Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results.

CYP2A6 metabolism in the development of smoking behaviors in young adults.

Cytochrome P450 2A6 (CYP2A6) encodes the enzyme responsible for the majority of nicotine metabolism. Previous studies support that slow metabolizers smoke fewer cigarettes once nicotine dependent but provide conflicting results on the role of CYP2A6 in the development of dependence. By focusing on the critical period of young adulthood, this study examines the relationship of CYP2A6 variation and smoking milestones.

Monthly Estimates of Alcohol Drinking During Pregnancy: United States, 2002-2011.

Objective: Taking a step beyond prior alcohol research on pregnancy trimesters, we produced pregnancy month-specific drinking estimates for women in the United States in order to shed light on time variations of alcohol drinking during pregnancy, as might be determined by alcohol dependence. We posited that (a) pregnancy might prompt cessation of drinking soon after pregnancy status is discovered, a finding obscured in trimester-specific estimates, and (b) a possible alcohol-dependence effect on drinking persistence among pregnant women might be observed via the monthly approach.

Method: Data are from the 2002-2011 National Surveys on Drug Use and Health (Restricted-Data Analysis System [R-DAS]), with large nationally representative samples of U.

Birth weight and asthma incidence by asthma phenotype pattern in a racially diverse cohort followed through adolescence.

Objective: Low birth weight (LBW) has been shown to be an independent risk factor for asthma. We hypothesized that LBW would have its greatest impact on early onset disease.

Methods: A racially diverse cohort of children born from 1983 to 1985 at two hospitals, one urban and one suburban in the same metropolitan area, and oversampled for babies weighing ≤2500 g, was identified retrospectively when the children were 6 years of age and followed periodically.

Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.

Latent classes of childhood trauma exposure predict the development of behavioral health outcomes in adolescence and young adulthood.

Background: To develop latent classes of exposure to traumatic experiences before the age of 13 years in an urban community sample and to use these latent classes to predict the development of negative behavioral outcomes in adolescence and young adulthood.

Method: A total of 1815 participants in an epidemiologically based, randomized field trial as children completed comprehensive psychiatric assessments as young adults. Reported experiences of nine traumatic experiences before age 13 years were used in a latent class analysis to create latent profiles of traumatic experiences.

Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation.

Objective: Recent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes.

Method: In two randomized smoking cessation trials comparing cNRT vs.

CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis.

Background: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis.

Methods: Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072).

Smoking cessation is associated with lower rates of mood/anxiety and alcohol use disorders.

Background: The psychological outcomes that accompany smoking cessation are not yet conclusive but positive outcomes could help to persuade quitting.

Method: We used data from the longitudinal National Epidemiological Study of Alcohol and Related Conditions. Logistic regression was used to examine associations between cigarette smoking reduction and Wave 2 status of addiction/mental health disorder among daily smokers at Wave 1, stratified by status of the diagnosis of interest at Wave 1.

A non-parametric approach for detecting gene-gene interactions associated with age-at-onset outcomes.

Background: Cox-regression-based methods have been commonly used for the analyses of survival outcomes, such as age-at-disease-onset. These methods generally assume the hazard functions are proportional among various risk groups. However, such an assumption may not be valid in genetic association studies, especially when complex interactions are involved.

Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans.

Aims: Studies have shown association between common variants in the α6-β3 nicotinic receptor subunit gene cluster and nicotine dependence in European ancestry populations. We investigate whether this generalizes to African Americans, whether the association is specific to nicotine dependence and whether this region contains additional genetic contributors to nicotine dependence.

Design: We examined consistency of association across studies and race between the α6β3 nicotinic receptor subunit locus and nicotine, alcohol, marijuana and cocaine dependence in three independent studies.

Protocol for a collaborative meta-analysis of 5-HTTLPR, stress, and depression.

Background: Debate is ongoing about what role, if any, variation in the serotonin transporter linked polymorphic region (5-HTTLPR) plays in depression. Some studies report an interaction between 5-HTTLPR variation and stressful life events affecting the risk for depression, others report a main effect of 5-HTTLPR variation on depression, while others find no evidence for either a main or interaction effect. Meta-analyses of multiple studies have also reached differing conclusions.

Childhood maltreatment, juvenile disorders and adult post-traumatic stress disorder: a prospective investigation.

Background: We examine prospectively the influence of two separate but potentially inter-related factors in the etiology of post-traumatic stress disorder (PTSD): childhood maltreatment as conferring a susceptibility to the PTSD response to adult trauma and juvenile disorders as precursors of adult PTSD.

Method: The Dunedin Multidisciplinary Health and Development Study (DMHDS) is a birth cohort (n = 1037) from the general population of New Zealand's South Island, with multiple assessments up to age 38 years. DSM-IV PTSD was assessed among participants exposed to trauma at ages 26-38.

Variants in two adjacent genes, EGLN2 and CYP2A6, influence smoking behavior related to disease risk via different mechanisms.

Genome-wide significant associations with cigarettes per day (CPD) and risk for lung cancer and chronic obstructive pulmonary disease (COPD) were previously reported in a region of 19q13, including CYP2A6 (nicotine metabolism enzyme) and EGLN2 (hypoxia response). The associated single nucleotide polymorphisms (SNPs) were assumed to be proxies for functional variation in CYP2A6. Here, we demonstrate that when CYP2A6 and EGLN2 genotypes are analyzed together, the key EGLN2 variant, rs3733829, is not associated with nicotine metabolism independent of CYP2A6, but is nevertheless independently associated with CPD, and with breath carbon monoxide (CO), a phenotype associated with cigarette consumption and relevant to hypoxia.

Assessing interchangeability at cluster levels with multiple-informant data.

Studies examining the relationship between neighborhood social disorder and health often rely on multiple informants. Such studies assume interchangeability of the latent constructs derived from multiple-informant data. Existing methods examining this assumption do not clearly delineate the uncertainty at individual levels from that at neighborhood levels.

The role of intelligence in posttraumatic stress disorder: does it vary by trauma severity?

Background: Only a small minority of trauma victims develops post-traumatic stress disorder (PTSD), suggesting that victims vary in their predispositions to the PTSD response to stressors. It is assumed that the role of predispositions in PTSD varies by trauma severity: when stressors are less severe, predispositions play a bigger role. In this study, we test whether the role of intelligence in PTSD varies by trauma severity.

Neuroticism and post-traumatic stress disorder: a prospective investigation.

Background: Neuroticism has been consistently correlated with the post-traumatic stress disorder (PTSD) response to traumatic events. Interpretation of these findings is limited by the retrospective nature of these findings: neuroticism was measured after the trauma had occurred. The prospective association of neuroticism with PTSD has not been examined (the relationship of neuroticism with PTSD symptoms was examined in a few prospective studies).

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.

Influence of predispositions on post-traumatic stress disorder: does it vary by trauma severity?

Background: Only a minority of trauma victims (<10%) develops post-traumatic stress disorder (PTSD), suggesting that victims vary in predispositions to the PTSD response to traumas. It is assumed that the influence of predispositions is inversely related to trauma severity: when trauma is extreme predispositions are assumed to play a secondary role. This assumption has not been tested.

Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation treatments in smoking cessation success.

Objective: Smoking is highly intractable, and the genetic influences on cessation are unclear. Identifying the genetic factors affecting smoking cessation could elucidate the nature of tobacco dependence, enhance risk assessment, and support development of treatment algorithms. This study tested whether variants in the nicotinic receptor gene cluster CHRNA5-CHRNA3-CHRNB4 predict age at smoking cessation and relapse after an attempt to quit smoking.

CHRNB3 is more strongly associated with Fagerström test for cigarette dependence-based nicotine dependence than cigarettes per day: phenotype definition changes genome-wide association studies results.

Aims: Nicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta-analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.

Nicotine dependence and comorbid psychiatric disorders: examination of specific genetic variants in the CHRNA5-A3-B4 nicotinic receptor genes.

Background: The associations between nicotine dependence and specific variants in the nicotinic receptor CHRNA5-A3-B4 subunit genes are irrefutable with replications in many studies. The relationship between the newly identified genetic risk variants for nicotine dependence and comorbid psychiatric disorders is unclear. We examined whether these genetic variants were associated with comorbid disorders and whether comorbid psychiatric disorders modified the genetic risk of nicotine dependence.