variants influencing ND in adult smokers.

Analysis of detailed phenotype profiles reveals CHRNA5-CHRNA3-CHRNB4 gene cluster association with several nicotine dependence traits.

INTRODUCTION: The role of the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25 in the etiology of nicotine dependence (ND) is still being defined. In this study, we included all 15 tagging single nucleotide polymorphisms (SNPs) within the CHRNA5-CHRNA3-CHRNB4 cluster and tested associations with 30 smoking-related phenotypes. METHODS: The study sample was ascertained from the Finnish Twin Cohort study. Twin pairs born 1938-1957 and concordant for a history of cigarette smoking were recruited along with their family members (mainly siblings), as part of the Nicotine Addiction Genetics consortium. The study sample consisted of 1,428 individuals (59% males) from 735 families, with mean age 55.6 years. RESULTS: We detected multiple novel associations for ND. DSM-IV ND symptoms associated significantly with the proxy SNP Locus 1 (rs2036527, p = .000009) and Locus 2 (rs578776, p = .0001) and tolerance factor of the Nicotine Dependence Syndrome Scale (NDSS) showed suggestive association to rs11636753 (p = .0059), rs11634351 (p = .0069), and rs1948 (p = .0071) in CHRNB4. Furthermore, we report significant association with DSM-IV ND diagnosis (rs2036527, p = .0003) for the first time in a Caucasian population. Several SNPs indicated suggestive association for traits related to ages at smoking initiation. Also, rs11636753 in CHRNB4 showed suggestive association with regular drinking (p = .0029) and the comorbidity of depression and ND (p = .0034). CONCLUSIONS: We demonstrate novel associations of DSM-IV ND symptoms and the NDSS tolerance subscale. Our results confirm and extend association findings for other ND measures. We show pleiotropic effects of this gene cluster on multiple measures of ND and also regular drinking and the comorbidity of ND and depression.

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 1,000 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.

Drinking motives in female smokers: factor structure, alcohol dependence, and genetic influences.

BACKGROUND: Alcohol and tobacco use often co-occur. Human and animal studies indicate that nicotine increases alcohol's rewarding effects and the motivation to consume it. The aims of this study were to examine whether the factorial architecture of self-reported motivations to consume alcohol differed between regular and nonregular cigarette smokers while taking into account the lifetime history of alcohol dependence and psychopathology, and to estimate the genetic and environmental influences on the motivations. METHODS: Using data on 2,189 monozygotic and dizygotic female twins, we examined the factorial structure (item thresholds and factor loadings, means, and variances) of the items from the Drinking Motives Questionnaire (DMQ) in regular and nonregular smokers. Post hoc tests examined the association between the latent drinking motives factors and alcohol dependence in both groups. Twin models were fitted to the latent drinking motives factors, testing for variations in the magnitude of additive genetic, shared, and nonshared environmental influences between the groups. RESULTS: The 4 DMQ factors (social, conformity, coping, and enhancement) were recovered in both groups, and their measurement structure was consistent across the groups. Regular smokers reported higher levels of coping, enhancement, and social motives while nonregular smokers reported higher conformity motives. Alcohol dependence was associated with higher scores on all motives in both groups; however, in a regression analysis that included all of the motives as predictor variables, only coping was significantly related to alcohol dependence. While twin models revealed evidence for substantially greater genetic influences on enhancement (h² = 0.40), coping (h² = 0.35) and social (h² = 0.37) drinking motives in regular compared to nonregular smokers, the power to statistically distinguish the 2 groups was low. CONCLUSIONS: While the measurement structure of the drinking motive factors appears to be similar across regular and nonregular smokers, regular smokers report more motivation to drink for internal affect-related reasons and to obtain social reward. Of all the motives, coping was the most robust predictor of alcohol dependence in both the regular and the nonregular smokers. Further, genetic influences might play a larger role in drinking motives among regular smokers, which provides tentative evidence for latent genetic × smoking status interactions.

A latent class analysis of DSM-IV and Fagerström (FTND) criteria for nicotine dependence.

BACKGROUND: Nicotine dependence is associated with considerable morbidity and mortality. Two predominant classification systems, the Diagnostic and Statistical Manual (DSM-IV) and Fagerström Test for Nicotine Dependence (FTND), have been used to measure liability to nicotine dependence, yet few studies have attempted to simultaneously examine both sets of criteria. METHODS: Using a sample of 624 regular smoking individuals who are offspring of Vietnam Era Twin fathers ascertained for an offspring of twin study, we applied latent class analysis to the 7 DSM-IV and the 6 FTND criteria to classify individuals by their nicotine dependence symptom profiles. Post-hoc across-class comparisons were conducted using a variety of smoking-related variables and aspects of psychopathology. Whether a single class identified offspring at high genetic and environmental vulnerability was also investigated. RESULTS: The cross-diagnosis kappa was .30. A 4-class solution fit these data best. The classes included a low DSM-low FTND class and a high DSM-high FTND class; a moderate DSM-moderate FTND class, which was distinguished by moderate levels of smoking and intermediate levels of comorbid psychopathology; and a light smoking-moderate FTND class consisting primarily of lighter smokers with a more recent onset of regular smoking. High genetic and environmental vulnerability to nicotine dependence was noted in all classes with no statistically significant across-class differences. CONCLUSIONS: In general, the DSM-IV and FTND criteria performed similarly to define a continuum of risk for nicotine dependence. The emerging class of light smokers should be further investigated to assess whether they transition to another class or remain as such.

Linkage analysis of alcohol dependence symptoms in the community.

BACKGROUND: We have previously identified suggestive linkage for alcohol consumption in a community-based sample of Australian adults. In this companion paper, we explore the strength of genetic linkage signals for alcohol dependence symptoms. METHODS: An alcohol dependence symptom score, based on DSM-IIIR and DSM-IV criteria, was examined. Twins and their nontwin siblings (1,654 males, 2,518 females), aged 21 to 81 years, were interviewed, with 803 individuals interviewed on 2 occasions, approximately 10 years apart. Linkage analyses were conducted on datasets compiled to maximize data collected at either the younger or the older age. In addition, linkage was compared between full samples and truncated samples that excluded the lightest drinkers (approximately 10% of the sample). RESULTS: Suggestive peaks on chromosome 5p (LODs >2.2) were found in a region previously identified in alcohol linkage studies using clinical populations. Linkage signal strength was found to vary between full and truncated samples and when samples differed only on the collection age for a sample subset. CONCLUSIONS: The results support the finding that large community samples can be informative in the study of alcohol-related traits.

The effects of maternal smoking during pregnancy on offspring outcomes.

OBJECTIVE: To evaluate the possible association between maternal smoking during pregnancy and offspring outcomes of birth weight, pre-term birth, remediation, low scholastic achievement, regular smoking, attention deficit hyperactivity disorder and conduct problems while controlling for similar behaviors in parents. METHODS: Using telephone interviews, data were collected, in 2001 and 2004, as a part of two United States offspring-of-twins projects. Fathers, who were twins participating in the Vietnam Era Twin Registry, their female spouse and their offspring were interviewed - information on 1,342 unique pregnancies in mothers with a history of regular smoking was utilized for these analyses. The association between maternal smoking during pregnancy and birth weight, pre-term birth, remediation, low scholastic achievement, regular smoking, attention deficit hyperactivity disorder and conduct disorder while controlling for similar behaviors in parents, was examined using regression. RESULTS: Maternal smoking during pregnancy was associated with decreased birth weight, low scholastic achievement, regular smoking and attention deficit hyperactivity disorder. However, the association between maternal smoking during pregnancy and offspring attention deficit hyperactivity disorder was explained by maternal attention deficit hyperactivity disorder. Maternal smoking during pregnancy was also associated with earlier age of offspring initiation of smoking and onset of regular smoking. CONCLUSIONS: Maternal smoking during pregnancy may influence certain offspring outcomes via mechanisms that are independent from genetic risk attributable to comorbid conditions. Assisting expecting mothers with their smoking cessation efforts will likely provide widespread health benefits to both mother and offspring.

H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse-associated risk for alcohol consumption and dependence.

Animal research supports a central role for corticotropin-releasing factor (CRF) in actions of ethanol on brain function. An examination of alcohol consumption in adolescents reported a significant genotype x environment (G x E) interaction involving rs1876831, a corticotropin-releasing hormone receptor 1 (CRHR1) polymorphism, and negative events. CRHR1 and at least four other genes are located at 17q21.31 in an extremely large block of high linkage disequilibrium resulting from a local chromosomal inversion; the minor allele of rs1876831 is contained within the H2 haplotype. Here, we examine whether G x E interactions involving this haplotype and childhood sexual abuse (CSA) are associated with risk for alcohol consumption and dependence in Australian participants (n = 1128 respondents from 476 families) of the Nicotine Addiction Genetics project. Telephone interviews provided data on DSM-IV alcohol dependence diagnosis and CSA and enabled calculation of lifetime alcohol consumption factor score (ACFS) from four indices of alcohol consumption. Individuals reporting a history of CSA had significantly higher ACFS and increased risk for alcohol dependence. A significant G x E interaction was found for ACFS involving the H2 haplotype and CSA (P < 0.017). A similar G x E interaction was associated with protective effects against alcohol dependence risk (odds ratio 0.42; 95% confidence interval 0.20-0.89). For each outcome, no significant CSA-associated risk was observed in H2 haplotype carriers. These findings support conducting further investigation of the H2 haplotype to determine the gene(s) responsible. Our results also suggest that severe early trauma may prove to be an important clinical covariate in the treatment of alcohol dependence.

Nicotine withdrawal symptoms in adolescent and adult twins.

We examined the variation and heritability of DSM-IV nicotine withdrawal (NW) in adult and adolescent male and female twin cigarette smokers (who reported smoking 100 or more cigarettes lifetime). Telephone diagnostic interviews were completed with 3,112 Australian adult male and female smokers (53% women; age: 24-36) and 702 Missouri adolescent male and female smokers (59% girls; age: 15-21). No gender or cohort differences emerged in rates of meeting criteria for NW (44%). Latent class analyses found that NW symptoms were best conceptualized as a severity continuum (three levels in adults and two levels in adolescents). Across all groups, increasing NW severity was associated with difficulty quitting, impairment following cessation, heavy smoking, depression, anxiety, conduct disorder and problems with alcohol use. NW was also associated with seeking smoking cessation treatment and with smoking persistence in adults. The latent class structure of NW was equally heritable across adult and adolescent smokers with additive genetic influences accounting for 49% of the variance and the remaining 51% of variance accounted for by unique environmental influences. Overall, findings suggest remarkable similarity in the pattern and heritability of NW across adult and adolescent smokers, and highlight the important role of NW in psychiatric comorbidity and the process of smoking cessation across both age groups.

A genomewide association study of nicotine and alcohol dependence in Australian and Dutch populations.

Persistent tobacco use and excessive alcohol consumption are major public health concerns worldwide. Both alcohol and nicotine dependence (AD, ND) are genetically influenced complex disorders that exhibit a high degree of comorbidity. To identify gene variants contributing to one or both of these addictions, we first conducted a pooling-based genomewide association study (GWAS) in an Australian population, using Illumina Infinium 1M arrays. Allele frequency differences were compared between pooled DNA from case and control groups for: (1) AD, 1224 cases and 1162 controls; (2) ND, 1273 cases and 1113 controls; and (3) comorbid AD and ND, 599 cases and 488 controls. Secondly, we carried out a GWAS in independent samples from the Netherlands for AD and for ND. Thirdly, we performed a meta-analysis of the 10,000 most significant AD- and ND-related SNPs from the Australian and Dutch samples. In the Australian GWAS, one SNP achieved genomewide significance (p < 5 x 10(-8)) for ND (rs964170 in ARHGAP10 on chromosome 4, p = 4.43 x 10(-8)) and three others for comorbid AD/ND (rs7530302 near MARK1 on chromosome 1 (p = 1.90 x 10(-9)), rs1784300 near DDX6 on chromosome 11 (p = 2.60 x 10(-9)) and rs12882384 in KIAA1409 on chromosome 14 (p = 4.86 x 10(-8))). None of the SNPs achieved genomewide significance in the Australian/Dutch meta-analysis, but a gene network diagram based on the top-results revealed overrepresentation of genes coding for ion-channels and cell adhesion molecules. Further studies will be required before the detailed causes of comorbidity between AD and ND are understood.

Depression and Nicotine Withdrawal Associations with Combustible and Electronic Cigarette Use.

Depression is a risk factor for nicotine use and withdrawal. Population level epidemiologic studies that include users of either combustible or electronic cigarette (NICUSER) could inform interventions to reduce nicotine dependence in vulnerable populations. The current study examined the relationship between depression diagnosis (DEPDX), NICUSER, and lifetime rates of DSM-V nicotine withdrawal (NW) symptoms in a nationally representative sample of US adults (N = 979), who answered related questions in surveys administered through GfK's KnowledgePanel. Over 42% of the sample reported lifetime ever combustible cigarette use, 15.6% electronic-cigarette use, and 45.9% either (NICUSER). Weighted logistic regression analyses (controlling for age and gender) found that DEPDX was associated with 2.3 times increased odds (ratio (OR); 95% Confidence Interval (CI): 1.5-3.5) of being a NICUSER. Regarding risks of NW symptoms among NICUSER, models that additionally controlled for frequency of nicotine use found that DEPDX was significantly associated with increased odds of concentration problems (OR = 2.4; 95% CI: 1.3-4.5) and depressed mood (OR = 2.2; 95% CI: 1.1-4.1) when quitting or cutting down on nicotine use. Results highlight the consistent comorbidity between depression, nicotine use, and symptomatic nicotine withdrawal in a population-based sample of combustible and electronic cigarette users.

Evidence for an interaction between age at first drink and genetic influences on DSM-IV alcohol dependence symptoms.

BACKGROUND: Research suggests that individuals who start drinking at an early age are more likely to subsequently develop alcohol dependence. Twin studies have demonstrated that the liability to age at first drink and to alcohol dependence are influenced by common genetic and environmental factors, however, age at first drink may also environmentally mediate increased risk for alcohol dependence. In this study, we examine whether age at first drink moderates genetic and environmental influences, via gene x environment interactions, on DSM-IV alcohol dependence symptoms. METHODS: Using data on 6,257 adult monozygotic and dizygotic male and female twins from Australia, we examined the extent to which age at first drink (i) increased mean alcohol dependence symptoms and (ii) whether the magnitude of additive genetic, shared, and nonshared environmental influences on alcohol dependence symptoms varied as a function of decreasing age. Twin models were fitted in Mx. RESULTS: Risk for alcohol dependence symptoms increased with decreasing age at first drink. Heritable influences on alcohol dependence symptoms were considerably larger in those who reported an age at first drink prior to 13 years of age. In those with later onset of alcohol use, variance in alcohol dependence was largely attributable to nonshared environmental variance (and measurement error). This evidence for unmeasured gene x measured environment interaction persisted even when controlling for the genetic influences that overlapped between age at first drink and alcohol dependence symptoms. CONCLUSIONS: Early age at first drink may facilitate the expression of genes associated with vulnerability to alcohol dependence symptoms. This is important to consider, not only from a public health standpoint, but also in future genomic studies of alcohol dependence.

Can we identify genes for alcohol consumption in samples ascertained for heterogeneous purposes?

BACKGROUND: Previous studies have identified evidence of genetic influence on alcohol use in samples selected to be informative for alcoholism research. However, there are a growing number of genome-wide association studies (GWAS) using samples unselected for alcohol consumption (i.e., selected on other traits and forms of psychopathology), which nevertheless assess consumption as a risk factor. Is it reasonable to expect that genes contributing to variation in alcohol consumption can be identified in such samples? METHODS: An exploratory approach was taken to determine whether linkage analyses for heaviness of alcohol consumption, using a sample collected for heterogeneous purposes, could replicate previous findings. Quantity and frequency measures of consumption were collected in telephone interviews from community samples. These measures, and genotyping, were available for 5,441 individuals (5,067 quasi-independent sibling pairs). For 1,533 of these individuals, data were collected on 2 occasions, about 8.2 years apart, providing 2 datasets that maximize data collected at either a younger or an older age. Analyses were conducted to address the question of whether age and heavier levels of alcohol consumption effects outcome. Linkage results were compared in the younger and older full samples, and with samples in which approximately 10, 20, and 40 of drinkers from the lower end of the distribution of alcohol consumption were dropped. RESULTS: Linkage peaks varied for the age differentiated samples and for percentage of light drinkers retained. Larger peaks (LOD scores >2.0) were typically found in regions previously identified in linkage studies and/or containing proposed candidate genes for alcoholism including AGT, CARTPT, OPRD1, PIK3R1, and PDYN. CONCLUSIONS: The results suggest that GWAS assessing alcohol consumption as a covariate for other conditions will have some success in identifying genes contributing to consumption-related variation. However, sample characteristics, such as participant age, and trait distribution, may have substantial effects on the strength of the genetic signal. These results can inform forthcoming GWAS where the same restrictions apply.