138 results on '"KLIMENTIDIS, YANN C."'
Search Results
102. A Comprehensive Genetic Approach for Improving Prediction of Skin Cancer Risk in Humans
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Vazquez, Ana I, primary, de los Campos, Gustavo, additional, Klimentidis, Yann C, additional, Rosa, Guilherme J M, additional, Gianola, Daniel, additional, Yi, Nengjun, additional, and Allison, David B, additional
- Published
- 2012
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103. Prediction of Expected Years of Life Using Whole-Genome Markers
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de los Campos, Gustavo, primary, Klimentidis, Yann C., additional, Vazquez, Ana I., additional, and Allison, David B., additional
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- 2012
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104. On the Limits of Diversity
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Klimentidis, Yann C., primary
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- 2012
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105. OPRM1 and EGFR contribute to skin pigmentation differences between Indigenous Americans and Europeans
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Quillen, Ellen E., primary, Bauchet, Marc, additional, Bigham, Abigail W., additional, Delgado-Burbano, Miguel E., additional, Faust, Franz X., additional, Klimentidis, Yann C., additional, Mao, Xianyun, additional, Stoneking, Mark, additional, and Shriver, Mark D., additional
- Published
- 2011
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106. Indigenous American Ancestry is Associated with Arsenic Methylation Efficiency in an Admixed Population of Northwest Mexico
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Gomez-Rubio, Paulina, primary, Klimentidis, Yann C., additional, Cantu-Soto, Ernesto, additional, Meza-Montenegro, Maria M., additional, Billheimer, Dean, additional, Lu, Zhenqiang, additional, Chen, Zhao, additional, and Klimecki, Walter T., additional
- Published
- 2011
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107. Associations of Obesity Genes with Obesity-related Outcomes in Multiethnic Children
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Klimentidis, Yann C., primary, Chen, Guo-Bo, additional, López-Alarcón, Mardia, additional, Harris, Jacqueline J., additional, Duarte, Christine W., additional, and Fernández, José R., additional
- Published
- 2011
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108. Natural selection among Eurasians at genomic regions associated with HIV-1 control
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Klimentidis, Yann C, primary, Aissani, Brahim, additional, Shriver, Mark D, additional, Allison, David B, additional, and Shrestha, Sadeep, additional
- Published
- 2011
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109. Beyond Missing Heritability: Prediction of Complex Traits
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Makowsky, Robert, primary, Pajewski, Nicholas M., additional, Klimentidis, Yann C., additional, Vazquez, Ana I., additional, Duarte, Christine W., additional, Allison, David B., additional, and de los Campos, Gustavo, additional
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- 2011
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110. Natural selection at genomic regions associated with obesity and type-2 diabetes: East Asians and sub-Saharan Africans exhibit high levels of differentiation at type-2 diabetes regions
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Klimentidis, Yann C., primary, Abrams, Marshall, additional, Wang, Jelai, additional, Fernandez, Jose R., additional, and Allison, David B., additional
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- 2010
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111. Canaries in the coal mine: a cross-species analysis of the plurality of obesity epidemics
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Klimentidis, Yann C., primary, Beasley, T. Mark, additional, Lin, Hui-Yi, additional, Murati, Giulianna, additional, Glass, Gregory E., additional, Guyton, Marcus, additional, Newton, Wendy, additional, Jorgensen, Matthew, additional, Heymsfield, Steven B., additional, Kemnitz, Joseph, additional, Fairbanks, Lynn, additional, and Allison, David B., additional
- Published
- 2010
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112. A Conserved Role for Syndecan Family Members in the Regulation of Whole-Body Energy Metabolism
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De Luca, Maria, primary, Klimentidis, Yann C., additional, Casazza, Krista, additional, Moses Chambers, Michelle, additional, Cho, Ruth, additional, Harbison, Susan T., additional, Jumbo-Lucioni, Patricia, additional, Zhang, Shaoyan, additional, Leips, Jeff, additional, and Fernandez, Jose R., additional
- Published
- 2010
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113. High Viremia Is Associated with High Levels of In Vivo Major Histocompatibility Complex Class I Downregulation in Rhesus Macaques Infected with Simian Immunodeficiency Virus SIVmac239
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Friedrich, Thomas C., primary, Piaskowski, Shari M., additional, León, Enrique J., additional, Furlott, Jessica R., additional, Maness, Nicholas J., additional, Weisgrau, Kimberly L., additional, Mac Nair, Caitlin E., additional, Weiler, Andrea M., additional, Loffredo, John T., additional, Reynolds, Matthew R., additional, Williams, K. Y., additional, Klimentidis, Yann C., additional, Wilson, Nancy A., additional, Allison, David B., additional, and Rakasz, Eva G., additional
- Published
- 2010
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114. T-Cell Correlates of Vaccine Efficacy after a Heterologous Simian Immunodeficiency Virus Challenge
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Martins, Mauricio A., primary, Wilson, Nancy A., additional, Reed, Jason S., additional, Ahn, Chanook D., additional, Klimentidis, Yann C., additional, Allison, David B., additional, and Watkins, David I., additional
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- 2010
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115. Infection with “Escaped” Virus Variants Impairs Control of Simian Immunodeficiency Virus SIVmac239 Replication in Mamu-B*08 -Positive Macaques
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Valentine, Laura E., primary, Loffredo, John T., additional, Bean, Alex T., additional, León, Enrique J., additional, MacNair, Caitlin E., additional, Beal, Dominic R., additional, Piaskowski, Shari M., additional, Klimentidis, Yann C., additional, Lank, Simon M., additional, Wiseman, Roger W., additional, Weinfurter, Jason T., additional, May, Gemma E., additional, Rakasz, Eva G., additional, Wilson, Nancy A., additional, Friedrich, Thomas C., additional, O'Connor, David H., additional, Allison, David B., additional, and Watkins, David I., additional
- Published
- 2009
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116. Estimating Genetic Ancestry Proportions from Faces
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Klimentidis, Yann C., primary and Shriver, Mark D., additional
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- 2009
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117. Genetic admixture, self‐reported ethnicity, self‐estimated admixture, and skin pigmentation among Hispanics and Native Americans
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Klimentidis, Yann C., primary, Miller, Geoffrey F., additional, and Shriver, Mark D., additional
- Published
- 2008
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118. Integrated genomic and BMI analysis for type 2 diabetes risk assessment.
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Lebrón-Aldea, Dayanara, Dhurandhar, Emily J., Pérez-Rodríguez, Paulino, Klimentidis, Yann C., Tiwari, Hemant K., and Vazquez, Ana I.
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GENETICS of type 2 diabetes ,GENOMICS ,INSULIN ,OBESITY ,PREVENTIVE medicine - Abstract
Type 2 Diabetes (T2D) is a chronic disease arising from the development of insulin absence or resistance within the body, and a complex interplay of environmental and genetic factors. The incidence of T2D has increased throughout the last few decades, together with the occurrence of the obesity epidemic. The consideration of variants identified by GenomeWide Association Studies (GWAS) into risk assessment models for T2D could aid in the identification of at-risk patients who could benefit from preventive medicine. In this study, we build several risk assessment models, evaluated with two different classification approaches (Logistic Regression and Neural Networks), to measure the effect of including genetic information in the prediction of T2D. We used data from to the Original and the Offspring cohorts of the Framingham Heart Study, which provides phenotypic and genetic information for 5245 subjects (4306 controls and 939 cases). Models were built by using several covariates: gender, exposure time, cohort, body mass index (BMI), and 65 SNPs associated to T2D. We fitted Logistic Regressions and Bayesian Regularized Neural Networks and then assessed their predictive ability by using a ten-fold cross validation. We found that the inclusion of genetic information into the risk assessment models increased the predictive ability by 2%, when compared to the baseline model. Furthermore, the models that included BMI at the onset of diabetes as a possible effector, gave an improvement of 6% in the area under the curve derived from the ROC analysis. The highest AUC achieved (0.75) belonged to the model that included BMI, and a genetic score based on the 65 established T2D-associated SNPs. Finally, the inclusion of SNPs and BMI raised predictive ability in all models as expected; however, results from the AUC in Neural Networks and Logistic Regression did not differ significantly in their prediction accuracy. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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119. Indigenous American Ancestry is Associated with Arsenic Methylation Efficiency in an Admixed Population of Northwest Mexico.
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Gomez-Rubio, Paulina, Klimentidis, Yann C., Cantu-Soto, Ernesto, Meza-Montenegro, Maria M., Billheimer, Dean, Lu, Zhenqiang, Chen, Zhao, and Klimecki, Walter T.
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NATIVE Americans , *ARSENIC metabolism , *GENEALOGY , *NUCLEOTIDE sequence , *MULTIPLE regression analysis - Abstract
Many studies provide evidence relating lower human arsenic (As) methylation efficiency, represented by high percent urinary monomethylarsonic acid (MMA(V)), with several As-induced diseases, possibly due to the fact that MMA(V) serves as a proxy for MMA(III), the most toxic As metabolite. Some epidemiological studies suggested that indigenous Americans (AME) methylate As more efficiently; however, data supporting this have been equivocal. The aim of this study was to characterize the association between AME ancestry and As methylation efficiency using a panel of ancestry informative genetic markers to determine individual ancestry proportions in an admixed population (composed of two or more isolated ancestral populations) of 746 individuals environmentally exposed to As in northwest Mexico. Total urinary As (TAs) mean and range were 170.4 and 2.3–1053.5 μg/L, while percent AME (%AME) mean and range were 72.4 and 23–100. Adjusted (gender, age, AS3MT 7388/M287T haplotypes, body mass index [BMI], and TAs) multiple regression model showed that higher AME ancestry is significantly associated with lower percentage of urinary As excreted as MMA(V) (%uMMA) in this population (p < .01). Data also demonstrated a significant interaction between BMI and gender, indicating negative association between BMI and %uMMA, stronger in women than men (p < .01). Moreover, age and the AS3MT variants 7388 (intronic) and M287T (nonsynonymous) were also significantly associated with As methylation efficiency (p < .01). This study highlights the importance of BMI and indigenous American ancestry in some of the observed variability in As methylation efficiency, underscoring the need to be considered in epidemiology studies, particularly those carried out in admixed populations. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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120. Mendelian Randomization of Blood Metabolites Suggests Circulating Glutamine Protects Against Late-Onset Alzheimer's Disease.
- Author
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Ramadan, Ferris A., Arani, Gayatri, Jafri, Ayan, Thompson, Tingting, Bland, Victoria L., Renquist, Benjamin, Raichlen, David A., Alexander, Gene E., and Klimentidis, Yann C.
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ALZHEIMER'S disease , *GLUTAMINE , *METABOLITES , *GENOME-wide association studies , *ODDS ratio - Abstract
Background: Late-onset Alzheimer's disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. Objective: We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. Methods: We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944). Results: MR analysis of metabolites as exposures revealed a negative association of genetically-predicted glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. Conclusions: Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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121. Genetic insights into the causal relationship between physical activity and cognitive functioning.
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Cheval, Boris, Darrous, Liza, Choi, Karmel W., Klimentidis, Yann C., Raichlen, David A., Alexander, Gene E., Cullati, Stéphane, Kutalik, Zoltán, and Boisgontier, Matthieu P.
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PHYSICAL activity , *COGNITIVE ability , *GENOME-wide association studies , *PHYSICAL mobility , *BONFERRONI correction - Abstract
Physical activity and cognitive functioning are strongly intertwined. However, the causal relationships underlying this association are still unclear. Physical activity can enhance brain functions, but healthy cognition may also promote engagement in physical activity. Here, we assessed the bidirectional relationships between physical activity and general cognitive functioning using Latent Heritable Confounder Mendelian Randomization (LHC-MR). Association data were drawn from two large-scale genome-wide association studies (UK Biobank and COGENT) on accelerometer-measured moderate, vigorous, and average physical activity (N = 91,084) and cognitive functioning (N = 257,841). After Bonferroni correction, we observed significant LHC-MR associations suggesting that increased fraction of both moderate (b = 0.32, CI95% = [0.17,0.47], P = 2.89e − 05) and vigorous physical activity (b = 0.22, CI95% = [0.06,0.37], P = 0.007) lead to increased cognitive functioning. In contrast, we found no evidence of a causal effect of average physical activity on cognitive functioning, and no evidence of a reverse causal effect (cognitive functioning on any physical activity measures). These findings provide new evidence supporting a beneficial role of moderate and vigorous physical activity (MVPA) on cognitive functioning. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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122. Exploring the association of weather variability on Campylobacter – A systematic review.
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Austhof, Erika, Warner, Shaylee, Helfrich, Kathryn, Pogreba-Brown, Kristen, Brown, Heidi E., Klimentidis, Yann C., Scallan Walter, Elaine, Jervis, Rachel H., and White, Alice E.
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EXTREME weather , *CAMPYLOBACTER infections , *CAMPYLOBACTER , *WEATHER , *MEDICAL climatology , *CLIMATE change & health ,EL Nino - Abstract
Previous work has found climate change-induced weather variability is suspected to increase the transmission of enteric pathogens, including Campylobacter , a leading cause of bacterial gastroenteritis. While the relationship between extreme weather events and diarrheal diseases has been documented, the specific impact on Campylobacter infections remains underexplored. To synthesize the peer-reviewed literature exploring the effect of weather variability on Campylobacter infections in humans. The review included English language, peer-reviewed articles, published up to September 1, 2022 in PubMed, Embase, GEOBASE, Agriculture and Environmental Science Database, and CABI Global Health exploring the effect of an antecedent weather event on human enteric illness caused by Campylobacter (PROSPERO Protocol # 351884). We extracted study information including data sources, methods, summary measures, and effect sizes. Quality and weight of evidence reported was summarized and bias assessed for each article. After screening 278 articles, 47 articles (34 studies, 13 outbreak reports) were included in the evidence synthesis. Antecedent weather events included precipitation (n = 35), temperature (n = 30), relative humidity (n = 7), sunshine (n = 6), and El Niño and La Niña (n = 3). Reviewed studies demonstrated that increases in precipitation and temperature were correlated with Campylobacter infections under specific conditions, whereas low relative humidity and sunshine were negatively correlated. Articles estimating the effect of animal operations (n = 15) found presence and density of animal operations were significantly associated with infections. However, most of the included articles did not assess confounding by seasonality, presence of animal operations, or describe estimates of risk. This review explores what is known about the influence of weather events on Campylobacter and identifies previously underreported negative associations between low relative humidity and sunshine on Campylobacter infections. Future research should explore pathogen-specific estimates of risk, which can be used to influence public health strategies, improve source attribution and causal pathways, and project disease burden due to climate change. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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123. Genetically predicted physical activity levels are associated with lower colorectal cancer risk: a Mendelian randomisation study.
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Zhang, Xiaomeng, Theodoratou, Evropi, Li, Xue, Farrington, Susan M., Law, Philip J., Broderick, Peter, Walker, Marion, Klimentidis, Yann C., Rees, Jessica M. B., Houlston, Richard S., Tomlinson, Ian P. M., Burgess, Stephen, Campbell, Harry, Dunlop, Malcolm G., and Timofeeva, Maria
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OBESITY complications , *OBESITY , *RESEARCH , *SEQUENCE analysis , *RESEARCH methodology , *PROGNOSIS , *MEDICAL cooperation , *EVALUATION research , *COLORECTAL cancer , *COMPARATIVE studies , *EXERCISE , *RESEARCH funding , *BODY mass index , *STATISTICAL sampling , *ADIPOSE tissues - Abstract
Background: We conducted a Mendelian randomisation (MR) study to investigate whether physical activity (PA) causes a reduction of colorectal cancer risk and to understand the contributions of effects mediated through changes in body fat.Methods: Common genetic variants associated with self-reported moderate-to-vigorous PA (MVPA), acceleration vector magnitude PA (AMPA) and sedentary time were used as instrumental variables. To control for confounding effects of obesity, we included instrumental variables for body mass index (BMI), body fat percentage, waist circumference and arm, trunk and leg fat ratios. We analysed the effect of these instrumental variables in a colorectal cancer genome-wide association study comprising 31,197 cases and 61,770 controls of European ancestry by applying two-sample and multivariable MR study designs.Results: We found decreased colorectal cancer risk for genetically represented measures of MVPA and AMPA that were additional to effects mediated through genetic measures of obesity. Odds ratio and 95% confidence interval (CI) per standard deviation increase in MVPA and AMPA was 0.56 (0.31, 1.01) and 0.60 (0.41, 0.88), respectively. No association has been found between sedentary time and colorectal cancer risk. The proportion of effect mediated through BMI was 2% (95% CI: 0, 14) and 32% (95% CI: 12, 46) for MVPA and AMPA, respectively.Conclusion: These findings provide strong evidence to reinforce public health measures on preventing colorectal cancer that promote PA at a population level regardless of body fatness. [ABSTRACT FROM AUTHOR]- Published
- 2021
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124. Exposure to air pollution and risk of incident dementia in the UK Biobank.
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Parra, Kimberly L., Alexander, Gene E., Raichlen, David A., Klimentidis, Yann C., and Furlong, Melissa A.
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AIR pollution , *DISEASE risk factors , *VASCULAR dementia , *FRONTOTEMPORAL dementia , *AIR pollutants , *ALZHEIMER'S disease - Abstract
Air pollution may cause inflammatory and oxidative stress damage to the brain, leading to neurodegenerative disease. The association between air pollution and dementia, and modification by apolipoprotein E genotype 4 (APOE -ε4) has yet to be fully investigated. To examine associations of air pollution with three types of incident dementias (Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VAD)), and their potential modification by APOE -ε4 genotype. The UK Biobank enrolled >500,000 participants (2006–2010) with ongoing follow-up. We used annual averages of air pollution (PM 2.5 , PM 10 , PM 2.5-10 , PM 2.5absorbance , NO 2 , NO X) for 2010 scaled to interquartile ranges (IQR). We included individuals aged ≥60 years, with no dementia diagnosis prior to January 1, 2010. Time to incident dementia and follow-up time were reported from baseline (January 01, 2010) to last censor event (death, last hospitalization, or loss to follow-up). Cox proportional hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated to estimate the association of air pollutants and incident dementia, and modification of these associations by APOE -ε4. Our sample included 187,194 individuals (including N = 680 AD, N = 377 VAD, N = 63 FTD) with a mean follow-up of 7.04 years. We observed consistent associations of PM 2.5 with greater risk of all-cause dementia (HR = 1.17, 95% CI: 1.10, 1.24) and AD (HR = 1.17, 95% CI: 1.06, 1.29). NO 2 was also associated with greater risk of any incident dementia (HR = 1.18, 95% CI: 1.10, 1.25), AD (HR = 1.15, 95% CI: 1.04, 1.28) and VAD (HR = 1.18, 95% CI: 1.03, 1.35). APOE -ε4 did not modify the association between any air pollutants and dementia. PM 2.5 and NO 2 levels were associated with several types of dementia, and these associations were not modified by APOE -ε4. Findings from the UK Biobank support and extend to other epidemiological evidence for the potential association of air pollutants with detrimental brain health during aging. • Examined air pollution and dementia incidence over 10 years in the UK Biobank. • PM2.5, NO2, and NOX, was associated with higher incidence of dementia. • APOE -ε4 did not modify the association of air pollution with dementia. [ABSTRACT FROM AUTHOR]
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- 2022
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125. Associations between accelerometer-derived sedentary behavior and physical activity with white matter hyperintensities in middle-aged to older adults.
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Raichlen DA, Ally M, Aslan DH, Sayre MK, Bharadwaj PK, Maltagliati S, Lai MHC, Wilcox RR, Habeck CG, Klimentidis YC, and Alexander GE
- Abstract
Introduction: We examined the relationship between sedentary behavior (SB), moderate-to-vigorous physical activity (MVPA), and white matter hyperintensity (WMH) volumes, a common magnetic resonance imaging (MRI) marker associated with risk of neurodegenerative disease in middle-aged to older adults., Methods: We used data from the UK Biobank ( n = 14,415; 45 to 81 years) that included accelerometer-derived measures of SB and MVPA, and WMH volumes from MRI., Results: Both MVPA and SB were associated with WMH volumes (β
MVPA = -0.03 [-0.04, -0.01], p < 0.001; βSB = 0.02 [0.01, 0.03], p = 0.007). There was a significant interaction between SB and MVPA on WMH volumes (βSB×MVPA = -0.015 [-0.028, -0.001], pSB×MVPA = 0.03) where SB was positively associated with WMHs at low MVPA, and MVPA was negatively associated with WMHs at high SB., Discussion: While this study cannot establish causality, the results highlight the potential importance of considering both MVPA and SB in strategies aimed at reducing the accumulation of WMH volumes in middle-aged to older adults., Highlights: SB is associated with greater WMH volumes and MVPA is associated with lower WMH volumes.Relationships between SB and WMH are strongest at low levels of MVPA.Associations between MVPA and WMH are strongest at high levels of SB.Considering both SB and MVPA may be effective strategies for reducing WMHs., Competing Interests: The authors declare no conflict of interest. Author disclosures are available in the Supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)- Published
- 2024
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126. Sedentary Behavior and Dementia-Reply.
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Raichlen DA, Klimentidis YC, and Alexander GE
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- Humans, Dementia, Sedentary Behavior
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- 2024
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127. Genetic QT Score and Sleep Apnea as Predictors of Sudden Cardiac Death in the UK Biobank.
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Arora A, Zareba W, Woosley RL, Klimentidis YC, Patel IY, Quan SF, Wendel C, Shamoun F, Guerra S, Parthasarathy S, and Patel SI
- Abstract
Introduction: The goal of this study was to evaluate the association between a polygenic risk score (PRS) for QT prolongation (QTc-PRS), QTc intervals and mortality in patients enrolled in the UK Biobank with and without sleep apnea., Methods: The QTc-PRS was calculated using allele copy number and previously reported effect estimates for each single nuclear polymorphism SNP. Competing-risk regression models adjusting for age, sex, BMI, QT prolonging medication, race, and comorbid cardiovascular conditions were used for sudden cardiac death (SCD) analyses., Results: 500,584 participants were evaluated (56.5 ±8 years, 54% women, 1.4% diagnosed with sleep apnea). A higher QTc-PRS was independently associated with the increased QTc interval duration (p<0.0001). The mean QTc for the top QTc-PRS quintile was 15 msec longer than the bottom quintile (p<0.001). Sleep apnea was found to be an effect modifier in the relationship between QTc-PRS and SCD. The adjusted HR per 5-unit change in QTc-PRS for SCD was 1.64 (95% CI 1.16 - 2.31, p=0.005) among those with sleep apnea and 1.04 (95% CI 0.95 - 1.14, p=0.44) among those without sleep apnea (p for interaction =0.01). Black participants with sleep apnea had significantly elevated adjusted risk of SCD compared to White participants (HR=9.6, 95% CI 1.24 - 74, p=0.03)., Conclusion: In the UK Biobank population, the QTc-PRS was associated with SCD among participants with sleep apnea but not among those without sleep apnea, indicating that sleep apnea is a significant modifier of the genetic risk. Black participants with sleep apnea had a particularly high risk of SCD.
- Published
- 2023
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128. Loneliness and depression: bidirectional mendelian randomization analyses using data from three large genome-wide association studies.
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Sbarra DA, Ramadan FA, Choi KW, Treur JL, Levey DF, Wootton RE, Stein MB, Gelernter J, and Klimentidis YC
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- Humans, Depression genetics, Loneliness, Mendelian Randomization Analysis, Prospective Studies, Genome-Wide Association Study, Depressive Disorder, Major genetics
- Abstract
Major depression (MD) is a serious psychiatric illness afflicting nearly 5% of the world's population. A large correlational literature suggests that loneliness is a prospective risk factor for MD; correlational assocations of this nature may be confounded for a variety of reasons. This report uses Mendelian Randomization (MR) to examine potentially causal associations between loneliness and MD. We report on analyses using summary statistics from three large genome wide association studies (GWAS). MR analyses were conducted using three independent sources of GWAS summary statistics. In the first set of analyses, we used available summary statistics from an extant GWAS of loneliness to predict MD risk. We used two sources of outcome data: the Psychiatric Genomics Consortium (PGC) meta-analysis of MD (PGC-MD; N = 142,646) and the Million Veteran Program (MVP-MD; N = 250,215). Finally, we reversed analyses using data from the MVP and PGC samples to identify risk variants for MD and used loneliness outcome data from UK Biobank. We find robust evidence for a bidirectional causal relationship between loneliness and MD, including between loneliness, depression cases status, and a continuous measure of depressive symptoms. The estimates remained significant across several sensitivity analyses, including models that account for horizontal pleiotropy. This paper provides the first genetically-informed evidence that reducing loneliness may play a causal role in decreasing risk for depressive illness, and these findings support efforts to reduce loneliness in order to prevent or ameliorate MD. Discussion focuses on the public health significance of these findings, especially in light of the SARS-CoV-2 pandemic., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2023
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129. Examining genetic associations with hepatic steatosis in Mexican-origin adults.
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Trejo MJ, Morrill KE, Klimentidis YC, and Garcia DO
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- Humans, Adult, Female, Adolescent, Young Adult, Middle Aged, Male, Genetic Predisposition to Disease, Genotype, Risk Factors, Polymorphism, Single Nucleotide, Liver, Non-alcoholic Fatty Liver Disease diagnostic imaging, Non-alcoholic Fatty Liver Disease epidemiology
- Abstract
Introduction and Objectives: Various studies have identified single-nucleotide polymorphisms (SNPs) associated with nonalcoholic fatty liver disease (NAFLD) and related traits, including ones located in or near the LYPLAL1, GCKR, PPP1R3B, TM6SF2, MBOAT7, and PNPLA3 genes. However, these SNPs were identified primarily in populations of European ancestry. This study examined the associations of these previously identified SNPs with hepatic steatosis in a sample of Mexican-origin adults living in Southern Arizona., Materials and Methods: A total of 307 Mexican-origin adults between the ages of 18 and 64 with a body mass index (BMI) of 25 kg/m2 or higher were genotyped at the following SNPs: rs12137855 (LYPLAL1), rs1260326 (GCKR), rs4240624 (PPP1R3B), rs58542926 (TM6SF2), rs641738 (MBOAT7), and rs738409 (PNPLA3). Hepatic steatosis was assessed by transient elastography (FibroScan®) with controlled attenuation parameter. Regression models examined the association between each of the six SNPs and hepatic steatosis. BMI was examined as a potential modifier of the genetic associations., Results: Participants were, on average, 45 years old and mostly female (63%) with an overall mean hepatic steatosis of 288.1 dB/m. Models showed no associations between LYPLAL1, GCKR, PPP1R3B, TM6SF2, or MBOAT7 and hepatic steatosis. Only PNPLA3 was statistically significantly associated with hepatic steatosis in both unadjusted and adjusted models (p<0.01). There was no effect modification observed with BMI., Conclusions: SNPs associated with NAFLD in populations of European descent did not strongly contribute to hepatic steatosis in individuals of Mexican-origin, except for rs738409 (PNPLA3). Further efforts are necessary to explore additional SNPs that may be associated with NAFLD in this high-risk population., Competing Interests: Declaration of interests None., (Copyright © 2023 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)
- Published
- 2023
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130. Genome-wide association study of a lipedema phenotype among women in the UK Biobank identifies multiple genetic risk factors.
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Klimentidis YC, Chen Z, Gonzalez-Garay ML, Grigoriadis D, Sackey E, Pittman A, Ostergaard P, and Herbst KL
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- Female, Humans, Genome-Wide Association Study, Biological Specimen Banks, Phenotype, Risk Factors, United Kingdom, Lipedema
- Abstract
Lipedema is a common disorder characterized by excessive deposition of subcutaneous adipose tissue (SAT) in the legs, hips, and buttocks, mainly occurring in adult women. Although it appears to be heritable, no specific genes have yet been identified. To identify potential genetic risk factors for lipedema, we used bioelectrical impedance analysis and anthropometric data from the UK Biobank to identify women with and without a lipedema phenotype. Specifically, we identified women with both a high percentage of fat in the lower limbs and a relatively small waist, adjusting for hip circumference. We performed a genome-wide association study (GWAS) for this phenotype, and performed multiple sensitivity GWAS. In an independent case/control study of lipedema based on strict clinical criteria, we attempted to replicate our top hits. We identified 18 significant loci (p < 5 × 10
-9 ), several of which have previously been identified in GWAS of waist-to-hip ratio with larger effects in women. Two loci (VEGFA and GRB14-COBLL1) were significantly associated with lipedema in the independent replication study. Follow-up analyses suggest an enrichment of genes expressed in blood vessels and adipose tissue, among other tissues. Our findings provide a starting point towards better understanding the genetic and physiological basis of lipedema., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)- Published
- 2023
- Full Text
- View/download PDF
131. Association of Air Pollution and Physical Activity With Brain Volumes.
- Author
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Furlong MA, Alexander GE, Klimentidis YC, and Raichlen DA
- Abstract
Background and Objectives: In high-pollution areas, physical activity may have a paradoxical effect on brain health by increasing particulate deposition in the lungs. We examined whether physical activity modifies associations of air pollution (AP) with brain volumes in an epidemiologic framework., Methods: The UK Biobank enrolled >500,000 adult participants from 2006 to 2010. Wrist accelerometers, multimodal MRI with T1 images and T2 fluid-attenuated inversion recovery data, and land use regression were used to estimate vigorous physical activity (VigPA), structural brain volumes, and AP, respectively, in subsets of the full sample. We evaluated associations among AP interquartile ranges, VigPA, and brain structure volumes and assessed interactions between AP and VigPA., Results: Eight thousand six hundred participants were included, with an average age of 55.55 (SD 7.46) years. After correction for multiple testing, in overall models, VigPA was positively associated with gray matter volume (GMV) and negatively associated with white matter hyperintensity volume (WMHV), while NO
2 , PM2.5absorbance , and PM2.5 were negatively associated with GMV. NO2 and PM2.5absorbance interacted with VigPA on WMHV (false discovery rate-corrected interaction p = 0.037). Associations between these air pollutants and WMHVs were stronger among participants with high VigPA. Similarly, VigPA was negatively associated with WMHV for those in areas of low NO2 and PM2.5absorbance but was null among those living in areas of high NO2 and PM2.5absorbance. DISCUSSION: Physical activity is associated with beneficial brain outcomes, while AP is associated with detrimental brain outcomes. VigPA may exacerbate associations of AP with white matter hyperintensity lesions, and AP may attenuate the beneficial associations of physical activity with these lesions., (© 2021 American Academy of Neurology.)- Published
- 2022
- Full Text
- View/download PDF
132. Genome-wide association study of body fat distribution traits in Hispanics/Latinos from the HCHS/SOL.
- Author
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Justice AE, Young K, Gogarten SM, Sofer T, Graff M, Love SAM, Wang Y, Klimentidis YC, Cruz M, Guo X, Hartwig F, Petty L, Yao J, Allison MA, Below JE, Buchanan TA, Chen YI, Goodarzi MO, Hanis C, Highland HM, Hsueh WA, Ipp E, Parra E, Palmas W, Raffel LJ, Rotter JI, Tan J, Taylor KD, Valladares A, Xiang AH, Sánchez-Johnsen L, Isasi CR, and North KE
- Subjects
- Alleles, Humans, Polymorphism, Single Nucleotide, Adiposity genetics, Body Fat Distribution, Genome-Wide Association Study, Hispanic or Latino genetics, Quantitative Trait, Heritable
- Abstract
Central obesity is a leading health concern with a great burden carried by ethnic minority populations, especially Hispanics/Latinos. Genetic factors contribute to the obesity burden overall and to inter-population differences. We aimed to identify the loci associated with central adiposity measured as waist-to-hip ratio (WHR), waist circumference (WC) and hip circumference (HIP) adjusted for body mass index (adjBMI) by using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL); determine if differences in associations differ by background group within HCHS/SOL and determine whether previously reported associations generalize to HCHS/SOL. Our analyses included 7472 women and 5200 men of mainland (Mexican, Central and South American) and Caribbean (Puerto Rican, Cuban and Dominican) background residing in the USA. We performed genome-wide association analyses stratified and combined across sexes using linear mixed-model regression. We identified 16 variants for waist-to-hip ratio adjusted for body mass index (WHRadjBMI), 22 for waist circumference adjusted for body mass index (WCadjBMI) and 28 for hip circumference adjusted for body mass index (HIPadjBMI), which reached suggestive significance (P < 1 × 10-6). Many loci exhibited differences in strength of associations by ethnic background and sex. We brought a total of 66 variants forward for validation in cohorts (N = 34 161) with participants of Hispanic/Latino, African and European descent. We confirmed four novel loci (P < 0.05 and consistent direction of effect, and P < 5 × 10-8 after meta-analysis), including two for WHRadjBMI (rs13301996, rs79478137); one for WCadjBMI (rs3168072) and one for HIPadjBMI (rs28692724). Also, we generalized previously reported associations to HCHS/SOL, (8 for WHRadjBMI, 10 for WCadjBMI and 12 for HIPadjBMI). Our study highlights the importance of large-scale genomic studies in ancestrally diverse Hispanic/Latino populations for identifying and characterizing central obesity susceptibility that may be ancestry-specific., (© The Author(s) 2021. Published by Oxford University Press.)
- Published
- 2021
- Full Text
- View/download PDF
133. Circulating Fibroblast Growth Factor-21 and Risk of Metachronous Colorectal Adenoma.
- Author
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Florea A, Harris RB, Klimentidis YC, Kohler LN, Jurutka PW, and Jacobs ET
- Subjects
- Adenoma drug therapy, Adenoma pathology, Aged, Aged, 80 and over, Arizona, Cholagogues and Choleretics therapeutic use, Clinical Trials, Phase III as Topic, Colonic Polyps blood, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Female, Humans, Male, Middle Aged, Neoplasms, Second Primary drug therapy, Neoplasms, Second Primary pathology, Prospective Studies, Randomized Controlled Trials as Topic, Risk Factors, Ursodeoxycholic Acid therapeutic use, Adenoma blood, Colorectal Neoplasms blood, Fibroblast Growth Factors blood, Neoplasms, Second Primary blood
- Abstract
Purpose: Prior work has shown that higher circulating concentrations of fibroblast growth factor-21 (FGF-21) are associated with an increased likelihood of developing colorectal cancer. We conducted a prospective study to assess the relationship between circulating FGF-21 and odds of developing early neoplastic lesions in the colorectum., Methods: A total of 94 study participants were included from the ursodeoxycholic acid (UDCA) trial, a phase III, randomized, double-blind, placebo-controlled clinical trial of the effect of 8-10 mg/kg of body weight UDCA vs. placebo. Logistic regression analyses were conducted to evaluate the association between baseline FGF-21 concentrations and odds of developing a metachronous adenoma., Results: Of the characteristics compared across tertiles of FGF-21 concentrations, including age, race, sex, BMI, and other variables, only a previous personal history of colorectal polyps prior to entry into the UDCA trial was statistically significantly related to FGF-21 levels, with a proportion of 26.7%, 56.7%, and 50.0% across the first, second, and third tertiles, respectively (p < 0.05). Higher circulating concentrations of FGF-21 were statistically significantly associated with greater odds of developing a metachronous colorectal adenoma. After adjusting for potential confounders and when compared with the lowest tertile of FGF-21, the adjusted ORs (95% CIs) for metachronous colorectal adenoma in the second and third tertiles were 4.72 (95% CI, 1.42-15.72) and 3.82 (95% CI, 1.15-12.68), respectively (p trend < 0.05)., Conclusion: Our results reveal for the first time that, in addition to a recently discovered association with colorectal cancer, circulating FGF-21 concentrations are significantly and directly associated with odds of developing metachronous colorectal adenoma., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2021
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134. Differential associations of engagement in physical activity and estimated cardiorespiratory fitness with brain volume in middle-aged to older adults.
- Author
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Raichlen DA, Klimentidis YC, Bharadwaj PK, and Alexander GE
- Subjects
- Aged, Aged, 80 and over, Female, Gray Matter anatomy & histology, Humans, Male, Middle Aged, Brain anatomy & histology, Cardiorespiratory Fitness physiology, Exercise physiology, Organ Size
- Abstract
Previous work has confirmed the benefits of aerobic exercise for brain aging, however mechanisms underlying these effects remain unclear. Two measures of exercise, time spent in moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF), may reflect different pathways linking activity to brain health. Using data from the UK Biobank, the largest sample combining neuroimaging and objectively measured MVPA available to date (n = 7148, n
male = 3062, nfemale = 4086; age = 62.14 ± 7.40 years), we found that, when adjusted for covariates including MVPA, CRF was positively associated with overall gray matter volume (FDR p = 1.28E-05). In contrast, when adjusted for covariates including CRF, MVPA was positively associated with left and right hippocampal (FDR pleft = 0.01; FDR pright = 0.02) volumes, but not overall gray matter volume. Both CRF and MVPA were inversely associated with white matter hyperintensity lesion loads (FDR pCRF = 0.002; pMVPA = 0.02). Our results suggest separable effects of engagement in exercise behaviors (MVPA) and the physiological effects of exercise (CRF) on structural brain volumes, which may have implications for differential pathways linking exercise and brain benefits.- Published
- 2020
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- View/download PDF
135. Ordered multinomial regression for genetic association analysis of ordinal phenotypes at Biobank scale.
- Author
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German CA, Sinsheimer JS, Klimentidis YC, Zhou H, and Zhou JJ
- Subjects
- Algorithms, Case-Control Studies, Computer Simulation, Humans, Hypertension genetics, Models, Genetic, Phenotype, Polymorphism, Single Nucleotide genetics, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Disease, Chronic Obstructive physiopathology, Regression Analysis, Respiratory Function Tests, Biological Specimen Banks, Genome-Wide Association Study
- Abstract
Logistic regression is the primary analysis tool for binary traits in genome-wide association studies (GWAS). Multinomial regression extends logistic regression to multiple categories. However, many phenotypes more naturally take ordered, discrete values. Examples include (a) subtypes defined from multiple sources of clinical information and (b) derived phenotypes generated by specific phenotyping algorithms for electronic health records (EHR). GWAS of ordinal traits have been problematic. Dichotomizing can lead to a range of arbitrary cutoff values, generating inconsistent, hard to interpret results. Using multinomial regression ignores trait value hierarchy and potentially loses power. Treating ordinal data as quantitative can lead to misleading inference. To address these issues, we analyze ordinal traits with an ordered, multinomial model. This approach increases power and leads to more interpretable results. We derive efficient algorithms for computing test statistics, making ordinal trait GWAS computationally practical for Biobank scale data. Our method is available as a Julia package OrdinalGWAS.jl. Application to a COPDGene study confirms previously found signals based on binary case-control status, but with more significance. Additionally, we demonstrate the capability of our package to run on UK Biobank data by analyzing hypertension as an ordinal trait., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2020
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- View/download PDF
136. Polymorphisms in stearoyl coa desaturase and sterol regulatory element binding protein interact with N-3 polyunsaturated fatty acid intake to modify associations with anthropometric variables and metabolic phenotypes in Yup'ik people.
- Author
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Lemas DJ, Klimentidis YC, Aslibekyan S, Wiener HW, O'Brien DM, Hopkins SE, Stanhope KL, Havel PJ, Allison DB, Fernandez JR, Tiwari HK, and Boyer BB
- Subjects
- Adult, Alaska ethnology, Anthropometry, Apolipoprotein A-I blood, Cholesterol blood, Cross-Sectional Studies, Diabetes Mellitus, Type 2 genetics, Diet, Female, Glucose Transporter Type 4 genetics, Glycated Hemoglobin metabolism, Humans, Male, Obesity genetics, Sterol Regulatory Element Binding Protein 1 genetics, Diabetes Mellitus, Type 2 ethnology, Fatty Acids, Omega-3 administration & dosage, Obesity ethnology, Polymorphism, Single Nucleotide, Stearoyl-CoA Desaturase genetics
- Abstract
Scope: n-3 polyunsaturated fatty acid (n-3 PUFA) intake is associated with protection from obesity; however, the mechanisms of protection remain poorly characterized. The stearoyl CoA desaturase (SCD), insulin-sensitive glucose transporter (SLC2A4), and sterol regulatory element binding protein (SREBF1) genes are transcriptionally regulated by n-3 PUFA intake and harbor polymorphisms associated with obesity. The present study investigated how consumption of n-3 PUFA modifies associations between SCD, SLC2A4, and SREBF1 polymorphisms and anthropometric variables and metabolic phenotypes., Materials and Methods: Anthropometric variables and metabolic phenotypes were measured in a cross-sectional sample of Yup'ik individuals (n = 1135) and 33 polymorphisms were tested for main effects and interactions using linear models that account for familial correlations. n-3 PUFA intake was estimated using red blood cell nitrogen stable isotope ratios. SCD polymorphisms were associated with ApoA1 concentration and n-3 PUFA interactions with SCD polymorphisms were associated with reduced fasting cholesterol levels and waist-to-hip ratio. SLC2A4 polymorphisms were associated with hip circumference, high-density lipoprotein and ApoA1 concentrations. SREBF1 polymorphisms were associated with low-density lipoprotein and HOMA-IR and n-3 PUFA interactions were associated with reduced fasting insulin and HOMA-IR levels., Conclusion: The results suggest that an individual's genotype may interact with dietary n-3 PUFAs in ways that are associated with protection from obesity-related diseases in Yup'ik people., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
- Full Text
- View/download PDF
137. CDKAL1 and HHEX are associated with type 2 diabetes-related traits among Yup'ik people.
- Author
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Klimentidis YC, Lemas DJ, Wiener HH, O'Brien DM, Havel PJ, Stanhope KL, Hopkins SE, Tiwari HK, and Boyer BB
- Subjects
- Adult, Alaska epidemiology, Blood Glucose metabolism, Body Mass Index, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 ethnology, Diet, Fasting blood, Fatty Acids, Omega-3 administration & dosage, Female, Gene Frequency, Genetic Predisposition to Disease ethnology, Genotype, Glycated Hemoglobin metabolism, Humans, Insulin blood, Linear Models, Male, Middle Aged, Polymorphism, Single Nucleotide, Prevalence, Risk Factors, Young Adult, tRNA Methyltransferases, Cyclin-Dependent Kinase 5 genetics, Diabetes Mellitus, Type 2 genetics, Genetic Predisposition to Disease genetics, Homeodomain Proteins genetics, Inuit genetics, Transcription Factors genetics
- Abstract
Background: Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D), mainly among individuals of European ancestry. In the present study, we examined the frequency of these SNPs and their association with T2D-related traits in an Alaska Native study population with a historically low prevalence of T2D. We also investigated whether dietary characteristics that may protect against T2D, such as n-3 polyunsaturated fatty acid (PUFA) intake, modify these associations., Methods: In 1144 Yup'ik people, we examined 17 SNPs repeatedly identified in GWAS for individual and cumulative associations with T2D-related traits. Cumulative associations were evaluated using a genetic risk score (GRS) calculated by summing risk alleles. Associations were tested for interactions with sex, body mass index (BMI), and n-3 PUFA intake., Results: The rs7754840 SNP in CDKAL1 is significantly associated with HbA1c (P = 0.00091). The rs5015480 SNP near HHEX is significantly associated (in opposite direction to that in Europeans) with a combined fasting glucose (FG) and HbA1c measure (P = 0.00046) and with homeostatic model assessment of β-cell function (HOMA-B; P = 0.0014). The GRS is significantly associated with FG and combined FG and HbA1c only when the HHEX SNP is dropped from the GRS. Associations are not modified by BMI or n-3 PUFA intake., Conclusion: Our results highlight the potential importance of CDKAL1 and HHEX in glucose homeostasis in this Alaska Native population with a low prevalence of T2D, and suggest that these loci should be examined in greater detail in this population., (© 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)
- Published
- 2014
- Full Text
- View/download PDF
138. A Hybrid Bayesian Network/Structural Equation (BN/SEM) Modeling Approach for Detecting Physiological Networks for Obesity-related Genetic Variants.
- Author
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Duarte CW, Klimentidis YC, Harris JJ, Cardel M, and Fernández JR
- Abstract
GWAS studies have been successful in finding genetic determinants of obesity. To translate discovered genetic variants into new therapies or prevention strategies, molecular or physiological mechanisms need to be discovered. One strategy is to perform data mining of data sets with detailed phenotypic data, such as those present in dbGAP (database of Genotypes and Phenotypes) for hypothesis generation. We propose a novel technique that combines the power and computational efficiency of existing Bayesian Network (BN) learning algorithms with the statistical rigor of Structural Equation Modeling (SEM) to produce an overall system that searches the space of potential networks and evaluates promising candidates using standard SEM model selection criteria. We demonstrate our method using the analysis of a candidate SNP data set from the AMERICO sample, a multi-ethnic cross-sectional cohort of roughly three hundred children with detailed obesity-related phenotypes. We demonstrate our approach by showing genetic mechanisms for three obesity-related SNPs.
- Published
- 2011
- Full Text
- View/download PDF
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