Gene-Environment Interactions Between Depressive Symptoms and Smoking Quantity.

We investigated genetic and environmental correlations and gene by environment interactions (GxE) between depressive symptoms measured by the Beck Depression Inventory (BDI) and quantity smoked measured by number of cigarettes smoked per day (CPD) using quantitative genetic modeling. The population-based sample consisted of 12,063 twin individuals from the Finnish Twin Cohort Study. Bivariate Cholesky decomposition revealed that the phenotypic correlation (r = 0.09) between BDI and CPD was explained by shared genetic (r g = 0.18) and environmental (r e = 0.08) factors. GxE models incorporating moderator effects were built by using CPD as trait and BDI as moderator and vice versa. The importance of the genetic variance component increased with increasing moderator value in both models. Thus, the influence of genetic effects on variance of smoking quantity was enhanced in individuals with elevated depression score and vice versa; the genetic effects on depression variance were potentiated among heavy smokers. In conclusion, shared genetic and environmental factors as well as GxE underlie the association of smoking with depression.

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.

Pleasantness of the odor of androstenone as a function of sexual intercourse experience in women and men.

Androstenone (5α-androst-16-en-3-one) and other androstenes, body odor components occurring in apocrine secretions, may play a role in human chemosignaling. We hypothesized that the odor of androstenone may gain hedonic value from sexual intercourse experiences via associative learning. Young adults (N = 397, 61.5% women, age 21-24 years, randomly sampled regarding sexual experience) rated the intensity and pleasantness of the odors of androstenone, cinnamon, chocolate, isovaleric acid, lemon, and turpentine. Among women who were able to perceive androstenone, the odor was rated as more pleasant (less unpleasant) by those who had had experienced sexual intercourse with at least one partner (n = 175) than by those who reported never having experienced intercourse (n = 12, p = .006). The difference was specific to women. The results suggest that, among women, sexual experience may modify the pleasantness of the odor of androstenone.

Genetic contribution to sour taste preference.

Genetic contribution to individual differences in sour taste perception and preference was investigated in a cohort of young adult Finnish twins (n=328, 21-25 years) including 46 complete monozygotic and 92 dizygotic twin pairs and 52 twin individuals without their co-twin. Responses to sour taste were recorded as pleasantness and intensity ratings of orange juice with added citric acid (4.2g/L) relative to untainted orange juice (sensory traits). Pleasantness and use-frequency of 21 food items varying in sourness were rated in a questionnaire. Three food categories emerged in factor analysis: sour berries and fruits, less-sour berries and fruits, and sour dairy products (questionnaire traits). The contribution of genetic and environmental factors to variation and co-variation of the traits were analyzed using quantitative genetic modeling. Genetic factors played a larger role than shared environment, explaining 14% and 31% of the variation in pleasantness and intensity of sour taste, respectively, and 34-50% of the variation in pleasantness and use-frequency of sour foods. Relatively large genetic correlations existed between sensory traits and between questionnaire traits. These results demonstrate a genetic contribution to preference for sour foods.

Nicotine, alcohol, and drug findings in young adults in a population-based postmortem database.

INTRODUCTION: To obtain reliable information on nicotine and drug use through a population-based study, the prevalence of nicotine use in deceased young adults was studied in the Finnish postmortem toxicology database for a 3-year period. The nicotine user and non-nicotine user groups were compared by alcohol, drug, and drug-of-abuse findings and by the manner of death. METHODS: Nicotine users were identified based on detection of nicotine, cotinine, and/or trans-3'-hydroxycotinine in urine from a population-based sample of deceased young adults aged 15-34 years at the time of death (n = 1,623, ∼60% of all fatalities). Background information from case referrals was used to distinguish the abuse of medicines from their therapeutic use. The manner of death was taken from death certificates. RESULTS: Nicotine use was more common in young adults (75%) than among all cases in the database (55%). There were twice as many ethanol-positive cases in nicotine users (60%) than in non-nicotine users (30%). Nicotine use was common (70%-79%) among individuals on antipsychotics, antidepressants, anxiolytics, and/or hypnotics and sedatives. The proportion of nicotine users was also high among the drugs-of-abuse positive cases (85%). There were fewer deaths that were classified as natural in the nicotine users group. CONCLUSIONS: Among deceased young adults, nicotine use was two to three times as common as has been estimated for the corresponding living population (20%-30%). Nicotine use was also strongly associated with substance abuse and mental illnesses requiring pharmacotherapy. This group of young adults usually cannot be reached by traditional health surveys.

Associations of nicotine intake measures with CHRN genes in Finnish smokers.

INTRODUCTION: Genetic effects contribute to individual differences in smoking behavior. Persistence to smoke despite known harmful health effects is mostly driven by nicotine addiction. As the physiological effects of nicotine are mediated by nicotinic acetylcholine receptors (nAChRs), we aimed at examining whether single nucleotide polymorphisms (SNPs) residing in nAChR subunit (CHRN) genes, other than CHRNA3/CHRNA5/CHRNB4 gene cluster previously showing association in our sample, are associated with smoking quantity or serum cotinine levels. METHODS: The study sample consisted of 485 Finnish adult daily smokers (age 30-75 years, 59% men) assessed for the number of cigarettes smoked per day (CPD) and serum cotinine level. We first studied SNPs residing on selected nAChR subunit genes (CHRNA2, CHRNA4, CHRNA6/CHRNB3, CHRNA7, CHRNA9, CHRNA10, CHRNB2, CHRNG/CHRND) genotyped within a genome-wide association study for single SNP and multiple SNP associations by ordinal regression. Next, we explored individual haplotype associations using sliding window technique. RESULTS: At one of the 8 loci studied, CHRNG/CHRND (chr2), single SNP (rs1190452), multiple SNP, and 2-SNP haplotype analyses (SNPs rs4973539-rs1190452) all showed statistically significant association with cotinine level. The median cotinine levels varied between the 2-SNP haplotypes from 220 ng/ml (AA haplotype) to 249 ng/ml (AG haplotype). We did not observe significant associations with CPD. CONCLUSIONS: These results provide further evidence that the γ-δ nAChR subunit gene region is associated with cotinine levels but not with the number of CPD, illustrating the usefulness of biomarkers in genetic analyses.

Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers.

CONTEXT: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES: Primary data. STUDY SELECTION: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01). CONCLUSION: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.

A 3p26-3p25 genetic linkage finding for DSM-IV major depression in heavy smoking families.

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 pairs 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.