A new Approach to Identify Gene-Environment Interactions and Reveal New Biological Insight in Complex traits.

There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. To address this issue, the CHARGE Gene-Lifestyle Interactions Working Group has been spearheading efforts to investigate G×E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identified and confirmed 5 loci (6 independent signals) interacting with either cigarette smoking or alcohol consumption for serum lipids, and empirically demonstrated that interaction and mediation are the major contributors to genetic effect size heterogeneity across populations. The estimated lower bound of the interaction and environmentally mediated contribution ranges from 1.76% to 14.05% of SNP heritability of serum lipids in Cross-Population data. Our study improves the understanding of the genetic architecture and environmental contributions to complex traits.

CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT. METHODS: We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test. RESULTS: The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 × 10(-9)). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 × 10(-5) (alpha threshold=3.1 × 10(-4)). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively. CONCLUSIONS: Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.

Th1 and Th2 cytokines and IgE levels in identical twins with varying levels of cigarette consumption.

Some have suggested that tobacco smoke may skew the immune system toward a Th2 pattern, however the effects of genetics or childhood exposures could explain these results. We compared PMBC supernatant or serum Th1 (INF-gamma) and Th2 (IL-4, IL-5, and IL-13) cytokine and IgE levels in members of 45 pairs of nonasthmatic monozygotic twins with varying levels of current cigarette consumption to determine if smoking was associated with Th1/Th2 function after accounting for genetic factors. A statistically significant dose-response was observed between levels of smoking and IL-13 (p=0.05). Mean IL-13 level among heavy smokers (20+ cigarettes/day) was 146% higher than that among nonsmokers (+26.2 pg/mL; p=0.04). The mean IL-5 level among heavy smokers was 166% higher than that among light (<20 cigarettes/day) smokers (+3.4 pg/mL; p=0.03). No statistically significant differences in INF-gamma, IL-4, or IgE levels were observed. Smoking appears to be associated with increased levels of IL-13.

Predictors of improved mood over time in clinical trials for major depression.

The objective of this exploratory analysis was to use a repeated measures modeling approach to identify potential predictors of improved mood over time in patients with major depression. Fifty-one subjects with major depressive disorder (MDD) were enrolled in a 1-week single blind placebo lead-in, followed by an 8-week, double-blind placebo-controlled treatment with either fluoxetine or venlafaxine. Hierarchical linear regression models were used to identify baseline and placebo lead-in predictors of change in repeated measures of the Hamilton Depression Rating Scale (HDRS) during treatment. Non-specific predictors of improved mood included decreased prefrontal activity during placebo lead-in as measured by quantitative electroencephalographic cordance, lower pretreatment depressed mood on the HDRS, shorter duration of current episode, increased verbalization of suicidal thoughts, no family history of mood disorders, less severe middle insomnia, higher guilt, lower somatic anxiety, and younger age. Moderators of improved mood included somatization, paranoid ideation, and self-reported depressed mood. We also found that change in prefrontal cordance after randomization mediated the effects of middle insomnia, suicidal thoughts, and family history of mood disorders. We recommend the use of repeated measures modeling, and the exploration of relationships among biological and psychological factors, for future analyses of clinical trial data.

Family history and the risk of early-onset persistent, early-onset transient, and late-onset asthma.

Family history of asthma and allergies strongly influences asthma risk in children, but the association may differ for early-onset persistent, early-onset transient, and late-onset asthma. We analyzed the relation between family history and these types of asthma using cross-sectional data from a school-based study of 5,046 Southern California children. Parental and/or sibling history of asthma and allergy were generally more strongly associated with early-onset persistent asthma compared with early-onset transient or late-onset asthma. For children with two asthmatic parents relative to those with none, the prevalence ratio for early-onset persistent asthma was 12.1 [95% confidence interval (CI) = 7.91-18.7] compared with 7.51 (95% CI = 2.62-21.5) for early-onset transient asthma and 5.38 (95% CI = 3.40-8.50) for late-onset asthma. Maternal smoking in pregnancy was predominantly related to the risk of early-onset persistent asthma in the presence of parental history of allergy and asthma, and the joint effects were more than additive (interaction contrast ratio = 3.10, 95% CI = 1.45-4.75). Our results confirm earlier data that parental history of asthma and allergy is most strongly associated with early-onset persistent asthma and suggest that among genetically predisposed children, an early-life environmental exposure, maternal smoking during pregnancy, favors the development of early-onset asthma that persists into later early childhood.