A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans.

We performed a hypothesis-generating phenome-wide association study (PheWAS) to identify and characterize cross-phenotype associations, where one SNP is associated with two or more phenotypes, between thousands of genetic variants assayed on the Metabochip and hundreds of phenotypes in 5,897 African Americans as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study. The PAGE I study was a National Human Genome Research Institute-funded collaboration of four study sites accessing diverse epidemiologic studies genotyped on the Metabochip, a custom genotyping chip that has dense coverage of regions in the genome previously associated with cardio-metabolic traits and outcomes in mostly European-descent populations. Here we focus on identifying novel phenome-genome relationships, where SNPs are associated with more than one phenotype. To do this, we performed a PheWAS, testing each SNP on the Metabochip for an association with up to 273 phenotypes in the participating PAGE I study sites. We identified 133 putative pleiotropic variants, defined as SNPs associated at an empirically derived p-value threshold of p<0.01 in two or more PAGE study sites for two or more phenotype classes. We further annotated these PheWAS-identified variants using publicly available functional data and local genetic ancestry. Amongst our novel findings is SPARC rs4958487, associated with increased glucose levels and hypertension. SPARC has been implicated in the pathogenesis of diabetes and is also known to have a potential role in fibrosis, a common consequence of multiple conditions including hypertension. The SPARC example and others highlight the potential that PheWAS approaches have in improving our understanding of complex disease architecture by identifying novel relationships between genetic variants and an array of common human phenotypes.

Neonatal Jaundice: Improved Quality and Cost Savings After Implementation of a Standard Pathway.

OBJECTIVES: Seattle Children's Hospital sought to optimize the value equation for neonatal jaundice patients by creating a standard care pathway. METHODS: An evidence-based pathway for management of neonatal jaundice was created. This included multidisciplinary team assembly, comprehensive literature review, creation of a treatment algorithm and computer order sets, formulation of goals and metrics, roll-out of an education program for end users, and ongoing pathway improvement. The pathway was implemented on May 31, 2012. Quality metrics before and after implementation were compared. External data were used to analyze cost impacts. RESULTS: Significant improvements were achieved across multiple quality dimensions. Time to recovery decreased: mean length of stay was 1.30 days for 117 prepathway patients compared with 0.87 days for 69 postpathway patients (P < .001). Efficiency was enhanced: mean time to phototherapy initiation was 101.26 minutes for 14 prepathway patients compared with 54.67 minutes for 67 postpathway patients (P = .03). Care was less invasive: intravenous fluid orders were reduced from 80% to 44% (P < .001). Inpatient use was reduced: 66% of prepathway patients were admitted from the emergency department to inpatient care, compared with 50% of postpathway patients (P = .01). There was no increase in the readmission rate. These achievements translated to statistically significant cost reductions in total charges, as well as in the following categories: intravenous fluids, laboratory, room cost, and emergency department charges. CONCLUSIONS: An evidence-based standard care pathway for neonatal jaundice can significantly improve multiple dimensions of value, including reductions in cost and length of stay.

Construct Validity and Responsiveness of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales and Infant Scales in the PICU.

OBJECTIVES: To assess the construct validity and the responsiveness of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales and Infant Scales in the medical-surgical (PICU) and cardiac PICU. DESIGN/SETTING/PARTICIPANTS: Prospective cohort study of 367 inpatients admitted either to the PICU or the cardiac ICU at Seattle Children's Hospital from January 2012 to June 2013. Parent/caregiver and child (≥ 8 yr old, developmentally appropriate, and critical illness resolved) Pediatric Quality of Life Inventory scores were obtained within 24 hours of PICU/cardiac ICU discharge and subsequently at 4-12 weeks following hospital discharge. Of the 491 eligible participants invited to participate, 367 (74.7% response rate) completed the Pediatric Quality of Life Inventory survey at ICU discharge, and of these, 263 (71.7% follow-up response rate) completed the follow-up survey 4-12 weeks after hospital discharge. MEASUREMENTS AND MAIN RESULTS: Responsiveness was assessed by calculating improvement scores (difference between follow-up and ICU discharge scores, Δ Pediatric Quality of Life Inventory). Construct validity was examined by comparing mean improvement scores for known groups differing by medical complexity. At follow-up, [INCREMENT] Pediatric Quality of Life Inventory scores were as follows (mean ± SD): physical domain, 34.8 ± 32.0; and psychosocial domain, 23.1 ± 23.5. Patients with complex chronic or noncomplex chronic disease had physical functioning improvement scores that were 17.4 points (95% CI, -28.3 to -6.5; p < 0.001) and 19.5 points (95% CI, -30.4 to -8.5; p < 0.002) lower than children with no chronic illness, respectively. Patients with complex chronic disease exhibited psychosocial improvement scores that were 9.6 points (95% CI, -18.4 to -0.8; p < 0.033) lower than patients without chronic disease. Patients with noncomplex chronic disease had similar psychosocial improvement scores when compared with patients without chronic disease. CONCLUSIONS: As a measure of health-related quality of live, Pediatric Quality of Life Inventory demonstrated responsiveness and construct validity in a broad population of critically ill children. This measure represents a patient-centered clinically meaningful patient-or-parent-reported outcome measure for pediatric research assessing the clinical effectiveness of PICU/cardiac ICU interventions. When using health-related quality of life recovery as an outcome measure to assess clinical effectiveness in the PICU/cardiac ICU setting, measuring and controlling for the level of medical complexity is important in order to understand the true impact of clinical interventions.

The association between park visitation and physical activity measured with accelerometer, GPS, and travel diary.

Public parks are promoted as places that support physical activity (PA), but evidence of how park visitation contributes to overall PA is limited. This study observed adults living in the Seattle metropolitan area (n=671) for one week using accelerometer, GPS, and travel diary. Park visits, measured both objectively (GPS) and subjectively (travel diary), were temporally linked to accelerometer-measured PA. Park visits occurred at 1.4 per person-week. Participants who visited parks at least once (n=308) had an adjusted average of 14.3 (95% CI: 8.9, 19.6)min more daily PA than participants who did not visit a park. Even when park-related activity was excluded, park visitors still obtained more minutes of daily PA than non-visitors. Park visitation contributes to a more active lifestyle, but is not solely responsible for it. Parks may best serve to complement broader public health efforts to encourage PA.

Fit 5 Kids TV Reduction Program for Latino Preschoolers: A Cluster Randomized Controlled Trial.

INTRODUCTION: Reducing Latino preschoolers' TV viewing is needed to reduce their risk of obesity and other chronic diseases. This study's objective was to evaluate the Fit 5 Kids (F5K) TV reduction program's impact on Latino preschooler's TV viewing. STUDY DESIGN: Cluster RCT with randomization at the center level and N=160 participants. SETTING/PARTICIPANTS: Latino children aged 3-5 years and their parents were recruited from six Head Start centers in Houston TX in 2010-2012 with analyses in 2013-2014. INTERVENTION: F5K was culturally adapted for Latino preschoolers and the overall goal was to reduce TV viewing. Study staff taught F5K over 7-8 weeks during the regular Head Start day directly to intervention students. Control schools provided the usual Head Start curriculum, which did not specifically cover TV viewing. MAIN OUTCOME MEASURES: Individual-level outcomes were measured prior to (Time 1) and immediately following (Time 2) the intervention. The primary outcome, TV viewing (minutes/day), was measured by validated 7-day TV diaries (parent-reported). Sedentary time was measured by accelerometers. RESULTS: Per the adjusted repeated measures linear mixed effects model for TV viewing (minutes/day), intervention children decreased from 76.2 (9.9) at Time 1 to 52.1 (10.0) at Time 2, whereas control children remained about the same from 84.2 (10.5) at Time 1 to 85.4 (10.5) at Time 2. The relative difference from Time 1 to Time 2 was -25.3 (95% CI= -45.2, -5.4) minutes for intervention versus control children (N=160, p=0.01). In a similar adjusted model, there was a relative decrease in sedentary time (minutes/day) from Time 1 to Time 2 favoring the intervention children (-9.5, 95% CI= -23.0, 4.1), although not significant at p<0.05. CONCLUSIONS: F5K reduced Latino preschoolers' TV viewing by >25 minutes daily. These findings have implications for prevention of obesity, related disorders, and health equity. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT01216306.

Telepsychiatrists' Medication Treatment Strategies in the Children's Attention-Deficit/Hyperactivity Disorder Telemental Health Treatment Study.

OBJECTIVE: The purpose of this study was to examine the prescribing strategies that telepsychiatrists used to provide pharmacologic treatment in the Children's Attention-Deficit/Hyperactivity Disorder (ADHD) Telemental Health Treatment Study (CATTS). METHODS: CATTS was a randomized controlled trial that demonstrated the superiority of a telehealth service delivery model for the treatment of ADHD with combined pharmacotherapy and behavior training (n=111), compared with management in primary care augmented with a telepsychiatry consultation (n=112). A diagnosis of ADHD was established with the Computerized Diagnostic Interview Schedule for Children (CDISC), and comorbidity for oppositional defiant disorder (ODD) and anxiety disorders (AD) was established using the CDISC and the Child Behavior Checklist. Telepsychiatrists used the Texas Children's Medication Algorithm Project (TCMAP) for ADHD to guide pharmacotherapy and the treat-to-target model to encourage their assertive medication management to a predetermined goal of 50% reduction in ADHD-related symptoms. We assessed whether telepsychiatrists' decision making about making medication changes was associated with baseline ADHD symptom severity, comorbidity, and attainment of the treat-to-target goal. RESULTS: Telepsychiatrists showed high fidelity (91%) to their chosen algorithms in medication management. At the end of the trial, the CATTS intervention showed 46.0% attainment of the treat-to-target goal compared with 13.6% for the augmented primary care condition, and significantly greater attainment of the goal by comorbidity status for the ADHD with one and ADHD with two comorbidities groups. Telepsychiatrists' were more likely to decide to make medication adjustments for youth with higher baseline ADHD severity and the presence of disorders comorbid with ADHD. Multiple mixed methods regression analyses controlling for baseline ADHD severity and comorbidity status indicated that the telepsychiatrists also based their decision making session to session on attainment of the treat-to-target goal. CONCLUSIONS: Telepsychiatry is an effective service delivery model for providing pharmacotherapy for ADHD, and the CATTS telepsychiatrists showed high fidelity to evidence-based protocols.

Correlates of Physical Activity in Latino Preschool Children Attending Head Start.

BACKGROUND: Physical activity is associated with long-term benefits for health and tracks from early childhood into later adolescence. Limited information exists about factors influencing physical activity among Latino preschoolers. We aimed to identify correlates of objectively measured light-to-vigorous-intensity physical activity as a proportion of wear time (% PA) in Latino 3-5 year olds. METHODS: Latino preschoolers (n = 96) were recruited from Head Start centers in Houston, TX, USA, from 2009 to 2010. Sociodemographics, anthropometrics, acculturation, neighborhood disorder, and TV viewing were measured. Actigraph GT1M accelerometers measured physical activity. Block linear regression was used with % PA as the dependent variable. RESULTS: Children achieved 285.7 ± 58.0 min/day of PA. In the final adjusted-model, child age, parental education and neighborhood disorder were positively associated with % PA (beta = 0.33, p = .002; beta = 0.25, p = .038; beta = 0.22, p = .039, respectively). TV viewing was inversely associated with % PA (beta=-0.23, p = .027). CONCLUSION: The majority of Latino preschoolers in our study exceeded US national and international guidelines of physical activity duration. Future interventions to sustain physical activity should focus on the influence of age, socioeconomic status, neighborhood disorder, and TV viewing on Latino preschoolers' attainment of physical activity.

How far from home? The locations of physical activity in an urban U.S. setting.

UNLABELLED: Little is known about where physical activity (PA) occurs, or whether different demographic groups accumulate PA in different locations. METHOD: Objective data on PA and location from 611 adults over 7days were collected in King County, WA in 2008-2009. The relative amounts of time spent in sedentary-to-low and moderate-to-vigorous PA (MVPA) were quantified at three locations: "home" (<125m from geocoded home locations); "near" home (125-1666m, defining the home neighborhood); and "away" from home (>1666m). Differences in MVPA by demographics and location were examined. The percent of daily time in MVPA was estimated using a mixed model adjusted for location, sex, age, race/ethnicity, employment, education, BMI, and income. RESULTS: Most MVPA time occurred in nonhome locations, and disproportionately "near" home; this location was associated with 16.46% greater time in MVPA, compared to at-home activity (p<0.001), whereas more time spent at "away" locations was associated with 3.74% greater time in MVPA (p<0.001). Location was found to be a predictor of MVPA independent of demographic factors. CONCLUSION: A large proportion of MVPA time is spent at "near" locations, corresponding to the home neighborhood studied in previous PA research. "Away" locations also host time spent in MVPA and should be the focus of future research.

The economic costs of chronic pain among a cohort of treatment-seeking adolescents in the United States.

UNLABELLED: The aim of this study was to assess the economic cost of chronic pain among adolescents receiving interdisciplinary pain treatment. Information was gathered from 149 adolescents (ages 10-17) presenting for evaluation and treatment at interdisciplinary pain clinics in the United States. Parents completed a validated measure of family economic attributes, the Client Service Receipt Inventory, to report on health service use and productivity losses due to their child's chronic pain retrospectively over 12 months. Health care costs were calculated by multiplying reported utilization estimates by unit visit costs from the 2010 Medical Expenditure Panel Survey. The estimated mean and median costs per participant were $11,787 and $6,770, respectively. Costs were concentrated in a small group of participants; the top 5% of those patients incurring the highest costs accounted for 30% of total costs, whereas the lower 75% of participants accounted for only 34% of costs. Total costs to society for adolescents with moderate to severe chronic pain were extrapolated to $19.5 billion annually in the United States. The cost of adolescent chronic pain presents a substantial economic burden to families and society. Future research should focus on predictors of increased health services use and costs in adolescents with chronic pain. PERSPECTIVE: This cost of illness study comprehensively estimates the economic costs of chronic pain in a cohort of treatment-seeking adolescents. The primary driver of costs was direct medical costs followed by productivity losses. Because of its economic impact, policy makers should invest resources in the prevention, diagnosis, and treatment of chronic pediatric pain.

Pleiotropic associations of risk variants identified for other cancers with lung cancer risk: the PAGE and TRICL consortia.

BACKGROUND: Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed. METHODS: We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non-lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10(-5) was used to assign statistical significance. RESULTS: The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10(-6)). This association was strongest for women with adenocarcinoma (P = 1.2×10(-4)) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10(-8)) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10(-5)), respectively. CONCLUSIONS: Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.

Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.

BACKGROUND: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S. METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites. RESULTS: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only. CONCLUSIONS: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.

Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study.

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.

Genetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study.

OBJECTIVE: Several genome-wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups. DESIGN AND METHODS: As part of the "Population Architecture using Genomics and Epidemiology (PAGE)" Consortium, we investigated the association between 13 GWAS-identified single-nucleotide polymorphisms (SNPs) and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African-Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI-increasing allele of each SNP, we calculated ß coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI ≥ 30) followed by fixed-effects meta-analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and were adjusted for age, sex, and current smoking. We defined "replicating SNPs" (in European Americans) and "generalizing SNPs" (in other racial/ethnic groups) as those associated with an allele frequency-specific increase in BMI. RESULTS: By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians. CONCLUSION: Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine-mapping in large samples is needed to comprehensively explore these loci in diverse populations.

Phenome-wide association study (PheWAS) for detection of pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network.

Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype-phenotype associations, 26 represented phenotypes closely related to previously known genotype-phenotype associations, and 33 represented potentially novel genotype-phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits.

A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.

Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study.

BACKGROUND: Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored. METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE)' Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses. RESULTS: We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (ß = 0.018, p = 0.002), vs. current smokers (ß = 0.001, p = 0.95, p(interaction) = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (ß = 0.017, p = 3.5 x 10(-5)), vs. former/never smokers (ß = 0.006, p = 0.05, p(interaction) = 0.08). CONCLUSIONS: These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results. CLINICAL TRIAL REGISTRATION: NCT00000611.

Fine-mapping and initial characterization of QT interval loci in African Americans.

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium.

Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.

Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.

The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.

HNF1B and endometrial cancer risk: results from the PAGE study.

We examined the association between HNF1B variants identified in a recent genome-wide association study and endometrial cancer in two large case-control studies nested in prospective cohorts: the Multiethnic Cohort Study (MEC) and the Women's Health Initiative (WHI) as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. A total of 1,357 incident cases of invasive endometrial cancer and 7,609 controls were included in the analysis (MEC: 426 cases/3,854 controls; WHI: 931 cases/3,755 controls). The majority of women in the WHI were European American, while the MEC included sizable numbers of African Americans, Japanese and Latinos. We estimated the odds ratios (ORs) per allele and 95% confidence intervals (CIs) of each SNP using unconditional logistic regression adjusting for age, body mass index, and four principal components of ancestry informative markers. The combined ORs were estimated using fixed effect models. Rs4430796 and rs7501939 were associated with endometrial cancer risk in MEC and WHI with no heterogeneity observed across racial/ethnic groups (P ≥ 0.21) or between studies (P ≥ 0.70). The OR(per allele) was 0.82 (95% CI: 0.75, 0.89; P = 5.63 × 10(-6)) for rs4430796 (G allele) and 0.79 (95% CI: 0.73, 0.87; P = 3.77 × 10(-7)) for rs7501939 (A allele). The associations with the risk of Type I and Type II tumors were similar (P ≥ 0.19). Adjustment for additional endometrial cancer risk factors such as parity, oral contraceptive use, menopausal hormone use, and smoking status had little effect on the results. In conclusion, HNF1B SNPs are associated with risk of endometrial cancer and that the associated relative risks are similar for Type I and Type II tumors.