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Walter, Stefan

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Walter

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Stefan

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Walter, Stefan
Author's Publications: search.filters.isAuthorOfPublication.6bcbc14c-a267-4bcd-ad89-bb401ea4a8c1

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    Performance of Polygenic Scores for Predicting Phobic Anxiety
    (Public Library of Science, 2013) Walter, Stefan; Glymour, M. Maria; Koenen, Karestan; Liang, Liming; Tchetgen Tchetgen, Eric; Cornelis, Marilyn; Chang, Shun-Chiao; Rimm, Eric; Kawachi, Ichiro; Kubzansky, Laura
    Context Anxiety disorders are common, with a lifetime prevalence of 20% in the U.S., and are responsible for substantial burdens of disability, missed work days and health care utilization. To date, no causal genetic variants have been identified for anxiety, anxiety disorders, or related traits. Objective: To investigate whether a phobic anxiety symptom score was associated with 3 alternative polygenic risk scores, derived from external genome-wide association studies of anxiety, an internally estimated agnostic polygenic score, or previously identified candidate genes. Design: Longitudinal follow-up study. Using linear and logistic regression we investigated whether phobic anxiety was associated with polygenic risk scores derived from internal, leave-one out genome-wide association studies, from 31 candidate genes, and from out-of-sample genome-wide association weights previously shown to predict depression and anxiety in another cohort. Setting and Participants: Study participants (n = 11,127) were individuals from the Nurses' Health Study and Health Professionals Follow-up Study. Main Outcome Measure: Anxiety symptoms were assessed via the 8-item phobic anxiety scale of the Crown Crisp Index at two time points, from which a continuous phenotype score was derived. Results: We found no genome-wide significant associations with phobic anxiety. Phobic anxiety was also not associated with a polygenic risk score derived from the genome-wide association study beta weights using liberal p-value thresholds; with a previously published genome-wide polygenic score; or with a candidate gene risk score based on 31 genes previously hypothesized to predict anxiety. Conclusion: There is a substantial gap between twin-study heritability estimates of anxiety disorders ranging between 20–40% and heritability explained by genome-wide association results. New approaches such as improved genome imputations, application of gene expression and biological pathways information, and incorporating social or environmental modifiers of genetic risks may be necessary to identify significant genetic predictors of anxiety.
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    Genome-wide polygenic scoring for a 14-year long-term average depression phenotype
    (Wiley Periodicals, Inc., 2014) Chang, Shun-Chiao; Glymour, M Maria; Walter, Stefan; Liang, Liming; Koenen, Karestan C; Tchetgen, Eric J; Cornelis, Marilyn; Kawachi, Ichiro; Rimm, Eric; Kubzansky, Laura
    Background: Despite moderate heritability estimates for depression-related phenotypes, few robust genetic predictors have been identified. Potential explanations for this discrepancy include the use of phenotypic measures taken from a single time point, rather than integrating information over longer time periods via multiple assessments, and the possibility that genetic risk is shaped by multiple loci with small effects. Methods: We developed a 14-year long-term average depression measure based on 14 years of follow-up in the Nurses' Health Study (NHS; N = 6989 women). We estimated polygenic scores (PS) with internal whole-genome scoring (NHS-GWAS-PS). We also constructed PS by applying two external PS weighting algorithms from independent samples, one previously shown to predict depression (GAIN-MDD-PS) and another from the largest genome-wide analysis currently available (PGC-MDD-PS). We assessed the association of all three PS with our long-term average depression phenotype using linear, logistic, and quantile regressions. Results: In this study, the three PS approaches explained at most 0.2% of variance in the long-term average phenotype. Quantile regressions indicated PS had larger impacts at higher quantiles of depressive symptoms. Quantile regression coefficients at the 75th percentile were at least 40% larger than at the 25th percentile in all three polygenic scoring algorithms. The interquartile range comparison suggested the effects of PS significantly differed at the 25th and 75th percentiles of the long-term depressive phenotype for the PGC-MDD-PS (P = 0.03), and this difference also reached borderline statistical significance for the GAIN-MDD-PS (P = 0.05). Conclusions: Integrating multiple phenotype assessments spanning 14 years and applying different polygenic scoring approaches did not substantially improve genetic prediction of depression. Quantile regressions suggested the effects of PS may be largest at high quantiles of depressive symptom scores, presumably among people with additional, unobserved sources of vulnerability to depression.
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    Common Genetic Variation at the IL1RL1 Locus Regulates IL-33/ST2 Signaling
    (American Society for Clinical Investigation, 2013) Ho, Jennifer E.; Chen, Wei-Yu; Chen, Ming-Huei; Larson, Martin G.; McCabe, Elizabeth L.; Cheng, Susan; Ghorbani, Anahita; Coglianese, Erin; Emilsson, Valur; Johnson, Andrew D.; Walter, Stefan; Franceschini, Nora; O'Donnell, Christopher; Dehghan, Abbas; Lu, Chen; Levy, Daniel; Newton-Cheh, Christopher; Lin, Honghuang; Felix, Janine F.; Schreiter, Eric R.; Vasan, Ramachandran S.; Januzzi, James; Lee, Richard; Wang, Thomas Jue-Fuu
    The suppression of tumorigenicity 2/IL-33 (ST2/IL-33) pathway has been implicated in several immune and inflammatory diseases. ST2 is produced as 2 isoforms. The membrane-bound isoform (ST2L) induces an immune response when bound to its ligand, IL-33. The other isoform is a soluble protein (sST2) that is thought to be a decoy receptor for IL-33 signaling. Elevated sST2 levels in serum are associated with an increased risk for cardiovascular disease. We investigated the determinants of sST2 plasma concentrations in 2,991 Framingham Offspring Cohort participants. While clinical and environmental factors explained some variation in sST2 levels, much of the variation in sST2 production was driven by genetic factors. In a genome-wide association study (GWAS), multiple SNPs within IL1RL1 (the gene encoding ST2) demonstrated associations with sST2 concentrations. Five missense variants of IL1RL1 correlated with higher sST2 levels in the GWAS and mapped to the intracellular domain of ST2, which is absent in sST2. In a cell culture model, IL1RL1 missense variants increased sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness (via ST2L). Our data suggest that genetic variation in IL1RL1 can result in increased levels of sST2 and alter immune and inflammatory signaling through the ST2/IL-33 pathway.
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    Social Integration and Reduced Risk of Coronary Heart Disease in WomenNovelty and Significance
    (Ovid Technologies (Wolters Kluwer Health), 2017) Chang, Shun-Chiao; Glymour, Maria; Cornelis, Marilyn; Walter, Stefan; Rimm, Eric; Tchetgen Tchetgen, Eric; Kawachi, Ichiro; Kubzansky, Laura
    RATIONALE: Higher social integration is associated with lower cardiovascular mortality; however, whether it is associated with incident coronary heart disease (CHD), especially in women, and whether associations differ by case fatality are unclear. OBJECTIVES: This study sought to examine the associations between social integration and risk of incident CHD in a large female prospective cohort. METHODS AND RESULTS: Seventy-six thousand three hundred and sixty-two women in the Nurses' Health Study, free of CHD and stroke at baseline (1992), were followed until 2014. Social integration was assessed by a simplified Berkman-Syme Social Network Index every 4 years. End points included nonfatal myocardial infarction and fatal CHD. Two thousand three hundred and seventy-two incident CHD events occurred throughout follow-up. Adjusting for demographic, health/medical risk factors, and depressive symptoms, being socially integrated was significantly associated with lower CHD risk, particularly fatal CHD. The most socially integrated women had a hazard ratio of 0.55 (95% confidence interval, 0.41-0.73) of developing fatal CHD compared with those least socially integrated (P for trend <0.0001). When additionally adjusting for lifestyle behaviors, findings for fatal CHD were maintained but attenuated (P for trend =0.02), whereas the significant associations no longer remained for nonfatal myocardial infarction. The inverse associations between social integration and nonfatal myocardial infarction risk were largely explained by health-promoting behaviors, particularly through differences in cigarette smoking; however, the association with fatal CHD risk remained after accounting for these behaviors and, thus, may involve more direct biological mechanisms. CONCLUSIONS: Social integration is inversely associated with CHD incidence in women, but is largely explained by lifestyle/behavioral pathways.
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    Changes in Depressive Symptoms and Incidence of First Stroke Among Middle-Aged and Older US Adults
    (Wiley Blackwell, 2015) Gilsanz, Paola; Walter, Stefan; Tchetgen, Eric; Patton, Kristen; Moon, James; Capistrant, Benjamin; Marden, Jessica Rachel; Kubzansky, Laura D; Kawachi, Ichiro; Glymour, Maria
    BACKGROUND: Although research has demonstrated that depressive symptoms predict stroke incidence, depressive symptoms are dynamic. It is unclear whether stroke risk persists if depressive symptoms remit. METHODS AND RESULTS: Health and Retirement Study participants (n=16 178, stroke free and noninstitutionalized at baseline) were interviewed biennially from 1998 to 2010. Stroke and depressive symptoms were assessed through self-report of doctors' diagnoses and a modified Center for Epidemiologic Studies - Depression scale (high was ≥3 symptoms), respectively. We examined whether depressive symptom patterns, characterized across 2 successive interviews (stable low/no, onset, remitted, or stable high depressive symptoms) predicted incident stroke (1192 events) during the subsequent 2 years. We used marginal structural Cox proportional hazards models adjusted for demographics, health behaviors, chronic conditions, and attrition. We also estimated effects stratified by age (≥65 years), race or ethnicity (non-Hispanic white, non-Hispanic black, Hispanic), and sex. Stroke hazard was elevated among participants with stable high (adjusted hazard ratio 2.14, 95% CI 1.69 to 2.71) or remitted (adjusted hazard ratio 1.66, 95% CI 1.22 to 2.26) depressive symptoms compared with participants with stable low/no depressive symptoms. Stable high depressive symptom predicted stroke among all subgroups. Remitted depressive symptoms predicted increased stroke hazard among women (adjusted hazard ratio 1.86, 95% CI 1.30 to 2.66) and non-Hispanic white participants (adjusted hazard ratio 1.66, 95% CI 1.18 to 2.33) and was marginally associated among Hispanics (adjusted hazard ratio 2.36, 95% CI 0.98 to 5.67). CONCLUSIONS:In this cohort, persistently high depressive symptoms were associated with increased stroke risk. Risk remained elevated even if depressive symptoms remitted over a 2-year period, suggesting cumulative etiologic mechanisms linking depression and stroke.