J Sun

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.

Subtypes of major depression: latent class analysis in depressed Han Chinese women.

BACKGROUND Despite substantial research, uncertainty remains about the clinical and etiological heterogeneity of major depression (MD). Can meaningful and valid subtypes be identified and would they be stable cross-culturally? METHOD Symptoms at their lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ⩾ 30 years, with recurrent DSM-IV MD. Latent class analysis (LCA) was performed in Mplus. RESULTS; Using the nine DSM-IV MD symptomatic A criteria, the 14 disaggregated DSM-IV criteria and all independently assessed depressive symptoms (n = 27), the best LCA model identified respectively three, four and six classes. A severe and non-suicidal class was seen in all solutions, as was a mild/moderate subtype. An atypical class emerged once bidirectional neurovegetative symptoms were included. The non-suicidal class demonstrated low levels of worthlessness/guilt and hopelessness. Patterns of co-morbidity, family history, personality, environmental precipitants, recurrence and body mass index (BMI) differed meaningfully across subtypes, with the atypical class standing out as particularly distinct. CONCLUSIONS MD is a clinically complex syndrome with several detectable subtypes with distinct clinical and demographic correlates. Three subtypes were most consistently identified in our analyses: severe, atypical and non-suicidal. Severe and atypical MD have been identified in multiple prior studies in samples of European ethnicity. Our non-suicidal subtype, with low levels of guilt and hopelessness, may represent a pathoplastic variant reflecting Chinese cultural influences.

Childhood sexual abuse and the development of recurrent major depression in Chinese women.

Background Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set? Method Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression. Results We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19–5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58–3.15), genital (OR 5.24, 95% CI 3.52–8.15) and intercourse (OR 10.65, 95% CI 5.56–23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11–2.27) and phobia (OR 1.41, 95%CI 1.09–1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20–1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02–2.02). Intercourse (OR 3.47, 95%CI 1.66–8.22), use of force and threats (OR 1.95, 95%CI 1.05–3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20–1.64) were significantly associated with recurrent MD. Conclusions In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD.

The structure of the symptoms of major depression: exploratory and confirmatory factor analysis in depressed Han Chinese women

Background The symptoms of major depression (MD) are clinically diverse. Do they form coherent factors that might clarify the underlying nature of this important psychiatric syndrome? Method Symptoms at lifetime worst depressive episode were assessed at structured psychiatric interview in 6008 women of Han Chinese descent, age ⩾30 years with recurrent DSM-IV MD. Exploratory factor analysis (EFA) and confirmatoryfactor analysis (CFA) were performed in Mplus in random split-half samples. Results The preliminary EFA results were consistently supported by the findings from CFA. Analyses of the nine DSM-IV MD symptomatic A criteria revealed two factors loading on: (i) general depressive symptoms; and (ii) guilt/suicidal ideation. Examining 14 disaggregated DSM-IV criteria revealed three factors reflecting: (i) weight/appetite disturbance; (ii) general depressive symptoms; and (iii) sleep disturbance. Using all symptoms (n = 27), we identified five factors that reflected: (i) weight/appetite symptoms; (ii) general retarded depressive symptoms; (iii) atypical vegetative symptoms; (iv) suicidality/hopelessness; and (v) symptoms of agitation and anxiety. Conclusions MD is a clinically complex syndrome with several underlying correlated symptom dimensions. In addition to a general depressive symptom factor, a complete picture must include factors reflecting typical/atypical vegetative symptoms, cognitive symptoms (hopelessness/suicidal ideation), and an agitated symptom factor characterized by anxiety, guilt, helplessness and irritability. Prior cross-cultural studies, factor analyses of MD in Western populations and empirical findings in this sample showing risk factor profiles similar to those seen in Western populations suggest that our results are likely to be broadly representative of the human depressive syndrome.

Suicidal Risk Factors of Recurrent Major Depression in Han Chinese Women

The relationship between suicidality and major depression is complex. Socio- demography, clinical features, comorbidity, clinical symptoms, and stressful life events are important factors influencing suicide in major depression, but these are not well defined. Thus, the aim of the present study was to assess the associations between the above-mentioned factors and suicide ideation, suicide plan, and suicide attempt in 6008 Han Chinese women with recurrent major depression (MD). Patients with any suicidality had significantly more MD symptoms, a significantly greater number of stressful life events, a positive family history of MD, a greater number of episodes, a significant experience of melancholia, and earlier age of onset. Comorbidity with dysthymia, generalized anxiety disorder (GAD), social phobia, and animal phobia was seen in suicidal patients. The present findings indicate that specific factors act to increase the likelihood of suicide in MD. Our results may help improve the clinical assessment of suicide risk in depressed patients, especially for women.

Associations of educational attainment, occupation, social class and major depressive disorder among Han Chinese women.

Background The prevalence of major depressive disorder (MDD) is higher in those with low levels of educational attainment, the unemployed and those with low social status. However the extent to which these factors cause MDD is unclear. Most of the available data comes from studies in developed countries, and these findings may not extrapolate to developing countries. Examining the relationship between MDD and socio economic status in China is likely to add to the debate because of the radical economic and social changes occurring in China over the last 30 years. Principal findings We report results from 3,639 Chinese women with recurrent MDD and 3,800 controls. Highly significant odds ratios (ORs) were observed between MDD and full time employment (OR = 0.36, 95% CI = 0.25–0.46, logP = 78), social status (OR = 0.83, 95% CI = 0.77–0.87, logP = 13.3) and education attainment (OR = 0.90, 95% CI = 0.86–0.90, logP = 6.8). We found a monotonic relationship between increasing age and increasing levels of educational attainment. Those with only primary school education have significantly more episodes of MDD (mean 6.5, P-value = 0.009) and have a clinically more severe disorder, while those with higher educational attainment are likely to manifest more comorbid anxiety disorders. Conclusions In China lower socioeconomic position is associated with increased rates of MDD, as it is elsewhere in the world. Significantly more episodes of MDD occur among those with lower educational attainment (rather than longer episodes of disease), consistent with the hypothesis that the lower socioeconomic position increases the likelihood of developing MDD. The phenomenology of MDD varies according to the degree of educational attainment: higher educational attainment not only appears to protect against MDD but alters its presentation, to a more anxious phenotype.

Smoking and major depressive disorder in Chinese women.

Objective To investigate the risk factors that contribute to smoking in female patients with major depressive disorder (MDD) and the clinical features in depressed smokers. Methods We examined the smoking status and clinical features in 6120 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and smoking status and between risk factors for MDD and smoking status. Results Among the recurrent MDD patients there were 216(3.6%) current smokers, 117 (2.0%) former smokers and 333(5.6%) lifetime smokers. Lifetime smokers had a slightly more severe illness, characterized by more episodes, longer duration, more comorbid illness (panic and phobias), with more DSM-IV A criteria and reported more symptoms of fatigue and suicidal ideation or attempts than never smokers. Some known risk factors for MDD were also differentially represented among smokers compared to non-smokers. Smokers reported more stressful life events, were more likely to report childhood sexual abuse, had higher levels of neuroticism and an increased rate of familial MDD. Only neuroticism was significantly related to nicotine dependence. Conclusions Although depressed women smokers experience more severe illness, smoking rates remain low in MDD patients. Family history of MDD and environmental factors contribute to lifetime smoking in Chinese women, consistent with the hypothesis that the association of smoking and depression may be caused by common underlying factors.

Clinical Features of Patients with Dysthymia in a Large Cohort of Han Chinese Women with Recurrent Major Depression

Background Dysthymia is a form of chronic mild depression that has a complex relationship with major depressive disorder (MDD). Here we investigate the role of environmental risk factors, including stressful life events and parenting style, in patients with both MDD and dysthymia. We ask whether these risk factors act in the same way in MDD with and without dysthymia. Results We examined the clinical features in 5,950 Han Chinese women with MDD between 30–60 years of age across China. We confirmed earlier results by replicating prior analyses in 3,950 new MDD cases. There were no significant differences between the two data sets. We identified sixteen stressful life events that significantly increase the risk of dysthymia, given the presence of MDD. Low parental warmth, from either mother or father, increases the risk of dysthymia. Highly threatening but short-lived threats (such as rape) are more specific for MDD than dysthymia. While for MDD more severe life events show the largest odds ratio versus controls, this was not seen for cases of MDD with or without dysthymia. Conclusions There are increased rates of stressful life events in MDD with dysthymia, but the impact of life events on susceptibility to dysthymia with MDD differs from that seen for MDD alone. The pattern does not fit a simple dose-response relationship, suggesting that there are moderating factors involved in the relationship between environmental precipitants and the onset of dysthymia. It is possible that severe life events in childhood events index a general susceptibility to chronic depression, rather than acting specifically as risk factors for dysthymia.