Helena Furberg

All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs.

Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1−FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohns disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well-established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci.

Genome-Wide Association Studies, Field Synopses, and the Development of the Knowledge Base on Genetic Variation and Human Diseases

Genome-wide association studies (GWAS) have led to a rapid increase in available data on common genetic variants and phenotypes and numerous discoveries of new loci associated with susceptibility to common complex diseases. Integrating the evidence from GWAS and candidate gene studies depends on concerted efforts in data production, online publication, database development, and continuously updated data synthesis. Here the authors summarize current experience and challenges on these fronts, which were discussed at a 2008 multidisciplinary workshop sponsored by the Human Genome Epidemiology Network. Comprehensive field synopses that integrate many reported gene-disease associations have been systematically developed for several fields, including Alzheimers disease, schizophrenia, bladder cancer, coronary heart disease, preterm birth, and DNA repair genes in various cancers. The authors summarize insights from these field synopses and discuss remaining unresolved issues—especially in the light of evidence from GWAS, for which they summarize empirical P-value and effect-size data on 223 discovered associations for binary outcomes (142 with P < 10−7). They also present a vision of collaboration that builds reliable cumulative evidence for genetic associations with common complex diseases and a transparent, distributed, authoritative knowledge base on genetic variation and human health. As a next step in the evolution of Human Genome Epidemiology reviews, the authors invite investigators to submit field synopses for possible publication in the American Journal of Epidemiology.

A comparison of the Fagerström Test for Nicotine Dependence and smoking prevalence across countries

AIMS To examine the correlation between the Fagerström Test for Nicotine Dependence (FTND) score and smoking prevalence across countries. DESIGN Cross-sectional study. SETTING Fifteen studies from 13 countries with FTND score data. PARTICIPANTS Samples of smokers were identified through systematic literature searches, web queries and colleagues. Smokers were considered representative of their countrys smoking population if they were drawn from population-based sources, were not seeking smoking cessation treatment and did not have significant comorbidities. Smoking prevalence data were derived from the study itself or the countrys population rate of daily smoking for the study year. MEASUREMENTS A Pearson correlation coefficient was used to examine the direction and magnitude of the correlation between FTND score and smoking prevalence across countries. FINDINGS FTND scores ranged from 2.8 to 4.6. Smokers in Germany and Norway had the lowest FTND scores, while smokers in Sweden and the United States had the highest FTND scores. The prevalence of daily smoking in these countries was very different: 37% and 30% in Germany and Norway, 19% and 16% in the United States and Sweden, respectively. An inverse correlation towards higher FTND scores in countries with lower smoking prevalence was found (r=-0.73, P=0.001). Current smokers had higher FTND scores than former smokers. CONCLUSIONS The significant inverse correlation between FTND score and smoking prevalence across countries and higher FTND score among current smokers supports the idea that remaining smokers may be hardening. Less dependent smokers may quit more easily and remaining dependent smokers may need more intensive treatment.

Feeling Bad in More Ways than One: Comorbidity Patterns of Medically Unexplained and Psychiatric Conditions

BackgroundConsiderable overlap in symptoms and disease comorbidity has been noted among medically unexplained and psychiatric conditions seen in the primary care setting, such as chronic fatigue syndrome, low back pain, irritable bowel syndrome, chronic tension headache, fibromyalgia, temporomandibular joint disorder, major depression, panic attacks, and posttraumatic stress disorder.ObjectiveTo examine interrelationships among these 9 conditions.DesignUsing data from a cross-sectional survey, we described associations and used latent class analysis to investigate complex interrelationships.Participants3,982 twins from the University of Washington Twin Registry.MeasurementsTwins self-reported a doctor’s diagnosis of the conditions.ResultsComorbidity among these 9 conditions far exceeded chance expectations; 31 of 36 associations were significant. Latent class analysis yielded a 4-class solution. Class I (2% prevalence) had high frequencies of each of the 9 conditions. Class II (8% prevalence) had high proportions of multiple psychiatric diagnoses. Class III (17% prevalence) participants reported high proportions of depression, low back pain, and headache. Participants in class IV (73% prevalence) were generally healthy. Class I participants had the poorest markers of health status.ConclusionsThese results support theories suggesting that medically unexplained conditions share a common etiology. Understanding patterns of comorbidity can help clinicians care for challenging patients.

Tumor characteristics in African American and white women

AbstractBackground. Previous studies provide evidence that breast cancers occurring in different age and ethnic groups are not evenly distributed with regard to their biologic, pathologic and clinical characteristics. We evaluated the distributions of 11 pathological and biological variables between African-American (AA) and white patients and between three different age groups (20–39, 40–59 and 60–74 years). We examined whether racial differences existed across levels of age. Methods. Data were obtained from the Carolina Breast Cancer Study (CBCS), a population-based, case-control study of breast cancer in North Carolina. Eighty hundred and sixty one women with a first diagnosis of invasive breast cancer participated in Phase I of the CBCS. Diagnostic paraffin blocks were obtained from 807 cases. One representative block was scored for histologic type and grade (architectural, nuclear, mitotic and overall). Medical chart review yielded tumor size, lymph node status, distant metastases, stage, hormone receptor status (ER/PR) and DNA ploidy. Results. Pathologically advanced tumors (large size, high grade, high stage, ER/PR negative) were significantly more common in young and AA women. Racial differences varied by age. Among younger, AAs whites differed only with respect to ER/PR status, while among older women AAs and whites differed only with respect to stage at diagnosis. Conclusions. The results of this study confirm the presence of poorer prognosis breast cancer among AA and younger women. They also highlight the need for age and race to be considered together when evaluating pathologic and biologic characteristics of disease and when making inferences regarding tumor aggressiveness.

An Epidemiologic and Genomic Investigation Into the Obesity Paradox in Renal Cell Carcinoma

BACKGROUND Obesity increases risk for clear-cell renal cell carcinoma (ccRCC), yet obese patients appear to experience longer survival than nonobese patients. We examined body mass index (BMI) in relation to stage, grade, and cancer-specific mortality (CSM) while considering detection bias, nutritional status, and molecular tumor features. METHODS Data were available from 2119 ccRCC patients who underwent renal mass surgery at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Logistic regression models produced associations between BMI and advanced disease. Multivariable competing risks regression models estimated associations between BMI and CSM. Somatic mutation, copy number, methylation, and expression data were examined by BMI among a subset of 126 patients who participated in the Cancer Genome Atlas Project for ccRCC using the Kruskal-Wallis or Fisher exact tests. All statistical tests were two-sided. RESULTS Obese and overweight patients were less likely to present with advanced-stage disease compared with normal-weight patients (odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.48 to 0.79 vs OR = 0.65, 95% CI = 0.51 to 0.83, respectively). Higher BMI was associated with reduced CSM in univariable analyses (P < .005). It remained statistically significant after adjustment for comorbidities and albumin level, but it became non-statistically significant after adjusting for stage and grade (P > .10). Genome-wide interrogation by BMI suggested differences in gene expression of metabolic and fatty acid genes, including fatty acid synthase (FASN), consistent with the obesity paradox. CONCLUSIONS Our findings suggest that although BMI is not an independent prognostic factor for CSM after controlling for stage and grade, tumors developing in an obesogenic environment may be more indolent.

Genome-wide meta-analyses of smoking behaviors in African Americans

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n=32 389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β=0.040, s.e.=0.007, P=1.84 × 10−8). This variant is present in the 5′-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

Impact of Smoking and Smoking Cessation on Oncologic Outcomes in Primary Non–muscle-invasive Bladder Cancer

BACKGROUND Cigarette smoking is the best-established risk factor for urothelial carcinoma (UC) development, but the impact on oncologic outcomes remains poorly understood. OBJECTIVE To analyse the effects of smoking status, cumulative exposure, and time from smoking cessation on the prognosis of patients with primary non-muscle-invasive bladder cancer (NMIBC). DESIGN, SETTING, AND PARTICIPANTS We collected smoking data from 2043 patients with primary NMIBC. Smoking variables included smoking status, average number of cigarettes smoked per day (CPD), duration in years, and time since smoking cessation. Lifetime cumulative smoking exposure was categorised as light short term (≤ 19 CPD, ≤ 19.9 yr), light long term (≤ 19 CPD, ≥ 20 yr), heavy short term (≥ 20 CPD, ≤ 19.9 yr) and heavy long term (≥ 20 CPD, ≥ 20 yr). The median follow-up in this retrospective study was 49 mo. INTERVENTIONS Transurethral resection of the bladder with or without intravesical instillation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Univariable and multivariable logistic regression and competing risk regression analyses assessed the effects of smoking on outcomes. RESULTS AND LIMITATIONS There was no difference in clinicopathologic factors among never (24%), former (47%), and current smokers (29%). Smoking status was associated with the cumulative incidence of disease progression in multivariable analysis (p=0.003); current smokers had the highest cumulative incidences. Among current and former smokers, cumulative smoking exposure was associated with disease recurrence (p<0.001), progression (p<0.001), and overall survival (p<0.001) in multivariable analyses that adjusted for the effects of standard clinicopathologic factors and smoking status; heavy long-term smokers had the worst outcomes, followed by light long-term, heavy short-term, and light short-term smokers. Smoking cessation >10 yr reduced the risk of disease recurrence (hazard ratio [HR]: 0.66; 95% confidence interval [CI], 0.52-0.84; p<0.001) and progression (HR: 0.42; 95% CI, 0.22-0.83; p=0.036) in multivariable analyses. The study is limited by its retrospective nature. CONCLUSIONS Smoking status and a higher cumulative smoking exposure are associated with worse prognosis in patients with NMIBC. Smoking cessation >10 yr abrogates this detrimental effect. These findings underscore the need for integrated smoking cessation and prevention programmes in the management of NMIBC patients.

Is Swedish snus associated with smoking initiation or smoking cessation

Nicotine replacement therapies (NRT) are an effective treatment for tobacco dependence, yet most smokers do not quit or remain abstinent. We investigated whether Swedish snus (snuff) use was associated with smoking cessation among males participating in a large population based twin study in Sweden. Snus use was associated with smoking cessation but not initiation. Given that snus delivers comparable nicotine concentrations but carries lesser cancer risk than cigarettes, snus may be a widely used, non-medical form of NRT. Evaluation of the efficacy of snus for smoking cessation should be evaluated in randomised clinical trials.

Conducting Molecular Epidemiological Research in the Age of HIPAA: A Multi-Institutional Case-Control Study of Breast Cancer in African-American and European-American Women

Breast cancer in African-American (AA) women occurs at an earlier age than in European-American (EA) women and is more likely to have aggressive features associated with poorer prognosis, such as high-grade and negative estrogen receptor (ER) status. The mechanisms underlying these differences are unknown. To address this, we conducted a case-control study to evaluate risk factors for high-grade ER- disease in both AA and EA women. With the onset of the Health Insurance Portability and Accountability Act of 1996, creative measures were needed to adapt case ascertainment and contact procedures to this new environment of patient privacy. In this paper, we report on our approach to establishing a multicenter study of breast cancer in New York and New Jersey, provide preliminary distributions of demographic and pathologic characteristics among case and control participants by race, and contrast participation rates by approaches to case ascertainment, with discussion of strengths and weaknesses.