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1.  Finding Novel Genes by Testing G×E Interactions in a Genomewide Association Study 
Genetic epidemiology  2013;37(6):603-613.
In a genomewide association study (GWAS), investigators typically focus their primary analysis on the direct (marginal) associations of each SNP with the trait. Some SNPs that are truly associated with the trait may not be identified in this scan if they have a weak marginal effect and thus low power to be detected. However, these SNPs may be quite important in subgroups of the population defined by an environmental or personal factor, and may be detectable if such a factor is carefully considered in a gene-environment (G×E) interaction analysis. We address the question “Using a genome wide interaction scan (GWIS), can we find new genes that were not found in the primary GWAS scan?” We review commonly used approaches for conducting a GWIS in case-control studies, and propose a new 2-step screening and testing method (EDG×E) that is optimized to find genes with a weak marginal effect. We simulate several scenarios in which our 2-step method provides 70–80% power to detect a disease locus while a marginal scan provides less than 5% power. We also provide simulations demonstrating that the EDG×E method outperforms other GWIS approaches (including case only and previously proposed 2-step methods) for finding genes with a weak marginal effect. Application of this method to a G × Sex scan for childhood asthma reveals two potentially interesting SNPs that were not identified in the marginal-association scan. We distribute a new software program (G×Escan, available at http://biostats.usc.edu/software) that implements this new method as well as several other GWIS approaches.
doi:10.1002/gepi.21748
PMCID: PMC4348012  PMID: 23873611
genomewide scan; environmental factor; power
2.  Respiratory Symptoms Following Wildfire Smoke Exposure 
Epidemiology (Cambridge, Mass.)  2009;20(3):451-459.
Background
Associations between exposure to smoke during wild-fire events and respiratory symptoms are well documented, but the role of airway size remains unclear. We conducted this analysis to assess whether small airway size modifies these relationships.
Methods
We analyzed data from 465 nonasthmatic 16- to 19-year-old participants in the Children’s Health Study. Following an outbreak of wildfires in 2003, each student completed a questionnaire about smoke exposure, dry and wet cough, wheezing, and eye symptoms. We used log-binomial regression to evaluate associations between smoke exposure and fire-related health symptoms, and to assess modification of the associations by airway size. As a marker of airway size, we used the ratio of maximum midexpiratory flow to forced vital capacity.
Results
Forty percent (186 of 465) of this population (including students from 11 of 12 surveyed communities) reported the odor of wildfire smoke at home. We observed increased respiratory and eye symptoms with increasing frequency of wildfire smoke exposure. Associations between smoke exposure and having any of 4 respiratory symptoms were stronger in the lowest quartile of the lung function ratio (eg, fire smoke 6+ days: prevalence ratio: 3.8; 95% confidence interval (CI = 2.0 –7.2), compared with the remaining quartiles (fire smoke 6+ days: prevalence ratio = 2.0; 1.2–3.2). Analysis of individual symptoms suggests that this interaction may be strongest for effects on wheezing.
Conclusions
Small airways may serve as a marker of susceptibility to effects of wildfire smoke. Future studies should investigate the role of airway size for more common exposures and should include persons with asthma.
doi:10.1097/EDE.0b013e31819d128d
PMCID: PMC4517186  PMID: 19276978
3.  Ethnic-Specific Associations of Rare and Low Frequency DNA Sequence Variants with Asthma 
Nature communications  2015;6:5965.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls, and 590 case-parent trios representing European Americans, African Americans/African Caribbeans, and Latinos. Our study reveals one low frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31×10−6; OR=1.25; MAF=1.21%) and two genes harboring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P=7.81×10−8 and 4.09×10−8, respectively) and MTHFR in the African ancestry sample (P=1.72×10−6). Our results suggest that associations with rare and low frequency variants are ethnic specific and not likely to explain a significant proportion of the “missing heritability” of asthma.
doi:10.1038/ncomms6965
PMCID: PMC4309441  PMID: 25591454
4.  Fractional exhaled nitric oxide in childhood is associated with 17q11.2-q12 and 17q12-q21 variants 
Background
The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes.
Objective
To identify genetic variants associated with childhood FeNO, and their relation with asthma.
Methods
FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110).
Results
We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.
Conclusion
This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma.
doi:10.1016/j.jaci.2013.08.053
PMCID: PMC4334587  PMID: 24315451
airway inflammation; asthma phenotypes; biomarker; genetics; genome-wide association study
5.  Associations of Children’s Lung Function with Ambient Air Pollution: Joint Effects of Regional and Near-roadway Pollutants 
Thorax  2013;69(6):540-547.
Background
Prior studies have reported adverse effects of either regional or near-roadway air pollution (NRAP) on lung function. However, there has been little study of the joint effects of these exposures.
Objectives
To assess the joint effects of NRAP and regional pollutants on childhood lung function in the Children’s Health Study.
Methods
Lung function was measured on 1,811 children from eight Southern Californian communities. NRAP exposure was assessed based on (1) residential distance to the nearest freeway or major road and (2) estimated near-roadway contributions to residential nitrogen dioxide (NO2), nitric oxide (NO), and total nitrogen oxides (NOx). Exposure to regional ozone (O3), NO2, particulate matter with aerodynamic diameter less than 10 μm (PM10) and 2.5 μm (PM2.5) was measured continuously at community monitors.
Results
A 17.9 ppb (two standard deviation) increase in near-roadway NOx was associated with deficits of 1.6% in FVC (p=0.005) and 1.1% in FEV1 (p=0.048). Effects were observed in all communities and were similar for NO2 and NO. Residential proximity to a freeway was associated with a reduction in FVC. Lung function deficits of 2–3% were associated with regional PM10 and PM2.5 (FVC and FEV1) and with O3 (FEV1), but not NO2, across the range of exposure between communities. Associations with regional pollution and NRAP were independent in models adjusted for each. Effects of NRAP were not modified by regional pollutant concentrations.
Conclusions
Results indicate that NRAP and regional air pollution have independent adverse effects on childhood lung function.
doi:10.1136/thoraxjnl-2012-203159
PMCID: PMC4191894  PMID: 24253832
traffic; lung function; air pollution; children; land-use regression
6.  Predictors of intra-community variation in air quality 
Air quality has emerged as a key determinant of important health outcomes in children and adults. This study aims to identify factors that influence local, within-community air quality, and to build a model for traffic-related air pollution (TRP).We utilized concentrations of NO2, NO, and total oxides of nitrogen (NOx), which were measured at 942 locations in 12 southern California communities. For each location, population density, elevation, land-use, and several indicators of traffic were calculated. A spatial random effects model was used to study the relationship of these predictors to each TRP.Variation in TRP was strongly correlated with traffic on nearby freeways and other major roads, and also with population density and elevation. After accounting for traffic, categories of land-use were not associated with the pollutants. Traffic had a larger relative impact in small urban (low regional pollution) communities than in large urban (high regional pollution) communities. For example, our best fitting model explained 70% of the variation in NOx in large urban areas and 76% in small urban areas. Compared with living at least 1,500m from a freeway, living within 250m of a freeway was associated with up to a 41% increase in TRP in a large urban area, and up to a 75% increase in small urban areas.Thus, traffic strongly affects local air quality in large and small urban areas, which has implications for exposure assessment and estimation of health risks.
doi:10.1038/jes.2011.45
PMCID: PMC4391642  PMID: 22252279
traffic-related air pollution; nitrogen oxides; exposure assessment; traffic; land-use; spatial random effects
7.  NOS1 Methylation and Carotid Artery Intima Media Thickness in Children 
Background
Nitric oxide (NO) plays an important role in cardiovascular health by maintaining and regulating vascular tone and blood flow. Epigenetic regulation of nitric oxide synthase (NOS), the genes responsible for NO production, may affect cardiovascular disease including development of atherosclerosis in children.
Methods and Results
We measured percentage DNA methylation using bisulfite conversion and Pyrosequencing assays on DNA from buccal cells provided by 377 participants of the Children’s Health Study on whom carotid artery intima-media thickness (CIMT) measurements were also collected. We examined a total of 16 CpG loci located within NOS1, NOS2A, NOS3, ARG1 and ARG, genes responsible for NO production. CIMT was measured using high-resolution B-mode carotid ultrasound. The association between percentage DNA methylation in ARG and NOS genes with CIMT was evaluated using linear regression adjusted for sex, Cethnicity, body mass index, age at CIMT, town of residence and experimental plate for pyrosequencing reactions. Differences in the association by ethnicity and ancestral group were also evaluated. For a 1% increase in average DNA methylation of NOS1, CIMT increased by 1.2 μm (p=0.02). This association was greater in Hispanic children of Native American descent (β = 2.3, p=0.004) than in Non-Hispanic Whites (β = 0.3, p=0.71) or Hispanic Whites (β = 1.0, p=0.35).
Conclusions
DNA methylation of NOS1 has a plausible role in atherogenesis through regulation of NO production, though ancestry may alter the magnitude of this association.
doi:10.1161/CIRCGENETICS.113.000320
PMCID: PMC4008829  PMID: 24622112
epigenetics; intima-media thickness; cardiovascular disease; nitric oxide synthase
8.  Native American Ancestry Is Associated With Severe Diabetic Retinopathy in Latinos 
Purpose.
Diabetic retinopathy (DR) is a leading cause of blindness in working age adults. Studies have observed that Latinos have a higher prevalence of DR than whites. The purpose of this study is to test the association between genetic admixture and severe DR in Latinos with type 2 diabetes mellitus (T2DM).
Methods.
We conducted a case–control study using 944 T2DM subjects from the Los Angeles Latino Eye Study. Cases (n = 135) were defined as proliferative or severe nonproliferative DR subjects. Controls (n = 809) were other diabetic subjects in the cohort. Genotyping was performed on the Illumina OmniExpress BeadChip. We estimated genetic ancestry in Latinos using STRUCTURE with the HapMap reference panels. Univariate and multivariate logistic regression analyses were used to test the relationship between the proportions of genetic ancestry and severe DR.
Results.
Native American ancestry (NAA) in Latino T2DM subjects is associated significantly with severe DR (P = 0.002). The association remained significant (P = 0.005) after adjusting for age, sex, duration of diabetes, hemoglobin A1c, body mass index, systolic blood pressure, education, and income. We also validated the NAA estimates in Latinos using ADMIXTURE with the 1000 Genomes Project reference panels and obtained consistent results.
Conclusions.
Our results demonstrate for the first time to our knowledge that NAA is a significant risk factor for severe DR in Latinos.
Our results demonstrate for the first time to our knowledge that Native American ancestry is a significant risk factor for severe diabetic retinopathy in Latinos. Therefore, genetic ancestry should be included in the risk assessment of severe diabetic retinopathy in research studies of Latinos with type 2 diabetes mellitus.
doi:10.1167/iovs.14-15044
PMCID: PMC4176415  PMID: 25146985
diabetic retinopathy; Latinos; genetic ancestry; Native American
9.  Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma 
Nature Communications  2015;6:5965.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case–parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10−6; OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12–21 asthma locus in the Latino and combined samples (P=7.81 × 10−8 and 4.09 × 10−8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10−6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the ‘missing heritability’ of asthma.
Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.
doi:10.1038/ncomms6965
PMCID: PMC4309441  PMID: 25591454
10.  Native American Ancestry Affects the Risk for Gene Methylation in the Lungs of Hispanic Smokers from New Mexico 
Rationale: Gene promoter methylation detected in sputum predicts lung cancer risk in smokers. Compared with non-Hispanic whites (NHW), Hispanics have a lower age-standardized incidence for lung cancer.
Objectives: This study compared the methylation prevalence in sputum of NHWs with Hispanics using the Lovelace Smokers cohort (n = 1998) and evaluated the effect of Native American ancestry (NAA) and diet on biomarkers for lung cancer risk.
Methods: Genetic ancestry was estimated using 48 ancestry markers. Diet was assessed by the Harvard University Dietary Assessment questionnaire. Methylation of 12 genes was measured in sputum using methylation-specific polymerase chain reaction. The association between NAA and risk for methylation was assessed using generalized estimating equations. The ethnic difference in the association between pack-years and risk for lung cancer was assessed in the New Mexico lung cancer study.
Measurements and Main Results: Overall Hispanics had a significantly increased risk for methylation across the 12 genes analyzed (odds ratio, 1.18; P = 0.007). However, the risk was reduced by 32% (P = 0.032) in Hispanics with high versus low NAA. In the New Mexico lung cancer study, Hispanic non–small cell lung cancer cases have significantly lower pack-years than NHW counterparts (P = 0.007). Furthermore, compared with NHW smokers, Hispanic smokers had a more rapidly increasing risk for lung cancer as a function of pack-years (P = 0.058).
Conclusions: NAA may be an important risk modifier for methylation in Hispanic smokers. Smoking intensity may have a greater impact on risk for lung cancer in Hispanics compared with NHWs.
doi:10.1164/rccm.201305-0925OC
PMCID: PMC3863742  PMID: 24032348
ethnicity; sputum; diet; risk; lung cancer
11.  Efficient Genome-Wide Association Testing of Gene-Environment Interaction in Case-Parent Trios 
American Journal of Epidemiology  2010;172(1):116-122.
Complex trait variation is likely to be explained by the combined effects of genes, environmental factors, and gene × environment (G × E) interaction. The authors introduce a novel 2-step method for detecting a G × E interaction in a genome-wide association study (GWAS) of case-parent trios. The method utilizes 2 sources of G × E information in a trio sample to construct a screening step and a testing step. Across a wide range of models, this 2-step procedure provides substantially greater power to detect G × E interaction than a standard test of G × E interaction applied genome-wide. For example, for a disease susceptibility locus with minor allele frequency of 15%, a binary exposure variable with 50% prevalence, and a GWAS scan of 1 million markers in 1,000 case-parent trios, the 2-step method provides 87% power to detect a G × E interaction relative risk of 2.3, as compared with only 25% power using a standard G × E test. The method is easily implemented using standard software. This 2-step scan for G × E interaction is independent of any prior scan that may have been conducted for genetic main effects, and thus has the potential to uncover new genes in a GWAS that have not been previously identified.
doi:10.1093/aje/kwq097
PMCID: PMC2915477  PMID: 20543031
environmental exposure; epidemiologic methods; genetic association studies; genetics; genome-wide association study; models, genetic
12.  Microsomal epoxide hydrolase, glutathione S‐transferase P1, traffic and childhood asthma 
Thorax  2007;62(12):1050-1057.
Background
Microsomal epoxide hydrolase (EPHX1) metabolises xenobiotics including polyaromatic hydrocarbons (PAHs). Functional variants at this locus have been associated with respiratory diseases. The effects of EPHX1 variants may depend upon exposures from tobacco smoke and traffic emissions that contain PAHs as well as variants in other enzymes in the PAH metabolic pathway such as glutathione S‐transferase (GST) genes. A study was undertaken to investigate associations of variants in EPHX1, GSTM1, GSTP1 and GSTT1 with asthma and the relationships between asthma, EPHX1 metabolic phenotypes and exposure to sources of PAHs.
Methods
Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate the associations of genetic variants and exposures with asthma phenotypes using data from 3124 children from the Children's Health Study.
Results
High EPHX1 activity was associated with an increased risk for lifetime asthma (OR 1.51, 95% CI 1.14 to 1.98) which varied by GSTP1 Ile105Val genotype and by residential proximity to major roads (p for interaction = 0.006 and 0.03, respectively). Among children with GSTP1 105Val/Val genotype, those who had high EPHX1 phenotype had a fourfold (95% CI 1.97 to 8.16) increased risk of lifetime asthma than children with low/intermediate EPHX1 phenotype. Among children living within 75 metres of a major road, those with high EPHX1 activity had a 3.2‐fold (95% CI 1.75 to 6.00) higher lifetime asthma risk than those with low/intermediate activity. The results were similar for current, early persistent and late onset asthma. Children with high EPHX1 phenotype, GSTP1 Val/Val genotype who lived <75 metres from a major road were at the highest asthma risk.
Conclusion
EPHX1 and GSTP1 variants contribute to the occurrence of childhood asthma and increase asthma susceptibility to exposures from major roads.
doi:10.1136/thx.2007.080127
PMCID: PMC2094290  PMID: 17711870
13.  Relationship between air pollution, lung function and asthma in adolescents 
Thorax  2007;62(11):957-963.
Background
The interrelationships between air pollution, lung function and the incidence of childhood asthma have yet to be established. A study was undertaken to determine whether lung function is associated with new onset asthma and whether this relationship varies by exposure to ambient air pollutants.
Methods
A cohort of children aged 9–10 years without asthma or wheeze at study entry were identified from the Children's Health Study and followed for 8 years. The participants resided in 12 communities with a wide range of ambient air pollutants that were measured continuously. Spirometric testing was performed and a medical diagnosis of asthma was ascertained annually. Proportional hazard regression models were fitted to investigate the relationship between lung function at study entry and the subsequent development of asthma and to determine whether air pollutants modify these associations.
Results
The level of airway flow was associated with new onset asthma. Over the 10th–90th percentile range of forced expiratory flow over the mid‐range of expiration (FEF25–75, 57.1%), the hazard ratio (HR) of new onset asthma was 0.50 (95% CI 0.35 to 0.71). This protective effect of better lung function was reduced in children exposed to higher levels of particulate matter with an aerodynamic diameter <2.5 μm (PM2.5). Over the 10th–90th percentile range of FEF25–75, the HR of new onset asthma was 0.34 (95% CI 0.21 to 0.56) in communities with low PM2.5 (<13.7 μg/m3) and 0.76 (95% CI 0.45 to 1.26) in communities with high PM2.5 (⩾13.7 μg/m3). A similar pattern was observed for forced expiratory volume in 1 s. Little variation in HR was observed for ozone.
Conclusion
Exposure to high levels of PM2.5 attenuates the protective effect of better lung function against new onset asthma.
doi:10.1136/thx.2007.078964
PMCID: PMC2117135  PMID: 17517830
14.  Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis 
BMC Medical Genomics  2014;7:48.
Background
Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.
Methods
We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.
Results
GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10−24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10−72).
Conclusions
Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.
doi:10.1186/1755-8794-7-48
PMCID: PMC4127082  PMID: 25085501
Genome-wide association study; Allergic rhinitis; Coexpression network; Expression single-nucleotide polymorphism; Coexpression module; Pathway; Mitochondria; Hay fever; Allergy
15.  Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer 
PLoS Genetics  2014;10(4):e1004228.
Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.
Author Summary
High intake of red and processed meat and low intake of fruits, vegetables and fiber are associated with a higher risk of colorectal cancer. We investigate if the effect of these dietary factors on colorectal cancer risk is modified by common genetic variants across the genome (total of about 2.7 million genetic variants), also known as gene-diet interactions. We included over 9,000 colorectal cancer cases and 9,000 controls that were not diagnosed with colorectal cancer. Our results provide strong evidence for a gene-diet interaction and colorectal cancer risk between a genetic variant (rs4143094) on chromosome 10p14 near the gene GATA3 and processed meat consumption (p = 8.7E-09). This genetic locus may have interesting biological significance given its location in the genome. Our results suggest that genetic variants may interact with diet and in combination affect colorectal cancer risk, which may have important implications for personalized cancer care and provide novel insights into prevention strategies.
doi:10.1371/journal.pgen.1004228
PMCID: PMC3990510  PMID: 24743840
16.  A Meta-analysis of Genome-wide Association Studies for Serum Total IgE in Diverse Study Populations 
Background
Immunoglobulin E (IgE) is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino individuals have not been well represented in genetic studies of total IgE.
Objective
To identify the genetic predictors of serum total IgE levels.
Methods
We used genome wide association (GWA) data from 4,292 individuals (2,469 African Americans, 1,564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (i.e., African American, Latino, and European American) and asthma status. The resulting p-values were meta-analyzed accounting for sample size and direction of effect. Top single nucleotide polymorphism (SNP) associations from the meta-analysis were reassessed in six additional cohorts comprising 5,767 individuals.
Results
We identified 10 unique regions where the combined association statistic was associated with total serum IgE levels (P-value <5.0×10−6) and the minor allele frequency was ≥5% in two or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the most significantly associated SNP with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P-value = 0.007 and 2.45×10−7, respectively). In addition, findings from earlier GWA studies were also validated in the current meta-analysis.
Conclusion
This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE in multiple race-ethnic groups. This study also extends and confirms the findings of earlier GWA analyses in African American and Latino individuals.
doi:10.1016/j.jaci.2012.10.002
PMCID: PMC3596497  PMID: 23146381
meta-analysis; genome wide association study; total immunoglobulin E; race-ethnicity; continental population groups
17.  Confounding and Heterogeneity in Genetic Association Studies with Admixed Populations 
American Journal of Epidemiology  2013;177(4):351-360.
Association studies among admixed populations pose many challenges including confounding of genetic effects due to population substructure and heterogeneity due to different patterns of linkage disequilibrium (LD). We use simulations to investigate controlling for confounding by indicators of global ancestry and the impact of including a covariate for local ancestry. In addition, we investigate the use of an interaction term between a single-nucleotide polymorphism (SNP) and local ancestry to capture heterogeneity in SNP effects. Although adjustment for global ancestry can control for confounding, additional adjustment for local ancestry may increase power when the induced admixture LD is in the opposite direction as the LD in the ancestral population. However, if the induced LD is in the same direction, there is the potential for reduced power because of overadjustment. Furthermore, the inclusion of a SNP by local ancestry interaction term can increase power when there is substantial differential LD between ancestry populations. We examine these approaches in genome-wide data using the University of Southern California's Children's Health Study investigating asthma risk. The analysis highlights rs10519951 (P = 8.5 × 10−7), a SNP lacking any evidence of association from a conventional analysis (P = 0.5).
doi:10.1093/aje/kws234
PMCID: PMC3626055  PMID: 23334005
confounding; genetic association studies; genome-wide association studies; heterogeneity; linkage disequilibrium; population stratification
18.  Further Replication Studies of the EVE Consortium Meta-Analysis Identifies Two Asthma Risk Loci in European Americans 
Background
Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk.
Objectives
We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis.
Methods
We selected 3186 SNPs for replication based on the p-values from the EVE Consortium meta-analysis. These SNPs were genotyped in ethnically diverse replication samples from nine different studies, totaling to 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study and the resulting test statistics were combined in a meta-analysis.
Results
Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined OR = 1.18; 95% CI 1.10 – 1.25) and rs9570077 (combined OR =1.20 95% CI 1.12–1.29) on chromosome 13q21. We could not replicate any additional associations in the African American or Latino individuals.
Conclusions
This extended replication study identified two additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latino individuals highlights the difficulty in replicating associations in admixed populations.
doi:10.1016/j.jaci.2012.07.054
PMCID: PMC3666859  PMID: 23040885
Asthma; genetic risk factors; meta-analysis; KLK3
19.  Parental Smoking and Risk of Childhood Brain Tumors by Functional Polymorphisms in Polycyclic Aromatic Hydrocarbon Metabolism Genes 
PLoS ONE  2013;8(11):e79110.
Background
A recent meta-analysis suggested an association between exposure to paternal smoking during pregnancy and childhood brain tumor risk, but no studies have evaluated whether this association differs by polymorphisms in genes that metabolize tobacco-smoke chemicals.
Methods
We assessed 9 functional polymorphisms in 6 genes that affect the metabolism of polycyclic aromatic hydrocarbons (PAH) to evaluate potential interactions with parental smoking during pregnancy in a population-based case-control study of childhood brain tumors. Cases (N = 202) were ≤10 years old, diagnosed from 1984–1991 and identified in three Surveillance, Epidemiology, and End Results (SEER) registries in the western U.S. Controls in the same regions (N = 286) were frequency matched by age, sex, and study center. DNA for genotyping was obtained from archived newborn dried blood spots.
Results
We found positive interaction odds ratios (ORs) for both maternal and paternal smoking during pregnancy, EPHX1 H139R, and childhood brain tumors (Pinteraction = 0.02; 0.10), such that children with the high-risk (greater PAH activation) genotype were at a higher risk of brain tumors relative to children with the low-risk genotype when exposed to tobacco smoke during pregnancy. A dose-response pattern for paternal smoking was observed among children with the EPHX1 H139R high-risk genotype only (ORno exposure = 1.0; OR≤3 hours/day = 1.32, 95% CI: 0.52–3.34; OR>3hours/day = 3.18, 95% CI: 0.92–11.0; Ptrend = 0.07).
Conclusion
Parental smoking during pregnancy may be a risk factor for childhood brain tumors among genetically susceptible children who more rapidly activate PAH in tobacco smoke.
doi:10.1371/journal.pone.0079110
PMCID: PMC3832498  PMID: 24260161
20.  A Genome-Wide Association Study of Central Corneal Thickness in Latinos 
Purpose.
Central corneal thickness (CCT) is a clinically important risk factor for primary open-angle glaucoma and keratoconus. Genetic factors controlling CCT in Latinos, the most populous minority population in the United States, are unclear. Here we describe the first genome-wide association study (GWAS) report of CCT in Latinos.
Methods.
We performed a GWAS for CCT on 1768 Latinos recruited in the Los Angeles Latino Eye Study (LALES) using Illumina's HumanOmniExpress BeadChip (∼730K markers). To discover additional associated single-nucleotide polymorphisms (SNPs), we imputed SNPs based on the 1000 Genomes Project reference panels. All subjects were 40 years of age and older. We used linear regression with adjustment for age, sex, and principal components of genetic ancestry.
Results.
We replicated the involvement of several previously reported loci, such as RXRA-COL5A1, FOXO1, and ZNF469, for CCT in Latinos (P < 0.002). Moreover, we discovered novel SNPs, rs3118515, rs943423, rs3118594, and rs3132307, that reached GWAS significance (P < 5 × 10−8) in the uncharacterized LOC100506532 (gene type: miscRNA) for CCT in Latinos. By conditional analysis, we demonstrate that rs3118515 in this gene is responsible for the GWAS signal in the chromosome 9 RXRA-COL5A1 region in Latinos. Moreover, multiple sources of ENCODE evidence suggest that rs3118515 is in a regulatory region. Reverse-transcription PCR products indicated that transcripts of LOC100506532 surrounding rs3118515 were expressed in human corneas.
Conclusions.
We discovered novel SNPs for CCT in Latinos and provided the first reported evidence of the corneal expression of LOC100506532. These results help to further increase our understanding of the genetic architecture of CCT.
In this first GWAS of central corneal thickness in Latinos, we discovered the involvement of novel SNPs, both directly genotyped and imputed, that reached genome-wide significance. This study provided the first reported evidence of the corneal expression of LOC100506532.
doi:10.1167/iovs.13-11692
PMCID: PMC3621577  PMID: 23493294
central corneal thickness; Latino; GWAS; rs3118515; LOC100506532
21.  Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene 
PLoS ONE  2013;8(2):e56179.
Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.
doi:10.1371/journal.pone.0056179
PMCID: PMC3572953  PMID: 23457522
22.  Invited Commentary: GE-Whiz! Ratcheting Gene-Environment Studies up to the Whole Genome and the Whole Exposome 
American Journal of Epidemiology  2011;175(3):203-207.
One goal in the post-genome-wide association study era is characterizing gene-environment interactions, including scanning for interactions with all available polymorphisms, not just those showing significant main effects. In recent years, several approaches to such “gene-environment-wide interaction studies” have been proposed. Two contributions in this issue of the American Journal of Epidemiology provide systematic comparisons of the performance of these various approaches, one based on simulation and one based on application to 2 real genome-wide association study scans for type 2 diabetes. The authors discuss some of the broader issues raised by these contributions, including the plausibility of the gene-environment independence assumption that some of these approaches rely upon, the need for replication, and various generalizations of these approaches.
doi:10.1093/aje/kwr365
PMCID: PMC3261438  PMID: 22199029
epidemiologic research design; genetic epidemiology; genome-wide association study; genotype-environment interaction; polymorphisms, single nucleotide
23.  Parental Stress Increases the Detrimental Effect of Traffic Exposure on Children's Lung Function 
Rationale: Emerging evidence indicates that psychosocial stress enhances the effect of traffic exposure on the development of asthma.
Objectives: We hypothesized that psychosocial stress would also modify the effect of traffic exposure on lung function deficits.
Methods: We studied 1,399 participants in the Southern California Children's Health Study undergoing lung function testing (mean age, 11.2 yr). We used hierarchical mixed models to assess the joint effect of traffic-related air pollution and stress on lung function.
Measurements and Main Results: Psychosocial stress in each child's household was assessed based on parental response to the perceived stress scale (range, 0–16) at study entry. Exposures to nitric oxide, nitrogen dioxide, and total oxides of nitrogen (NOx), surrogates of the traffic-related pollution mixture, were estimated at schools and residences based on a land-use regression model. Among children from high-stress households (parental perceived stress scale >4) deficits in FEV1 of 4.5 (95% confidence interval, −6.5 to −2.4) and of 2.8% (−5.7 to 0.3) were associated with each 21.8 ppb increase in NOx at homes and schools, respectively. These pollutant effects were significantly larger in the high-stress compared with lower-stress households (interaction P value 0.007 and 0.05 for residential and school NOx, respectively). No significant NOx effects were observed in children from low-stress households. A similar pattern of association was observed for FVC. The observed associations for FEV1 and FVC remained after adjusting for sociodemographic factors and after restricting the analysis to children who do not have asthma.
Conclusions: A high-stress home environment is associated with increased susceptibility to lung function effects of air pollution both at home and at school.
doi:10.1164/rccm.201104-0720OC
PMCID: PMC3208647  PMID: 21700914
parental stress; traffic exposure; lung function; children
24.  Meta-analysis of Genome-wide Association Studies of Asthma In Ethnically Diverse North American Populations 
Torgerson, Dara G. | Ampleford, Elizabeth J. | Chiu, Grace Y. | Gauderman, W. James | Gignoux, Christopher R. | Graves, Penelope E. | Himes, Blanca E. | Levin, Albert M. | Mathias, Rasika A. | Hancock, Dana B. | Baurley, James W. | Eng, Celeste | Stern, Debra A. | Celedón, Juan C. | Rafaels, Nicholas | Capurso, Daniel | Conti, David V. | Roth, Lindsey A. | Soto-Quiros, Manuel | Togias, Alkis | Li, Xingnan | Myers, Rachel A. | Romieu, Isabelle | Van Den Berg, David J. | Hu, Donglei | Hansel, Nadia N. | Hernandez, Ryan D. | Israel, Elliott | Salam, Muhammad T. | Galanter, Joshua | Avila, Pedro C. | Avila, Lydiana | Rodriquez-Santana, Jose R. | Chapela, Rocio | Rodriguez-Cintron, William | Diette, Gregory B. | Adkinson, N. Franklin | Abel, Rebekah A. | Ross, Kevin D. | Shi, Min | Faruque, Mezbah U. | Dunston, Georgia M. | Watson, Harold R. | Mantese, Vito J. | Ezurum, Serpil C. | Liang, Liming | Ruczinski, Ingo | Ford, Jean G. | Huntsman, Scott | Chung, Kian Fan | Vora, Hita | Li, Xia | Calhoun, William J. | Castro, Mario | Sienra-Monge, Juan J. | del Rio-Navarro, Blanca | Deichmann, Klaus A. | Heinzmann, Andrea | Wenzel, Sally E. | Busse, William W. | Gern, James E. | Lemanske, Robert F. | Beaty, Terri H. | Bleecker, Eugene R. | Raby, Benjamin A. | Meyers, Deborah A. | London, Stephanie J. | Gilliland, Frank D. | Burchard, Esteban G. | Martinez, Fernando D. | Weiss, Scott T. | Williams, L. Keoki | Barnes, Kathleen C. | Ober, Carole | Nicolae, Dan L.
Nature genetics  2011;43(9):887-892.
Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies (GWAS) of asthma in 5,416 asthma cases representing European Americans, African Americans/African Caribbeans, and Latinos, and replicated five regions among the most significant signals in 12,649 individuals from the same ethnic groups. Four were at previously reported loci on 17q21, and near the IL1RL1, TSLP, and IL33, genes, but we report for the first time that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a novel association with asthma in the PYHIN1, gene that was specific to individuals of African descent (p=3.9×10−9). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
doi:10.1038/ng.888
PMCID: PMC3445408  PMID: 21804549
25.  Association of the Calcyon Neuron-Specific Vesicular Protein Gene (CALY) With Adolescent Smoking Initiation in China and California 
American Journal of Epidemiology  2011;173(9):1039-1048.
Although previous investigations have indicated a role for genetic factors in smoking initiation, the underlying genetic mechanisms are still unknown. In 2,339 adolescents from a Chinese Han population in the Wuhan Smoking Prevention Trial (Wuhan, China, 1998–1999), the authors explored the association of 57 genes in the dopamine pathway with smoking initiation. Using a conservative approach for declaring significance, positive findings were further examined in an independent sample of 603 Caucasian adolescents followed for up to 10 years as part of the Children's Health Study (Southern California, 1993–2009). The authors identified 1 single nucleotide polymorphism (rs2298122) in the calcyon neuron-specific vesicular protein gene (CALY) that was positively associated with smoking initiation in females (odds ratio = 2.21, 95% confidence interval: 1.49, 3.27; P = 8.4 × 10−5) in the Wuhan Smoking Prevention Trial cohort, and they replicated the association in females from the Children's Health Study cohort (hazard rate ratio = 2.05, 95% confidence interval: 1.27, 3.31; P = 0.003). These results suggest that the CALY gene may influence smoking initiation in adolescents, although the potential roles of underlying psychological characteristics that may be components of the smoking-initiation phenotype, such as impulsivity or novelty-seeking, remain to be explored.
doi:10.1093/aje/kwq471
PMCID: PMC3121219  PMID: 21415033
adolescent; dopamine; genetic association studies; smoking

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