Lack of Association of a Functional Polymorphism in the Serotonin Receptor Gene With Body Mass Index and Depressive Symptoms in a Large Meta-Analysis of Population Based Studies.
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2018-01
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Abstract
The serotonin receptor 5-HTR2C is thought to be involved in the function of multiple brain structures. Consequently, the HTR2C gene has been studied extensively with respect to its association with a variety of phenotypes. One coding variant in the HTR2C gene, Cys23Ser (rs6318), has been associated with depressive symptoms. and adiposity; however, these findings have been inconsistent. The reasons for this mixed picture may be due to low statistical power or due to other factors such as failure to account for possible interacting environmental factors, such as psychosocial stress. Further, the literature around this polymorphism is marked by limited inclusion of persons of African ancestry. The present study sought to overcome these limitations and definitively determine the relationship of this polymorphism with depressive and obesity phenotypes in a large sample meta-analysis. Thus, we harmonized individual level data from 10 studies including the Women's Health Initiative, CARDIA, ARIC, Framingham Offspring, and the Jackson Heart Study, resulting in a sample of 27,161 individuals (10,457 Black women, 2,819 Black men, 7,419 White women, and 6,466 White men). We conducted a random effects meta-analysis using individual level data to examine whether the Cys23Ser variant-either directly, or conditionally depending on the level of psychosocial stress-was associated with depressive symptoms and body mass index (BMI). We found that psychosocial stress was associated with both depression and BMI, but that Cys23Ser was not directly associated with, nor did it modify the associations of psychosocial stress with depression or BMI. Thus, in the largest study of this polymorphism, we have determined that rs6318 is not associated with depression, or BMI.
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Brummett, Beverly H, Michael A Babyak, Abanish Singh, Elizabeth R Hauser, Rong Jiang, Kim M Huffman, William E Kraus, Svati H Shah, et al. (2018). Lack of Association of a Functional Polymorphism in the Serotonin Receptor Gene With Body Mass Index and Depressive Symptoms in a Large Meta-Analysis of Population Based Studies. Frontiers in genetics, 9(OCT). p. 423. 10.3389/fgene.2018.00423 Retrieved from https://hdl.handle.net/10161/26765.
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Scholars@Duke
Beverly H. Brummett
In the early part of my career, my work generally focused on examining psychosocial determinants or correlates (e.g., emotion, personality, and socioeconomic status) of cardiovascular disease. However, in the past several years, my work has also expanded to include examining how stressful emotional responses, combined with proposed genetic markers, influence metabolic functioning, cognitive decline, functional capacity and quality of live in the elderly, depressive symptomology, and major depressive disorder. I also have an interest in statistical methodology.
Michael Alan Babyak
Since coming to Duke as an intern in 1994 I have collaborated as a biostatistician and co-investigator at Duke on numerous observational and experimental studies involving behavior, psychosocial factors, health, and disease. The substantive topics have ranged across questions concerning exercise and depression, hypertension, weight loss, the genetics of stress and heart disease, sickle cell disease, to name a few. I am particularly interested in the issue of improving reproducibility and transparency in data analysis.
Abanish Singh
With a unique skill set resulting from outstanding training, my sole aim was to help improve human health through cutting-edge translational research. Specifically, I have been interested in illuminating the mechanisms responsible for the causes and progression of the leading public health conditions, which may help with the development and enhancement of precision medicine. As part of this endeavor, I also became interested in studying the measurement of biobehavioral risk factors and environmental stressors and their interactions with genes that may influence cardiovascular disease (CVD) risk factors and endophenotypes, adversely affecting the CVD pathways.
I joined medical research with my early research training on computational biology, high-throughput genomics, next-gen DNA sequencing, genome-wide studies, and big data analytics, which resulted in some of prominent findings on human genome (PMID: 18048317, PMID: 20223737, PMID: 20598109, PMID: 21703177). These findings included a significant contribution to the scientific community’s understanding that I made during my postdoctoral fellowship with Dr. David Goldstein at Duke Center for Human Genome Variation that how well RNA-Seq can identify human coding variants just using a small fraction of genome (transcriptome) as compared to whole genome (PMID: 20598109). This work was important not only scientifically, but also in pragmatic terms, given the high cost of sequencing.
In relatively recent work I discovered a novel CVD risk gene EBF1, where a common genetic variant contributed to inter-individual differences in human central obesity, fasting blood glucose, diabetes, and CVD risk factors in the presence of chronic psychosocial stress (PMID: 25271088). This work demonstrated the genetic variant-specific significant path from chronic psychosocial stress to common carotid intimal–media thickness (CCIMT), a surrogate marker for atherosclerosis, via central obesity and fasting glucose. I also developed an algorithm to create a synthetic measure of stress using the proxy indicators of its components (PMID: 26202568). Other more recent work has elucidated the race, sex, and age related differences in the EBF1 gene-by-stress interaction (PMID: 33077726), which suggests the need for careful evaluation of environmental measures in different ethnicities in cross-ethnic gene-by-stress interaction studies.
More recently, I have expanded my research interest in studying the genetic architecture of Alzheimer’s disease (AD) and the role of psychosocial stress in modifying the effect of genetic variants on the disease risks.
Elizabeth Rebecca Hauser
The incorporation of personalized medicine to all areas of human health represents a turning point for human genetics studies, a point at which the discoveries made have real implications for clinical medicine. It is important for students to gain experience in how human genetics studies are conducted and how results of those studies may be used. As a statistical geneticist and biostatistician my research interests are focused on developing and applying statistical methods to search for genes causing common human diseases. My research programs combine development and application of statistical methods for genetic studies, with a particular emphasis on understanding the joint effects of genes and environment.
These studies I work on cover diverse areas in biomedicine but are always collaborative, with the goal of bringing robust data science and statistical methods to the project. Collaborative studies include genetic and ‘omics studies of cardiovascular disease, health effects of air pollution, genetic analysis of adherence to an exercise program, genetic analysis in evaluating colon cancer risk, genetic analysis of suicide, and systems biology analysis of Gulf War Illness.
Keywords: human genetics, genetic association, gene mapping, genetic epidemiology, statistical genetics, biostatistics, cardiovascular disease, computational biology, diabetes, aging, colon cancer, colon polyps, kidney disease, Gulf War Illness, exercise behavior, suicide
Rong Jiang
Kim Marie Huffman
Determining the role of physical activity in modulating health outcomes (cardiovascular disease risk) in persons with rheumatologic diseases (rheumatoid arthritis, gout, osteoarthritis)
Integrating clinical rheumatology, basic immunology, metabolism, and exercise science in order to reduce morbidity in individuals with arthritis
Evaluating relationships between circulating and intra-muscular metabolic intermediates and insulin resistance in sedentary as well as individuals engaging in regular exercise
Addressing the role of physical activity in modulating inflammation, metabolism, and functional health in aging populations
William Erle Kraus
My training, expertise and research interests range from human integrative physiology and genetics to animal exercise models to cell culture models of skeletal muscle adaptation to mechanical stretch. I am trained clinically as an internist and preventive cardiologist, with particular expertise in preventive cardiology and cardiac rehabilitation. My research training spans molecular biology and cell culture, molecular genetics, and integrative human exercise physiology and metabolism. I practice as a preventive cardiologist with a focus on cardiometabolic risk and exercise physiology for older athletes. My research space has both a basic wet laboratory component and a human integrative physiology one.
One focus of our work is an integrative physiologic examination of exercise effects in human subjects in clinical studies of exercise training in normal individuals, in individuals at risk of disease (such as pre-diabetes and metabolic syndrome; STRRIDE), and in individuals with disease (such as coronary heart disease, congestive heart failure and cancer).
A second focus of my research group is exploration of genetic determinates of disease risk in human subjects. We conduct studies of early onset cardiovascular disease (GENECARD; CATHGEN), congestive heart failure (HF-ACTION), peripheral arterial disease (AMNESTI), and metabolic syndrome. We are exploring analytic models of predicting disease risk using established and innovative statistical methodology.
A third focus of my group’s work is to understand the cellular signaling mechanisms underlying the normal adaptive responses of skeletal muscle to physiologic stimuli, such as occur in exercise conditioning, and to understand the abnormal maladaptive responses that occur in response to pathophysiologic stimuli, such as occur in congestive heart failure, aging and prolonged exposure to microgravity.
Recently we have begun to investigate interactions of genes and lifestyle interventions on cardiometabolic outcomes. We have experience with clinical lifestyle intervention studies, particularly the contributions of genetic variants to interventions responses. We call this Lifestyle Medicopharmacogenetics.
KEY WORDS:
exercise, skeletal muscle, energy metabolism, cell signaling, gene expression, cell stretch, heart failure, aging, spaceflight, human genetics, early onset cardiovascular disease, lifestyle medicine
Svati Hasmukh Shah
Ilene C. Siegler
My research efforts are in the area of developmental health psychology and organized around understanding the role of personality in health and disease in middle and later life.
My primary research activity is as Principal Investigator of the UNC Alumni Heart Study (UNCAHS) a prospective epidemiologic study of 5000 middle aged men and women and 1200 of their spouses that evaluates the role of personality on coronary heart disease and coronary heart disease risk, cancer, and normal aging.
As head of Cancer Prevention Research Unit , I study the role of psychological factors related to mammography behavior and estrogen replacement therapy is being studied in UNCAHS women.
REPRESENTATIVE PUBLICATIONS
Siegler, I.C., Zonderman, A.B., Barefoot, J.C., Williams, R.B., Jr., Costa, P.T., Jr., & McCrae, R. R. (1990). Predicting personality from college MMPI scores: Implications for follow-up studies in psychosomatic medicine. Psychosomatic Medicine, 52, 644-652.
Siegler, I.C., Peterson, B.L., Barefoot, J.C., & Williams, R.B. (1992). Hostility during late adolescence predicts coronary risk factors at midlife. American Journal of Epidemiology, 138(2), 146-154.
Siegler, I.C., Peterson, B.L., Barefoot, J.C., Harvin, S.H. Dahlstrom, W.G., Kaplan, B.H., Costa, P.T. Jr., & Williams, R.B. (1992). Using college alumni populations in epidemiologic research: The UNC Alumni Heart Study. Journal of Clinical Epidemiology, 45(11), 1243-1250.
Siegler, I.C., Dawson, D.V., & Welsh, K.A. (1994). Caregiver ratings of personality change in Alzheimer's disease patients: A replication. Psychology and Aging, 9, 464-466.
Siegler, I.C., Feaganes, J.R., & Rimer, B.K. (1995). Predictors of adoption of mammography in women under age 50. Health Psychology, 14, 274-278.
1/13/99
Redford B. Williams
My research aims to identify psychosocial factors that are involved in the pathogenesis and course of major medical disorders, to characterize the biobehavioral mechanisms whereby such factors influence disease, and to develop both behavioral and pharmacologic means of preventing or ameliorating the adverse impact of psychosocial factors on health and disease. Specific projects that are currently active include: 1) The influence of hostile personality, social isolation, depression and other psychosocial risk factors upon the development and course of cardiometabolic disease; 2) Biological and genetic mechanisms whereby psychosocial risk factors influence disease development and course; and 3) Behavioral and pharmacologic approaches to ameliorate impact of psychosocial risk factors on disease risk and course.
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