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3. Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts

Author

Wani, Agaz H., Katrinli, Seyma, Zhao, Xiang, Daskalakis, Nikolaos P., Zannas, Anthony S., Aiello, Allison E., Baker, Dewleen G., Boks, Marco P., Brick, Leslie A., Chen, Chia-Yen, Dalvie, Shareefa, Fortier, Catherine, Geuze, Elbert, Hayes, Jasmeet P., Kessler, Ronald C., King, Anthony P., Koen, Nastassja, Liberzon, Israel, Lori, Adriana, Luykx, Jurjen J., Maihofer, Adam X., Milberg, William, Miller, Mark W., Mufford, Mary S., Nugent, Nicole R., Rauch, Sheila, Ressler, Kerry J., Risbrough, Victoria B., Rutten, Bart P. F., Stein, Dan J., Stein, Murray B., Ursano, Robert J., Verfaellie, Mieke H., Vermetten, Eric, Vinkers, Christiaan H., Ware, Erin B., Wildman, Derek E., Wolf, Erika J., Nievergelt, Caroline M., Logue, Mark W., Smith, Alicia K., and Uddin, Monica

Published
2024
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7. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

Author

Mullins, Niamh, Kang, JooEun, Campos, Adrian I, Coleman, Jonathan RI, Edwards, Alexis C, Galfalvy, Hanga, Levey, Daniel F, Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J, Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D, Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B, Bergen, Andrew W, Berrettini, Wade H, Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J, Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M, Gallinger, Steven, Glatt, Stephen J, Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A, Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Keel, Pamela K, Kennedy, James L, Klump, Kelly L, Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J, Marshall, Christian R, Mitchell, James E, Monson, Eric T, Myers, Richard M, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W, Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M, Treasure, Janet, Tsuang, Ming T, Witt, Stephanie H, Woodside, D Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M, Alda, Martin, Alfredsson, Lars, Andreassen, Ole A, Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M Helena, Bass, Nicholas, Bau, Claiton HD, Baune, Bernhard T, Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M, Bigdeli, Tim B, Binder, Elisabeth B, Boehnke, Michael, Boks, Marco P, Bosch, Rosa, and Braff, David L

Subjects
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Eating Disorders Working Group of the Psychiatric Genomics Consortium, German Borderline Genomics Consortium, MVP Suicide Exemplar Workgroup, VA Million Veteran Program, Humans, Risk Factors, Suicide, Attempted, Mental Disorders, Depressive Disorder, Major, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic correlation, Genome-wide association study, Pleiotropy, Polygenicity, Suicide, Suicide attempt, Human Genome, Behavioral and Social Science, Mental Health, Prevention, Genetics, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundSuicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.MethodsWe conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.ResultsTwo loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.ConclusionsOur results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Published
2022

8. A data-driven prospective study of incident dementia among older adults in the United States

Author

Weiss, Jordan, Puterman, Eli, Prather, Aric A., Ware, Erin B., and Rehkopf, David H.

Subjects
Statistics - Applications
Abstract

We conducted a prospective analysis of incident dementia and its association with 65 sociodemographic, early-life, economic, health and behavioral, social, and genetic risk factors in a sample of 7,908 adults over the age of 50 from the nationally representative US-based Health and Retirement Study. We used traditional survival analysis methods (Fine-Gray models) and a data-driven approach (random survival forests for competing risks) which allowed us to account for the competing risk of death with up to 14 years of follow-up. Overall, the top five predictors across all groups were lower education, loneliness, lower wealth and income, and lower self-reported health. However, we observed variation in the leading predictors of dementia across racial/ethnic and gender groups. Our ranked lists may be useful for guiding future observational and quasi-experimental research that investigates understudied domains of risk and emphasizes life course economic and health conditions as well as disparities therein.

Published
2020
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9. Assessing Selection Bias in Regression Coefficients Estimated from Non-Probability Samples, with Applications to Genetics and Demographic Surveys

Author

West, Brady T., Little, Roderick J. A., Andridge, Rebecca R., Boonstra, Philip S., Ware, Erin B., Pandit, Anita, and Alvarado-Leiton, Fernanda

Subjects
Statistics - Methodology, Statistics - Applications
Abstract

Selection bias is a serious potential problem for inference about relationships of scientific interest based on samples without well-defined probability sampling mechanisms. Motivated by the potential for selection bias in (a) estimated relationships of polygenic scores (PGSs) with phenotypes in genetic studies of volunteers, and (b) estimated differences in subgroup means in surveys of smartphone users, we derive novel measures of selection bias for estimates of the coefficients in linear and probit regression models fitted to non-probability samples, when aggregate-level auxiliary data are available for the selected sample and the target population. The measures arise from normal pattern-mixture models that allow analysts to examine the sensitivity of their inferences to assumptions about non-ignorable selection in these samples. We examine the effectiveness of the proposed measures in a simulation study, and then use them to quantify the selection bias in (a) estimated PGS-phenotype relationships in a large study of volunteers recruited via Facebook, and (b) estimated subgroup differences in mean past-year employment duration in a non-probability sample of low-educated smartphone users. We evaluate the performance of the measures in these applications using benchmark estimates from large probability samples., Comment: 29 pages, 4 figures, 2 tables, supplementary material

Published
2020

10. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Author

de Las Fuentes, Lisa, Sung, Yun Ju, Noordam, Raymond, Winkler, Thomas, Feitosa, Mary F, Schwander, Karen, Bentley, Amy R, Brown, Michael R, Guo, Xiuqing, Manning, Alisa, Chasman, Daniel I, Aschard, Hugues, Bartz, Traci M, Bielak, Lawrence F, Campbell, Archie, Cheng, Ching-Yu, Dorajoo, Rajkumar, Hartwig, Fernando P, Horimoto, ARVR, Li, Changwei, Li-Gao, Ruifang, Liu, Yongmei, Marten, Jonathan, Musani, Solomon K, Ntalla, Ioanna, Rankinen, Tuomo, Richard, Melissa, Sim, Xueling, Smith, Albert V, Tajuddin, Salman M, Tayo, Bamidele O, Vojinovic, Dina, Warren, Helen R, Xuan, Deng, Alver, Maris, Boissel, Mathilde, Chai, Jin-Fang, Chen, Xu, Christensen, Kaare, Divers, Jasmin, Evangelou, Evangelos, Gao, Chuan, Girotto, Giorgia, Harris, Sarah E, He, Meian, Hsu, Fang-Chi, Kühnel, Brigitte, Laguzzi, Federica, Li, Xiaoyin, Lyytikäinen, Leo-Pekka, Nolte, Ilja M, Poveda, Alaitz, Rauramaa, Rainer, Riaz, Muhammad, Rueedi, Rico, Shu, Xiao-Ou, Snieder, Harold, Sofer, Tamar, Takeuchi, Fumihiko, Verweij, Niek, Ware, Erin B, Weiss, Stefan, Yanek, Lisa R, Amin, Najaf, Arking, Dan E, Arnett, Donna K, Bergmann, Sven, Boerwinkle, Eric, Brody, Jennifer A, Broeckel, Ulrich, Brumat, Marco, Burke, Gregory, Cabrera, Claudia P, Canouil, Mickaël, Chee, Miao Li, Chen, Yii-Der Ida, Cocca, Massimiliano, Connell, John, de Silva, H Janaka, de Vries, Paul S, Eiriksdottir, Gudny, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Fox, Ervin F, Friedlander, Yechiel, Gao, He, Gigante, Bruna, Giulianini, Franco, Gu, Chi Charles, Gu, Dongfeng, Harris, Tamara B, He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven, Ikram, M Arfan, Irvin, Marguerite R, Kähönen, Mika, and Kavousi, Maryam

Subjects
Lifelines Cohort Study, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P

Published
2021

11. Multi-ancestry genome-wide association study accounting for gene-psychosocial factor interactions identifies novel loci for blood pressure traits

Author

Sun, Daokun, Richard, Melissa A, Musani, Solomon K, Sung, Yun Ju, Winkler, Thomas W, Schwander, Karen, Chai, Jin Fang, Guo, Xiuqing, Kilpeläinen, Tuomas O, Vojinovic, Dina, Aschard, Hugues, Bartz, Traci M, Bielak, Lawrence F, Brown, Michael R, Chitrala, Kumaraswamy, Hartwig, Fernando P, Horimoto, Andrea RVR, Liu, Yongmei, Manning, Alisa K, Noordam, Raymond, Smith, Albert V, Harris, Sarah E, Kühnel, Brigitte, Lyytikäinen, Leo-Pekka, Nolte, Ilja M, Rauramaa, Rainer, van der Most, Peter J, Wang, Rujia, Ware, Erin B, Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R, Arking, Dan E, Arnett, Donna K, Barac, Ana, Boerwinkle, Eric, Broeckel, Ulrich, Chakravarti, Aravinda, Chen, Yii-Der Ida, Cupples, L Adrienne, Davigulus, Martha L, de las Fuentes, Lisa, de Mutsert, Renée, de Vries, Paul S, Delaney, Joseph AC, Roux, Ana V Diez, Dörr, Marcus, Faul, Jessica D, Fretts, Amanda M, Gallo, Linda C, Grabe, Hans Jörgen, Gu, C Charles, Harris, Tamara B, Hartman, Catharina CA, Heikkinen, Sami, Ikram, M Arfan, Isasi, Carmen, Johnson, W Craig, Jonas, Jost Bruno, Kaplan, Robert C, Komulainen, Pirjo, Krieger, Jose E, Levy, Daniel, Study, Lifelines Cohort, Liu, Jianjun, Lohman, Kurt, Luik, Annemarie I, Martin, Lisa W, Meitinger, Thomas, Milaneschi, Yuri, O’Connell, Jeff R, Palmas, Walter R, Peters, Annette, Peyser, Patricia A, Pulkki-Råback, Laura, Raffel, Leslie J, Reiner, Alex P, Rice, Kenneth, Robinson, Jennifer G, Rosendaal, Frits R, Schmidt, Carsten Oliver, Schreiner, Pamela J, Schwettmann, Lars, Shikany, James M, Shu, Xiao-ou, Sidney, Stephen, Sims, Mario, Smith, Jennifer A, Sotoodehnia, Nona, Strauch, Konstantin, Tai, E Shyong, Taylor, Kent D, Uitterlinden, André G, van Duijn, Cornelia M, Waldenberger, Melanie, Wee, Hwee-Lin, Wei, Wen-Bin, Wilson, Gregory, Xuan, Deng, and Yao, Jie

Subjects
Hypertension, Mental Health, Genetics, Cardiovascular, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Lifelines Cohort Study
Abstract

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value

Published
2021

12. Association of low-frequency and rare coding variants with information processing speed

Author

Bressler, Jan, Davies, Gail, Smith, Albert V, Saba, Yasaman, Bis, Joshua C, Jian, Xueqiu, Hayward, Caroline, Yanek, Lisa, Smith, Jennifer A, Mirza, Saira S, Wang, Ruiqi, Adams, Hieab HH, Becker, Diane, Boerwinkle, Eric, Campbell, Archie, Cox, Simon R, Eiriksdottir, Gudny, Fawns-Ritchie, Chloe, Gottesman, Rebecca F, Grove, Megan L, Guo, Xiuqing, Hofer, Edith, Kardia, Sharon LR, Knol, Maria J, Koini, Marisa, Lopez, Oscar L, Marioni, Riccardo E, Nyquist, Paul, Pattie, Alison, Polasek, Ozren, Porteous, David J, Rudan, Igor, Satizabal, Claudia L, Schmidt, Helena, Schmidt, Reinhold, Sidney, Stephen, Simino, Jeannette, Smith, Blair H, Turner, Stephen T, van der Lee, Sven J, Ware, Erin B, Whitmer, Rachel A, Yaffe, Kristine, Yang, Qiong, Zhao, Wei, Gudnason, Vilmundur, Launer, Lenore J, Fitzpatrick, Annette L, Psaty, Bruce M, Fornage, Myriam, Arfan Ikram, M, van Duijn, Cornelia M, Seshadri, Sudha, Mosley, Thomas H, and Deary, Ian J

Subjects
Genetics, Brain Disorders, Aging, Human Genome, Adult, Cognition, Genome-Wide Association Study, Geroscience, Humans, Polymorphism, Single Nucleotide, Ubiquitin-Protein Ligases, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10-6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

Published
2021

13. Social regulation of inflammation related gene expression in the multi-ethnic study of atherosclerosis

Author

Brown, Kristen M, Diez-Roux, Ana V, Smith, Jennifer A, Needham, Belinda L, Mukherjee, Bhramar, Ware, Erin B, Liu, Yongmei, Cole, Steven W, Seeman, Teresa E, and Kardia, Sharon LR

Subjects
Biomedical and Clinical Sciences, Psychology, Genetics, Atherosclerosis, 2.1 Biological and endogenous factors, Aged, Female, Gene Expression, Gene Expression Profiling, Health Surveys, Humans, Inflammation, Loneliness, Male, Middle Aged, Social Determinants of Health, Social Discrimination, Stress, Psychological, Social stress, Gene expression, Human social genomics, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biomedical and clinical sciences
Abstract

BackgroundExposure to adverse social factors has been associated with an altered inflammatory profile, a risk factor for several acute and chronic diseases. Differential gene expression may be a biological mediator in the relationship. In this study, associations between a range of social factors and expression of inflammation-related genes were investigated.MethodsSocial factor and gene expression data were collected from 1,264 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA). Inflammation-related genes were identified from the Gene Ontology database. The associations between social factors and gene expression were first assessed using the Global Analysis of Covariance (Global ANCOVA) gene set enrichment test. When the global test was significant, linear regression and elastic net penalized regression were employed to identify the individual gene transcripts within each gene set associated with the social factor.ResultsLoneliness (p = 0.003), chronic burden (p = 0.002), and major or lifetime discrimination (p = 0.045) were significantly associated with global expression of the chronic inflammatory gene set. Of the 20 transcripts that comprise this gene set, elastic net selected 12 transcripts for loneliness, 8 for chronic burden, and 3 for major or lifetime discrimination. Major or lifetime discrimination was also associated with the inflammatory response (p = 0.029), regulation of the inflammatory response (p = 0.041), and immune response (p = 0.025) gene sets in global analyses, and 53, 136, and 26 transcripts were selected via elastic net for these gene sets respectively. There were no significant associations in linear regression analyses after adjustment for multiple testing.ConclusionsThis study highlights gene expression as a biological mechanism through which social factors may affect inflammation.

Published
2020

14. A meta-analysis of genome-wide association studies identifies multiple longevity genes.

Author

Deelen, Joris, Evans, Daniel S, Arking, Dan E, Tesi, Niccolò, Nygaard, Marianne, Liu, Xiaomin, Wojczynski, Mary K, Biggs, Mary L, van der Spek, Ashley, Atzmon, Gil, Ware, Erin B, Sarnowski, Chloé, Smith, Albert V, Seppälä, Ilkka, Cordell, Heather J, Dose, Janina, Amin, Najaf, Arnold, Alice M, Ayers, Kristin L, Barzilai, Nir, Becker, Elizabeth J, Beekman, Marian, Blanché, Hélène, Christensen, Kaare, Christiansen, Lene, Collerton, Joanna C, Cubaynes, Sarah, Cummings, Steven R, Davies, Karen, Debrabant, Birgit, Deleuze, Jean-François, Duncan, Rachel, Faul, Jessica D, Franceschi, Claudio, Galan, Pilar, Gudnason, Vilmundur, Harris, Tamara B, Huisman, Martijn, Hurme, Mikko A, Jagger, Carol, Jansen, Iris, Jylhä, Marja, Kähönen, Mika, Karasik, David, Kardia, Sharon LR, Kingston, Andrew, Kirkwood, Thomas BL, Launer, Lenore J, Lehtimäki, Terho, Lieb, Wolfgang, Lyytikäinen, Leo-Pekka, Martin-Ruiz, Carmen, Min, Junxia, Nebel, Almut, Newman, Anne B, Nie, Chao, Nohr, Ellen A, Orwoll, Eric S, Perls, Thomas T, Province, Michael A, Psaty, Bruce M, Raitakari, Olli T, Reinders, Marcel JT, Robine, Jean-Marie, Rotter, Jerome I, Sebastiani, Paola, Smith, Jennifer, Sørensen, Thorkild IA, Taylor, Kent D, Uitterlinden, André G, van der Flier, Wiesje, van der Lee, Sven J, van Duijn, Cornelia M, van Heemst, Diana, Vaupel, James W, Weir, David, Ye, Kenny, Zeng, Yi, Zheng, Wanlin, Holstege, Henne, Kiel, Douglas P, Lunetta, Kathryn L, Slagboom, P Eline, and Murabito, Joanne M

Subjects
Humans, Heat-Shock Proteins, Longevity, Apolipoprotein E2, Apolipoprotein E4, Genome-Wide Association Study
Abstract

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

Published
2019

15. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author

de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugues, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelos, Graff, Mariaelisa, Alver, Maris, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea RVR, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stančáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, and Giulianini, Franco

Subjects
Epidemiology, Health Sciences, Substance Misuse, Alcoholism, Alcohol Use and Health, Human Genome, Prevention, Genetics, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Adolescent, Adult, Aged, Alcohol Drinking, Cholesterol, HDL, Cholesterol, LDL, Female, Genome-Wide Association Study, Genotype, Humans, Life Style, Lipids, Male, Middle Aged, Phenotype, Racial Groups, Triglycerides, Vascular Endothelial Growth Factor B, Young Adult, alcohol consumption, cholesterol, gene-environment interactions, gene-lifestyle interactions, genome-wide association studies, lipids, triglycerides, InterAct Consortium, Lifelines Cohort, Groningen, The Netherlands, Mathematical Sciences, Medical and Health Sciences
Abstract

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

Published
2019

16. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Author

Davies, Gail, Lam, Max, Harris, Sarah E, Trampush, Joey W, Luciano, Michelle, Hill, W David, Hagenaars, Saskia P, Ritchie, Stuart J, Marioni, Riccardo E, Fawns-Ritchie, Chloe, Liewald, David CM, Okely, Judith A, Ahola-Olli, Ari V, Barnes, Catriona LK, Bertram, Lars, Bis, Joshua C, Burdick, Katherine E, Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E, Hayward, Caroline, Hofer, Edith, Ikram, M Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A, Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A, Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A, Smith, Albert V, Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J, Ware, Erin B, Windham, B Gwen, Wright, Margaret J, Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A, Armstrong, Nicola J, Assareh, Amelia A, Attia, John R, Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A, Böhmer, Anne C, Boyle, Patricia A, Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D, Cirulli, Elizabeth T, Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R, Dale, Anders M, Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G, Evangelou, Evangelos, Faul, Jessica D, Ford, Ian, Freimer, Nelson A, Gao, He, Giegling, Ina, Gillespie, Nathan A, Gordon, Scott D, Gottesman, Rebecca F, Griswold, Michael E, Gudnason, Vilmundur, Harris, Tamara B, Hartmann, Annette M, Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G, Joshi, Peter K, Kähönen, Mika, Kardia, Sharon LR, Karlsson, Ida, and Kleineidam, Luca

Abstract

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Published
2019

17. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Author

Kilpeläinen, Tuomas O, Bentley, Amy R, Noordam, Raymond, Sung, Yun Ju, Schwander, Karen, Winkler, Thomas W, Jakupović, Hermina, Chasman, Daniel I, Manning, Alisa, Ntalla, Ioanna, Aschard, Hugues, Brown, Michael R, de Las Fuentes, Lisa, Franceschini, Nora, Guo, Xiuqing, Vojinovic, Dina, Aslibekyan, Stella, Feitosa, Mary F, Kho, Minjung, Musani, Solomon K, Richard, Melissa, Wang, Heming, Wang, Zhe, Bartz, Traci M, Bielak, Lawrence F, Campbell, Archie, Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P, Horimoto, Andrea RVR, Li, Changwei, Lohman, Kurt K, Marten, Jonathan, Sim, Xueling, Smith, Albert V, Tajuddin, Salman M, Alver, Maris, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Evangelou, Evangelos, Gao, Chuan, Graff, Mariaelisa, Harris, Sarah E, He, Meian, Hsu, Fang-Chi, Jackson, Anne U, Zhao, Jing Hua, Kraja, Aldi T, Kühnel, Brigitte, Laguzzi, Federica, Lyytikäinen, Leo-Pekka, Nolte, Ilja M, Rauramaa, Rainer, Riaz, Muhammad, Robino, Antonietta, Rueedi, Rico, Stringham, Heather M, Takeuchi, Fumihiko, van der Most, Peter J, Varga, Tibor V, Verweij, Niek, Ware, Erin B, Wen, Wanqing, Li, Xiaoyin, Yanek, Lisa R, Amin, Najaf, Arnett, Donna K, Boerwinkle, Eric, Brumat, Marco, Cade, Brian, Canouil, Mickaël, Chen, Yii-Der Ida, Concas, Maria Pina, Connell, John, de Mutsert, Renée, de Silva, H Janaka, de Vries, Paul S, Demirkan, Ayşe, Ding, Jingzhong, Eaton, Charles B, Faul, Jessica D, Friedlander, Yechiel, Gabriel, Kelley P, Ghanbari, Mohsen, Giulianini, Franco, Gu, Chi Charles, Gu, Dongfeng, Harris, Tamara B, He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven C, Ikram, M Arfan, Jonas, Jost B, Koh, Woon-Puay, Komulainen, Pirjo, and Krieger, Jose E

Subjects
Lifelines Cohort Study, Humans, Cholesterol, Lipids, Triglycerides, Calcium-Binding Proteins, Muscle Proteins, Microtubule-Associated Proteins, Membrane Proteins, Nerve Tissue Proteins, Transcription Factors, Exercise, Genotype, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, African Continental Ancestry Group, Asian Continental Ancestry Group, European Continental Ancestry Group, Hispanic Americans, Brazil, Female, Male, Lipid Metabolism, Cholesterol, LDL, Cholesterol, HDL, Genome-Wide Association Study, Young Adult, Genetic Loci, LIM-Homeodomain Proteins, and over, HDL, LDL
Abstract

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

Published
2019

18. Correction: Association of low-frequency and rare coding variants with information processing speed

Author

Bressler, Jan, Davies, Gail, Smith, Albert V., Saba, Yasaman, Bis, Joshua C., Jian, Xueqiu, Hayward, Caroline, Yanek, Lisa, Smith, Jennifer A., Mirza, Saira S., Wang, Ruiqi, Adams, Hieab H. H., Becker, Diane, Boerwinkle, Eric, Campbell, Archie, Cox, Simon R., Eiriksdottir, Gudny, Fawns-Ritchie, Chloe, Gottesman, Rebecca F., Grove, Megan L., Guo, Xiuqing, Hofer, Edith, Kardia, Sharon L. R., Knol, Maria J., Koini, Marisa, Lopez, Oscar L., Marioni, Riccardo E., Nyquist, Paul, Pattie, Alison, Polasek, Ozren, Porteous, David J., Rudan, Igor, Satizabal, Claudia L., Schmidt, Helena, Schmidt, Reinhold, Sidney, Stephen, Simino, Jeannette, Smith, Blair H., Turner, Stephen T., van der Lee, Sven J., Ware, Erin B., Whitmer, Rachel A., Yaffe, Kristine, Yang, Qiong, Zhao, Wei, Gudnason, Vilmundur, Launer, Lenore J., Fitzpatrick, Annette L., Psaty, Bruce M., Fornage, Myriam, Arfan Ikram, M., van Duijn, Cornelia M., Seshadri, Sudha, Mosley, Thomas H., and Deary, Ian J.

Published
2022
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20. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Author

Davies, Gail, Lam, Max, Harris, Sarah E, Trampush, Joey W, Luciano, Michelle, Hill, W David, Hagenaars, Saskia P, Ritchie, Stuart J, Marioni, Riccardo E, Fawns-Ritchie, Chloe, Liewald, David CM, Okely, Judith A, Ahola-Olli, Ari V, Barnes, Catriona LK, Bertram, Lars, Bis, Joshua C, Burdick, Katherine E, Christoforou, Andrea, DeRosse, Pamela, Djurovic, Srdjan, Espeseth, Thomas, Giakoumaki, Stella, Giddaluru, Sudheer, Gustavson, Daniel E, Hayward, Caroline, Hofer, Edith, Ikram, M Arfan, Karlsson, Robert, Knowles, Emma, Lahti, Jari, Leber, Markus, Li, Shuo, Mather, Karen A, Melle, Ingrid, Morris, Derek, Oldmeadow, Christopher, Palviainen, Teemu, Payton, Antony, Pazoki, Raha, Petrovic, Katja, Reynolds, Chandra A, Sargurupremraj, Muralidharan, Scholz, Markus, Smith, Jennifer A, Smith, Albert V, Terzikhan, Natalie, Thalamuthu, Anbupalam, Trompet, Stella, van der Lee, Sven J, Ware, Erin B, Windham, B Gwen, Wright, Margaret J, Yang, Jingyun, Yu, Jin, Ames, David, Amin, Najaf, Amouyel, Philippe, Andreassen, Ole A, Armstrong, Nicola J, Assareh, Amelia A, Attia, John R, Attix, Deborah, Avramopoulos, Dimitrios, Bennett, David A, Böhmer, Anne C, Boyle, Patricia A, Brodaty, Henry, Campbell, Harry, Cannon, Tyrone D, Cirulli, Elizabeth T, Congdon, Eliza, Conley, Emily Drabant, Corley, Janie, Cox, Simon R, Dale, Anders M, Dehghan, Abbas, Dick, Danielle, Dickinson, Dwight, Eriksson, Johan G, Evangelou, Evangelos, Faul, Jessica D, Ford, Ian, Freimer, Nelson A, Gao, He, Giegling, Ina, Gillespie, Nathan A, Gordon, Scott D, Gottesman, Rebecca F, Griswold, Michael E, Gudnason, Vilmundur, Harris, Tamara B, Hartmann, Annette M, Hatzimanolis, Alex, Heiss, Gerardo, Holliday, Elizabeth G, Joshi, Peter K, Kähönen, Mika, Kardia, Sharon LR, Karlsson, Ida, and Kleineidam, Luca

Subjects
Humans, Neurodegenerative Diseases, Genetic Predisposition to Disease, Cognition, Reaction Time, Mental Disorders, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Young Adult, Genetic Loci, Neurodevelopmental Disorders, Prevention, Behavioral and Social Science, Mental Health, Neurosciences, Biotechnology, Genetics, Human Genome, Neurological, Mental health
Abstract

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P

Published
2018

21. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

Author

Feitosa, Mary F, Kraja, Aldi T, Chasman, Daniel I, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K, Li, Changwei, Bentley, Amy R, Brown, Michael R, Schwander, Karen, Richard, Melissa A, Noordam, Raymond, Aschard, Hugues, Bartz, Traci M, Bielak, Lawrence F, Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P, Horimoto, Andrea RVR, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Wojczynski, Mary K, Alver, Maris, Boissel, Mathilde, Cai, Qiuyin, Campbell, Archie, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, He, Meian, Hsu, Fang-Chi, Jackson, Anne U, Kähönen, Mika, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Luan, Jian'an, Matoba, Nana, Nolte, Ilja M, Padmanabhan, Sandosh, Riaz, Muhammad, Rueedi, Rico, Robino, Antonietta, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stančáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Vitart, Veronique, Wang, Yajuan, Ware, Erin B, Warren, Helen R, Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Boerwinkle, Eric, Borecki, Ingrid, Broeckel, Ulrich, Brown, Morris, Brumat, Marco, Burke, Gregory L, Canouil, Mickaël, Chakravarti, Aravinda, Charumathi, Sabanayagam, Ida Chen, Yii-Der, Connell, John M, Correa, Adolfo, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Deng, Xuan, Ding, Jingzhong, Duan, Qing, Eaton, Charles B, and Ehret, Georg

Subjects
InterAct Consortium, Humans, Hypertension, Genetic Predisposition to Disease, Cohort Studies, Pedigree, Alcohol Drinking, Blood Pressure, Polymorphism, Single Nucleotide, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Continental Population Groups, Female, Male, Genome-Wide Association Study, Young Adult, Gene-Environment Interaction, General Science & Technology
Abstract

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Published
2018

22. Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

Author

Liang, Jingjing, Le, Thu H, Edwards, Digna R Velez, Tayo, Bamidele O, Gaulton, Kyle J, Smith, Jennifer A, Lu, Yingchang, Jensen, Richard A, Chen, Guanjie, Yanek, Lisa R, Schwander, Karen, Tajuddin, Salman M, Sofer, Tamar, Kim, Wonji, Kayima, James, McKenzie, Colin A, Fox, Ervin, Nalls, Michael A, Young, J Hunter, Sun, Yan V, Lane, Jacqueline M, Cechova, Sylvia, Zhou, Jie, Tang, Hua, Fornage, Myriam, Musani, Solomon K, Wang, Heming, Lee, Juyoung, Adeyemo, Adebowale, Dreisbach, Albert W, Forrester, Terrence, Chu, Pei-Lun, Cappola, Anne, Evans, Michele K, Morrison, Alanna C, Martin, Lisa W, Wiggins, Kerri L, Hui, Qin, Zhao, Wei, Jackson, Rebecca D, Ware, Erin B, Faul, Jessica D, Reiner, Alex P, Bray, Michael, Denny, Joshua C, Mosley, Thomas H, Palmas, Walter, Guo, Xiuqing, Papanicolaou, George J, Penman, Alan D, Polak, Joseph F, Rice, Kenneth, Taylor, Ken D, Boerwinkle, Eric, Bottinger, Erwin P, Liu, Kiang, Risch, Neil, Hunt, Steven C, Kooperberg, Charles, Zonderman, Alan B, Laurie, Cathy C, Becker, Diane M, Cai, Jianwen, Loos, Ruth JF, Psaty, Bruce M, Weir, David R, Kardia, Sharon LR, Arnett, Donna K, Won, Sungho, Edwards, Todd L, Redline, Susan, Cooper, Richard S, Rao, DC, Rotter, Jerome I, Rotimi, Charles, Levy, Daniel, Chakravarti, Aravinda, Zhu, Xiaofeng, and Franceschini, Nora

Subjects
Animals, Humans, Mice, Hypertension, Cadherins, Membrane Proteins, Case-Control Studies, Blood Pressure, Multifactorial Inheritance, Polymorphism, Single Nucleotide, African Americans, Female, Male, Basic Helix-Loop-Helix Transcription Factors, Genome-Wide Association Study, Genetic Loci, Kidney Disease, Cardiovascular, Human Genome, Genetics, Biotechnology, Clinical Research, 2.1 Biological and endogenous factors, Developmental Biology
Abstract

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

Published
2017

23. Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium.

Author

Ng, Maggie CY, Graff, Mariaelisa, Lu, Yingchang, Justice, Anne E, Mudgal, Poorva, Liu, Ching-Ti, Young, Kristin, Yanek, Lisa R, Feitosa, Mary F, Wojczynski, Mary K, Rand, Kristin, Brody, Jennifer A, Cade, Brian E, Dimitrov, Latchezar, Duan, Qing, Guo, Xiuqing, Lange, Leslie A, Nalls, Michael A, Okut, Hayrettin, Tajuddin, Salman M, Tayo, Bamidele O, Vedantam, Sailaja, Bradfield, Jonathan P, Chen, Guanjie, Chen, Wei-Min, Chesi, Alessandra, Irvin, Marguerite R, Padhukasahasram, Badri, Smith, Jennifer A, Zheng, Wei, Allison, Matthew A, Ambrosone, Christine B, Bandera, Elisa V, Bartz, Traci M, Berndt, Sonja I, Bernstein, Leslie, Blot, William J, Bottinger, Erwin P, Carpten, John, Chanock, Stephen J, Chen, Yii-Der Ida, Conti, David V, Cooper, Richard S, Fornage, Myriam, Freedman, Barry I, Garcia, Melissa, Goodman, Phyllis J, Hsu, Yu-Han H, Hu, Jennifer, Huff, Chad D, Ingles, Sue A, John, Esther M, Kittles, Rick, Klein, Eric, Li, Jin, McKnight, Barbara, Nayak, Uma, Nemesure, Barbara, Ogunniyi, Adesola, Olshan, Andrew, Press, Michael F, Rohde, Rebecca, Rybicki, Benjamin A, Salako, Babatunde, Sanderson, Maureen, Shao, Yaming, Siscovick, David S, Stanford, Janet L, Stevens, Victoria L, Stram, Alex, Strom, Sara S, Vaidya, Dhananjay, Witte, John S, Yao, Jie, Zhu, Xiaofeng, Ziegler, Regina G, Zonderman, Alan B, Adeyemo, Adebowale, Ambs, Stefan, Cushman, Mary, Faul, Jessica D, Hakonarson, Hakon, Levin, Albert M, Nathanson, Katherine L, Ware, Erin B, Weir, David R, Zhao, Wei, Zhi, Degui, Bone Mineral Density in Childhood Study (BMDCS) Group, Arnett, Donna K, Grant, Struan FA, Kardia, Sharon LR, Oloapde, Olufunmilayo I, Rao, DC, Rotimi, Charles N, Sale, Michele M, Williams, L Keoki, Zemel, Babette S, Becker, Diane M, and Borecki, Ingrid B

Subjects
Bone Mineral Density in Childhood Study (BMDCS) Group, Humans, Obesity, Genetic Predisposition to Disease, Serine Endopeptidases, Anthropometry, Body Mass Index, Waist-Hip Ratio, Chromosome Mapping, Gene Frequency, Linkage Disequilibrium, Polymorphism, Single Nucleotide, African Continental Ancestry Group, European Continental Ancestry Group, Female, Male, Adiposity, Genome-Wide Association Study, Transcription Factor 7-Like 2 Protein, Genetics, Human Genome, 2.1 Biological and endogenous factors, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (

Published
2017

24. DNA Methylation at C-Reactive Protein-Associated CpG Sites May Mediate the Pathway Between Educational Attainment and Cognition.

Author

Stoldt, Meike, Ammous, Farah, Lin, Lisha, Ratliff, Scott M, Ware, Erin B, Faul, Jessica D, Zhao, Wei, Kardia, Sharon L R, and Smith, Jennifer A

Subjects
LEUKOCYTE count, DISEASE risk factors, DNA methylation, OLDER people, SECONDARY education
Abstract

Growing evidence has linked inflammatory processes to cognitive decline and dementia. This work examines whether an epigenetic marker of C-reactive protein (CRP), a common clinical inflammatory biomarker, may mediate the relationship between educational attainment and cognition. We first evaluated whether 53 previously reported CRP-associated DNA methylation sites (CpGs) are associated with CRP, both individually and aggregated into a methylation risk score (MRSCRP), in 3 298 participants from the Health and Retirement Study (HRS, mean age = 69.7 years). Forty-nine CpGs (92%) were associated with the natural logarithm of CRP in HRS after adjusting for age, sex, smoking, BMI, genetic ancestry, and white blood cell counts (p  < .05), and each standard deviation increase in MRSCRP was associated with a 0.38 unit increase in lnCRP (p  = 4.02E-99). In cross-sectional analysis, for each standard deviation increase in MRSCRP, total memory score and total cognitive score decreased, on average, by 0.28 words and 0.43 items, respectively (p  < .001). Further, MRSCRP mediated 6.9% of the relationship between high school education and total memory score in a model adjusting for age, sex, and genetic ancestry (p  < .05); this was attenuated to 2.4% with additional adjustment for marital status, APOE ε4 status, health behaviors, and comorbidities (p  < .05). Thus, CRP-associated methylation may partially mediate the relationship between education and cognition at older ages. Further research is warranted to determine whether DNA methylation at these sites may improve current prediction models for cognitive impairment in older adults. [ABSTRACT FROM AUTHOR]

Published
2024
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26. Genome-wide Association Studies of Posttraumatic Stress Disorder in 2 Cohorts of US Army Soldiers

Author

Stein, Murray B, Chen, Chia-Yen, Ursano, Robert J, Cai, Tianxi, Gelernter, Joel, Heeringa, Steven G, Jain, Sonia, Jensen, Kevin P, Maihofer, Adam X, Mitchell, Colter, Nievergelt, Caroline M, Nock, Matthew K, Neale, Benjamin M, Polimanti, Renato, Ripke, Stephan, Sun, Xiaoying, Thomas, Michael L, Wang, Qian, Ware, Erin B, Borja, Susan, Kessler, Ronald C, and Smoller, Jordan W

Subjects
Mental Health, Clinical Research, Anxiety Disorders, Human Genome, Genetics, Post-Traumatic Stress Disorder (PTSD), Brain Disorders, 2.3 Psychological, social and economic factors, Aetiology, Inflammatory and immune system, Mental health, Good Health and Well Being, Adult, Carrier Proteins, Case-Control Studies, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 5, Cohort Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Military Personnel, Polymorphism, Single Nucleotide, Stress Disorders, Post-Traumatic, Young Adult, Army Study to Assess Risk and Resilience in Servicemembers (STARRS) Collaborators, Other Medical and Health Sciences, Psychology, Cognitive Sciences
Abstract

ImportancePosttraumatic stress disorder (PTSD) is a prevalent, serious public health concern, particularly in the military. The identification of genetic risk factors for PTSD may provide important insights into the biological foundation of vulnerability and comorbidity.ObjectiveTo discover genetic loci associated with the lifetime risk for PTSD in 2 cohorts from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS).Design, setting, and participantsTwo coordinated genome-wide association studies of mental health in the US military contributed participants. The New Soldier Study (NSS) included 3167 unique participants with PTSD and 4607 trauma-exposed control individuals; the Pre/Post Deployment Study (PPDS) included 947 unique participants with PTSD and 4969 trauma-exposed controls. The NSS data were collected from February 1, 2011, to November 30, 2012; the PDDS data, from January 9 to April 30, 2012. The primary analysis compared lifetime DSM-IV PTSD cases with trauma-exposed controls without lifetime PTSD. Data were analyzed from March 18 to December 27, 2015.Main outcomes and measuresAssociation analyses for PTSD used logistic regression models within each of 3 ancestral groups (European, African, and Latino American) by study, followed by meta-analysis. Heritability and genetic correlation and pleiotropy with other psychiatric and immune-related disorders were estimated.ResultsThe NSS population was 80.7% male (6277 of 7774 participants; mean [SD] age, 20.9 [3.3] years); the PPDS population, 94.4% male (5583 of 5916 participants; mean [SD] age, 26.5 [6.0] years). A genome-wide significant locus was found in ANKRD55 on chromosome 5 (rs159572; odds ratio [OR], 1.62; 95% CI, 1.37-1.92; P = 2.34 × 10-8) and persisted after adjustment for cumulative trauma exposure (adjusted OR, 1.64; 95% CI, 1.39-1.95; P = 1.18 × 10-8) in the African American samples from the NSS. A genome-wide significant locus was also found in or near ZNF626 on chromosome 19 (rs11085374; OR, 0.77; 95% CI, 0.70-0.85; P = 4.59 × 10-8) in the European American samples from the NSS. Similar results were not found for either single-nucleotide polymorphism in the corresponding ancestry group from the PPDS sample, in other ancestral groups, or in transancestral meta-analyses. Single-nucleotide polymorphism-based heritability was nonsignificant, and no significant genetic correlations were observed between PTSD and 6 mental disorders or 9 immune-related disorders. Significant evidence of pleiotropy was observed between PTSD and rheumatoid arthritis and, to a lesser extent, psoriasis.Conclusions and relevanceIn the largest genome-wide association study of PTSD to date, involving a US military sample, limited evidence of association for specific loci was found. Further efforts are needed to replicate the genome-wide significant association with ANKRD55-associated in prior research with several autoimmune and inflammatory disorders-and to clarify the nature of the genetic overlap observed between PTSD and rheumatoid arthritis and psoriasis.

Published
2016

29. A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Author

Jhun, Min-A, Mendelson, Michael, Wilson, Rory, Gondalia, Rahul, Joehanes, Roby, Salfati, Elias, Zhao, Xiaoping, Braun, Kim Valeska Emilie, Do, Anh Nguyet, Hedman, Åsa K., Zhang, Tao, Carnero-Montoro, Elena, Shen, Jincheng, Bartz, Traci M., Brody, Jennifer A., Montasser, May E., O’Connell, Jeff R., Yao, Chen, Xia, Rui, Boerwinkle, Eric, Grove, Megan, Guan, Weihua, Liliane, Pfeiffer, Singmann, Paula, Müller-Nurasyid, Martina, Meitinger, Thomas, Gieger, Christian, Peters, Annette, Zhao, Wei, Ware, Erin B., Smith, Jennifer A., Dhana, Klodian, van Meurs, Joyce, Uitterlinden, Andre, Ikram, Mohammad Arfan, Ghanbari, Mohsen, Zhi, Deugi, Gustafsson, Stefan, Lind, Lars, Li, Shengxu, Sun, Dianjianyi, Spector, Tim D., Chen, Yii-der Ida, Damcott, Coleen, Shuldiner, Alan R., Absher, Devin M., Horvath, Steve, Tsao, Philip S., Kardia, Sharon, Psaty, Bruce M., Sotoodehnia, Nona, Bell, Jordana T., Ingelsson, Erik, Chen, Wei, Dehghan, Abbas, Arnett, Donna K., Waldenberger, Melanie, Hou, Lifang, Whitsel, Eric A., Baccarelli, Andrea, Levy, Daniel, Fornage, Myriam, Irvin, Marguerite R., and Assimes, Themistocles L.

Published
2021
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30. Publisher Correction: A meta-analysis of genome-wide association studies identifies multiple longevity genes

Author

Deelen, Joris, Evans, Daniel S., Arking, Dan E., Tesi, Niccolò, Nygaard, Marianne, Liu, Xiaomin, Wojczynski, Mary K., Biggs, Mary L., van der Spek, Ashley, Atzmon, Gil, Ware, Erin B., Sarnowski, Chloé, Smith, Albert V., Seppälä, Ilkka, Cordell, Heather J., Dose, Janina, Amin, Najaf, Arnold, Alice M., Ayers, Kristin L., Barzilai, Nir, Becker, Elizabeth J., Beekman, Marian, Blanché, Hélène, Christensen, Kaare, Christiansen, Lene, Collerton, Joanna C., Cubaynes, Sarah, Cummings, Steven R., Davies, Karen, Debrabant, Birgit, Deleuze, Jean-François, Duncan, Rachel, Faul, Jessica D., Franceschi, Claudio, Galan, Pilar, Gudnason, Vilmundur, Harris, Tamara B., Huisman, Martijn, Hurme, Mikko A., Jagger, Carol, Jansen, Iris, Jylhä, Marja, Kähönen, Mika, Karasik, David, Kardia, Sharon L. R., Kingston, Andrew, Kirkwood, Thomas B. L., Launer, Lenore J., Lehtimäki, Terho, Lieb, Wolfgang, Lyytikäinen, Leo-Pekka, Martin-Ruiz, Carmen, Min, Junxia, Nebel, Almut, Newman, Anne B., Nie, Chao, Nohr, Ellen A., Orwoll, Eric S., Perls, Thomas T., Province, Michael A., Psaty, Bruce M., Raitakari, Olli T., Reinders, Marcel J. T., Robine, Jean-Marie, Rotter, Jerome I., Sebastiani, Paola, Smith, Jennifer, Sørensen, Thorkild I. A., Taylor, Kent D., Uitterlinden, André G., van der Flier, Wiesje, van der Lee, Sven J., van Duijn, Cornelia M., van Heemst, Diana, Vaupel, James W., Weir, David, Ye, Kenny, Zeng, Yi, Zheng, Wanlin, Holstege, Henne, Kiel, Douglas P., Lunetta, Kathryn L., Slagboom, P. Eline, and Murabito, Joanne M.

Published
2021
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31. Publisher Correction: A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Author

Jhun, Min-A, Mendelson, Michael, Wilson, Rory, Gondalia, Rahul, Joehanes, Roby, Salfati, Elias, Zhao, Xiaoping, Braun, Kim Valeska Emilie, Do, Anh Nguyet, Hedman, Åsa K., Zhang, Tao, Carnero-Montoro, Elena, Shen, Jincheng, Bartz, Traci M., Brody, Jennifer A., Montasser, May E., O’Connell, Jeff R., Yao, Chen, Xia, Rui, Boerwinkle, Eric, Grove, Megan, Guan, Weihua, Liliane, Pfeiffer, Singmann, Paula, Müller-Nurasyid, Martina, Meitinger, Thomas, Gieger, Christian, Peters, Annette, Zhao, Wei, Ware, Erin B., Smith, Jennifer A., Dhana, Klodian, van Meurs, Joyce, Uitterlinden, Andre, Ikram, Mohammad Arfan, Ghanbari, Mohsen, Zhi, Deugi, Gustafsson, Stefan, Lind, Lars, Li, Shengxu, Sun, Dianjianyi, Spector, Tim D., Chen, Yii-der Ida, Damcott, Coleen, Shuldiner, Alan R., Absher, Devin M., Horvath, Steve, Tsao, Philip S., Kardia, Sharon, Psaty, Bruce M., Sotoodehnia, Nona, Bell, Jordana T., Ingelsson, Erik, Chen, Wei, Dehghan, Abbas, Arnett, Donna K., Waldenberger, Melanie, Hou, Lifang, Whitsel, Eric A., Baccarelli, Andrea, Levy, Daniel, Fornage, Myriam, Irvin, Marguerite R., and Assimes, Themistocles L.

Published
2021
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33. Association between Stress Response Genes and Features of Diurnal Cortisol Curves in the Multi-Ethnic Study of Atherosclerosis: A New Multi-Phenotype Approach for Gene-Based Association Tests.

Author

He, Zihuai, Payne, Erin K, Mukherjee, Bhramar, Lee, Seunggeun, Smith, Jennifer A, Ware, Erin B, Sánchez, Brisa N, Seeman, Teresa E, Kardia, Sharon LR, and Diez Roux, Ana V

Subjects
Humans, Hydrocortisone, Receptors, Adrenergic, beta-2, Regression Analysis, Gene Expression Regulation, Circadian Rhythm, Aged, Aged, 80 and over, Middle Aged, African Americans, European Continental Ancestry Group, Hispanic Americans, United States, Female, Male, Atherosclerosis, Stress, Physiological, Genetic Association Studies, and over, Receptors, Adrenergic, beta-2, Stress, Physiological, General Science & Technology
Abstract

The hormone cortisol is likely to be a key mediator of the stress response that influences multiple physiologic systems that are involved in common chronic disease, including the cardiovascular system, the immune system, and metabolism. In this paper, a candidate gene approach was used to investigate genetic contributions to variability in multiple correlated features of the daily cortisol profile in a sample of European Americans, African Americans, and Hispanic Americans from the Multi-Ethnic Study of Atherosclerosis (MESA). We proposed and applied a new gene-level multiple-phenotype analysis and carried out a meta-analysis to combine the ethnicity specific results. This new analysis, instead of a more routine single marker-single phenotype approach identified a significant association between one gene (ADRB2) and cortisol features (meta-analysis p-value=0.0025), which was not identified by three other commonly used existing analytic strategies: 1. Single marker association tests involving each single cortisol feature separately; 2. Single marker association tests jointly testing for multiple cortisol features; 3. Gene-level association tests separately carried out for each single cortisol feature. The analytic strategies presented consider different hypotheses regarding genotype-phenotype association and imply different costs of multiple testing. The proposed gene-level analysis integrating multiple cortisol features across multiple ethnic groups provides new insights into the gene-cortisol association.

Published
2015

35. Contributors

Author

Aceto, Giuseppe, primary, Aguilar-Valles, Argel, additional, Ahmad, Mir Hilal, additional, Ahmed, Aisha Asad, additional, Ahmed, Amani, additional, Ali, Muneer, additional, Alsaleh, Muaweah Ahmad, additional, Amen, Daniel, additional, Araos, Pedro, additional, Araújo, João Ronielly Campêlo, additional, Arsenault, Emily, additional, Atanasova, Dimitrinka, additional, Bengoetxea, Xabier, additional, Bennett, Nelson, additional, Bettis, Alexandra H., additional, Beyer, Cordian, additional, Bialek, Katarzyna, additional, Bodurka, Jerzy, additional, Borsotto, Marc, additional, Brocardo, Patricia S., additional, Broderick, Patricia A., additional, Brust, Tarsis F., additional, Cofresi, Steven L., additional, Cook, Ryan, additional, Czarny, Piotr, additional, D’Ascenzo, Marcello, additional, Daneshmend, Ayeila, additional, Dean, Brian, additional, Di Re, Jessica, additional, Djafarian, Kurosh, additional, Dozois, David J.A., additional, Ellard, Kristen K., additional, Eloy, Jean Daniel, additional, Faber, Jay, additional, Fatima, Mahino, additional, Flores-López, María, additional, Forsblom, Anita, additional, Funes, Christopher J., additional, Gage, Fred H., additional, Gałecki, Piotr, additional, Gao, Keming, additional, García-Marchena, Nuria, additional, Gard, Arianna M., additional, Giacoletti, Gianna, additional, Gillies, Jennifer C.P., additional, Gil-Mohapel, Joana, additional, Gonda, Xenia, additional, Green, Thomas A, additional, Grover, Sandeep, additional, Gupta, Girdhari Lal, additional, Hamilton, Jessica L., additional, Heard, Kelly J., additional, Heurteaux, Catherine, additional, Hoffmann, Stefanie, additional, Hosseini, Azar, additional, Hosseinzadeh, Hossein, additional, Huang, Li-Ting, additional, Hyvönen, Katriina, additional, Ising, Marcus, additional, Jafarirad, Sima, additional, Jihad-Mohamad, Zeynep, additional, Jiménez-Navarro, Manuel, additional, Juhász, Gábor, additional, Karbownik, Michał Seweryn, additional, Karimpour, Mona, additional, Kazemi, Asma, additional, Kékesi, Katalin Adrienna, additional, Kéri, Szabolcs, additional, Klein, Daniel N., additional, Kowalczyk, Edward, additional, Kowalczyk, Mateusz, additional, Lacaille, Jean-Claude, additional, Laezza, Fernanda, additional, Landsman, Anna, additional, Lazarov, Nikolai, additional, Liu, Richard T., additional, Mackin, Daniel M., additional, Mangiavacchi, Paula M., additional, Matta-Camacho, Edna, additional, Mazella, Jean, additional, Mehrabi, Soraya, additional, Mendonça, Mariana S., additional, Milagro, Fermin, additional, Mishra, Akanksha, additional, Mittli, Dániel, additional, Mondal, Amal Chandra, additional, Msdi, Abdulwhab Shremo, additional, Muotka, Joona, additional, Nahavandi, Arezo, additional, Nelson, Brady D., additional, Nyveld, Melissa, additional, de Oliveira Monteiro-Moreira, Ana Cristina, additional, Patel, Vinood B., additional, de Paula Nascimento-Castro, Cristine, additional, Pavón, Francisco Javier, additional, Petschner, Peter, additional, Pirdoğan Aydın, Efruz, additional, Plácido, Evelini, additional, Porras-Perales, Oscar, additional, Portella, Maria J., additional, Preedy, Victor R., additional, Price, Rebecca B., additional, Pylvänäinen (Maria), Päivi, additional, Rahbardar, Mahboobeh Ghasemzadeh, additional, Rahimlou, Mehran, additional, Rajendram, Rajkumar, additional, Ramirez, Maria J., additional, Razavi, Bibi Marjan, additional, Rengasamy, Manivel, additional, Requena-Ocaña, Nerea, additional, Rios, Álvaro F.L., additional, Rizvi, M. Moshahid Alam, additional, Rodríguez de Fonseca, Fernando, additional, Sahoo, Swapnajeet, additional, Sanblas, Mirian, additional, Semkovska, Maria, additional, Serrano, Antonia, additional, Shah, Priyank, additional, Shukla, Shubha, additional, Sienkiewicz, Monika, additional, Singh, Sonu, additional, Śliwiński, Tomasz, additional, Sonawane, Minal, additional, Sonenberg, Nahum, additional, Sood, Rishi, additional, Sullivan, Kelly L., additional, Taghavi-Abkuh, Fatimeh-Frouh, additional, Talarowska, Monika, additional, Tchekalarova, Jana Dimitrova, additional, Tukacs, Vanda, additional, Türkyılmaz Uyar, Ece, additional, Uribe, Sofia, additional, Vadodaria, Krishna C., additional, Vicent-Gil, Muriel, additional, Ware, Erin B., additional, Welter, Priscilla Gomes, additional, Wigner, Paulina, additional, Wilde, Jesse Lee, additional, Wu, Chunfu, additional, Yang, Jingyu, additional, Ye, Jiang-Hong, additional, Zhang, Jian, additional, Zhang, Kuo, additional, Zhang, Molly, additional, Ziolkowska, Sylwia, additional, Zotev, Vadim, additional, Zuo, Qi Kang, additional, and Zuo, Wanhong, additional

Published
2021
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37. List of contributors

Author

Abramson, Corey M., primary, Brooks, Jennifer D., additional, Burr, Jeffrey A., additional, Carr, Deborah, additional, Clarke, Philippa, additional, Cotten, Shelia R., additional, Faul, Jessica D., additional, Ferraro, Kenneth F., additional, French, Eric, additional, Gitlin, Laura N., additional, Gonyea, Judith G., additional, Govil, Dipti, additional, Han, Sae Hwang, additional, Henkens, Kène, additional, Hu, Mengyao, additional, Huisman, Martijn, additional, Idler, Ellen L., additional, Iveniuk, James, additional, Jain, Urvashi, additional, Johnson, Rucker C., additional, Jones, John Bailey, additional, Kelley, Jessica A., additional, Kelly, Elaine, additional, LaFave, Sarah E., additional, Lee, Haena, additional, Lee, Jinkook, additional, London, Andrew S., additional, Lubet, Alyssa, additional, McCauley, Jeremy, additional, Montez, Jennifer Karas, additional, Mooney, Heather, additional, Mutchler, Jan E., additional, Park, Sung S., additional, Perkins, Molly M., additional, Qualls, Sara Honn, additional, Sekher, T V, additional, Smets, Kaat, additional, Smith, Jacqui, additional, Szanton, Sarah L., additional, Thorpe, Roland J., additional, Twardzik, Erica, additional, van Solinge, Hanna, additional, van Tilburg, Theo G., additional, Waite, Linda J., additional, Ware, Erin B., additional, Wiemers, Emily E., additional, and Wilmoth, Janet M., additional

Published
2021
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39. Relationship between alcohol consumption and dementia with Mendelian randomization approaches among older adults in the United States.

Author

Campbell, Kyle A., Fu, Mingzhou, MacDonald, Elizabeth, Zawistowski, Matthew, Bakulski, Kelly M., and Ware, Erin B.

Subjects
ALCOHOL drinking, OLDER people, DEMENTIA, ALZHEIMER'S disease, GENOME-wide association studies
Abstract

INTRODUCTION: In observational studies, the association between alcohol consumption and dementia is mixed. METHODS: We performed two‐sample Mendelian randomization (MR) using summary statistics from genome‐wide association studies of weekly alcohol consumption and late‐onset Alzheimer's disease and one‐sample MR in the Health and Retirement Study (HRS), wave 2012. Inverse variance weighted two‐stage regression provided odds ratios of association between alcohol exposure and dementia or cognitively impaired, non‐dementia relative to cognitively normal. RESULTS: Alcohol consumption was not associated with late‐onset Alzheimer's disease using two‐sample MR (odds ratio [OR] = 1.15, 95% confidence interval [CI]: [0.78, 1.72]). In HRS, doubling weekly alcohol consumption was not associated with dementia (African ancestries, n = 1,322, OR = 1.00, 95% CI [0.45, 2.25]; European ancestries, n = 7,160, OR = 1.37, 95% CI [0.53, 3.51]) or cognitively impaired, non‐dementia (African ancestries, n = 1,322, OR = 1.17, 95% CI [0.69, 1.98]; European ancestries, n = 7,160, OR = 0.75, 95% CI [0.47, 1.22]). DISCUSSION: Alcohol consumption was not associated with cognitively impaired, non‐dementia or dementia status. Highlights: Cross‐sectionally in a large, diverse sample, alcohol appears protective for dementia.We apply two‐ and one‐sample Mendelian randomization to test inferred causality.Mendelian randomization approaches show no association with alcohol and dementia.We conclude that alcohol consumption should not be considered protective. [ABSTRACT FROM AUTHOR]

Published
2024
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40. Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

Author

de las Fuentes, Lisa, primary, Schwander, Karen L., additional, Brown, Michael R., additional, Bentley, Amy R., additional, Winkler, Thomas W., additional, Sung, Yun Ju, additional, Munroe, Patricia B., additional, Miller, Clint L., additional, Aschard, Hugo, additional, Aslibekyan, Stella, additional, Bartz, Traci M., additional, Bielak, Lawrence F., additional, Chai, Jin Fang, additional, Cheng, Ching-Yu, additional, Dorajoo, Rajkumar, additional, Feitosa, Mary F., additional, Guo, Xiuqing, additional, Hartwig, Fernando P., additional, Horimoto, Andrea, additional, Kolčić, Ivana, additional, Lim, Elise, additional, Liu, Yongmei, additional, Manning, Alisa K., additional, Marten, Jonathan, additional, Musani, Solomon K., additional, Noordam, Raymond, additional, Padmanabhan, Sandosh, additional, Rankinen, Tuomo, additional, Richard, Melissa A., additional, Ridker, Paul M., additional, Smith, Albert V., additional, Vojinovic, Dina, additional, Zonderman, Alan B., additional, Alver, Maris, additional, Boissel, Mathilde, additional, Christensen, Kaare, additional, Freedman, Barry I., additional, Gao, Chuan, additional, Giulianini, Franco, additional, Harris, Sarah E., additional, He, Meian, additional, Hsu, Fang-Chi, additional, Kühnel, Brigitte, additional, Laguzzi, Federica, additional, Li, Xiaoyin, additional, Lyytikäinen, Leo-Pekka, additional, Nolte, Ilja M., additional, Poveda, Alaitz, additional, Rauramaa, Rainer, additional, Riaz, Muhammad, additional, Robino, Antonietta, additional, Sofer, Tamar, additional, Takeuchi, Fumihiko, additional, Tayo, Bamidele O., additional, van der Most, Peter J., additional, Verweij, Niek, additional, Ware, Erin B., additional, Weiss, Stefan, additional, Wen, Wanqing, additional, Yanek, Lisa R., additional, Zhan, Yiqiang, additional, Amin, Najaf, additional, Arking, Dan E., additional, Ballantyne, Christie, additional, Boerwinkle, Eric, additional, Brody, Jennifer A., additional, Broeckel, Ulrich, additional, Campbell, Archie, additional, Canouil, Mickaël, additional, Chai, Xiaoran, additional, Chen, Yii-Der Ida, additional, Chen, Xu, additional, Chitrala, Kumaraswamy Naidu, additional, Concas, Maria Pina, additional, de Faire, Ulf, additional, de Mutsert, Renée, additional, de Silva, H. Janaka, additional, de Vries, Paul S., additional, Do, Ahn, additional, Faul, Jessica D., additional, Fisher, Virginia, additional, Floyd, James S., additional, Forrester, Terrence, additional, Friedlander, Yechiel, additional, Girotto, Giorgia, additional, Gu, C. Charles, additional, Hallmans, Göran, additional, Heikkinen, Sami, additional, Heng, Chew-Kiat, additional, Homuth, Georg, additional, Hunt, Steven, additional, Ikram, M. Arfan, additional, Jacobs, David R., additional, Kavousi, Maryam, additional, Khor, Chiea Chuen, additional, Kilpeläinen, Tuomas O., additional, Koh, Woon-Puay, additional, Komulainen, Pirjo, additional, Langefeld, Carl D., additional, Liang, Jingjing, additional, Liu, Kiang, additional, Liu, Jianjun, additional, Lohman, Kurt, additional, Mägi, Reedik, additional, Manichaikul, Ani W., additional, McKenzie, Colin A., additional, Meitinger, Thomas, additional, Milaneschi, Yuri, additional, Nauck, Matthias, additional, Nelson, Christopher P., additional, O’Connell, Jeffrey R., additional, Palmer, Nicholette D., additional, Pereira, Alexandre C., additional, Perls, Thomas, additional, Peters, Annette, additional, Polašek, Ozren, additional, Raitakari, Olli T., additional, Rice, Kenneth, additional, Rice, Treva K., additional, Rich, Stephen S., additional, Sabanayagam, Charumathi, additional, Schreiner, Pamela J., additional, Shu, Xiao-Ou, additional, Sidney, Stephen, additional, Sims, Mario, additional, Smith, Jennifer A., additional, Starr, John M., additional, Strauch, Konstantin, additional, Tai, E. Shyong, additional, Taylor, Kent D., additional, Tsai, Michael Y., additional, Uitterlinden, André G., additional, van Heemst, Diana, additional, Waldenberger, Melanie, additional, Wang, Ya-Xing, additional, Wei, Wen-Bin, additional, Wilson, Gregory, additional, Xuan, Deng, additional, Yao, Jie, additional, Yu, Caizheng, additional, Yuan, Jian-Min, additional, Zhao, Wei, additional, Becker, Diane M., additional, Bonnefond, Amélie, additional, Bowden, Donald W., additional, Cooper, Richard S., additional, Deary, Ian J., additional, Divers, Jasmin, additional, Esko, Tõnu, additional, Franks, Paul W., additional, Froguel, Philippe, additional, Gieger, Christian, additional, Jonas, Jost B., additional, Kato, Norihiro, additional, Lakka, Timo A., additional, Leander, Karin, additional, Lehtimäki, Terho, additional, Magnusson, Patrik K. E., additional, North, Kari E., additional, Ntalla, Ioanna, additional, Penninx, Brenda, additional, Samani, Nilesh J., additional, Snieder, Harold, additional, Spedicati, Beatrice, additional, van der Harst, Pim, additional, Völzke, Henry, additional, Wagenknecht, Lynne E., additional, Weir, David R., additional, Wojczynski, Mary K., additional, Wu, Tangchun, additional, Zheng, Wei, additional, Zhu, Xiaofeng, additional, Bouchard, Claude, additional, Chasman, Daniel I., additional, Evans, Michele K., additional, Fox, Ervin R., additional, Gudnason, Vilmundur, additional, Hayward, Caroline, additional, Horta, Bernardo L., additional, Kardia, Sharon L. R., additional, Krieger, Jose Eduardo, additional, Mook-Kanamori, Dennis O., additional, Peyser, Patricia A., additional, Province, Michael M., additional, Psaty, Bruce M., additional, Rudan, Igor, additional, Sim, Xueling, additional, Smith, Blair H., additional, van Dam, Rob M., additional, van Duijn, Cornelia M., additional, Wong, Tien Yin, additional, Arnett, Donna K., additional, Rao, Dabeeru C., additional, Gauderman, James, additional, Liu, Ching-Ti, additional, Morrison, Alanna C., additional, Rotter, Jerome I., additional, and Fornage, Myriam, additional

Published
2023
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41. DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis

Author

Ward-Caviness, Cavin K., Huffman, Jennifer E., Everett, Karl, Germain, Marine, van Dongen, Jenny, Hill, W. David, Jhun, Min A., Brody, Jennifer A., Ghanbari, Mohsen, Du, Lei, Roetker, Nicholas S., de Vries, Paul S., Waldenberger, Melanie, Gieger, Christian, Wolf, Petra, Prokisch, Holger, Koenig, Wolfgang, O'Donnell, Christopher J., Levy, Daniel, Liu, Chunyu, Truong, Vinh, Wells, Philip S., Trégouët, David-Alexandre, Tang, Weihong, Morrison, Alanna C., Boerwinkle, Eric, Wiggins, Kerri L., McKnight, Barbara, Guo, Xiuqing, Psaty, Bruce M., Sotoodenia, Nona, Boomsma, Dorret I., Willemsen, Gonneke, Ligthart, Lannie, Deary, Ian J., Zhao, Wei, Ware, Erin B., Kardia, Sharon L.R., Van Meurs, Joyce B.J., Uitterlinden, Andre G., Franco, Oscar H., Eriksson, Per, Franco-Cereceda, Anders, Pankow, James S., Johnson, Andrew D., Gagnon, France, Morange, Pierre-Emmanuel, de Geus, Eco J.C., Starr, John M., Smith, Jennifer A., Dehghan, Abbas, Björck, Hanna M., Smith, Nicholas L., and Peters, Annette

Published
2018
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42. Combined linkage and association analysis identifies rare and low frequency variants for blood pressure at 1q31

Author

Wang, Heming, Nandakumar, Priyanka, Tekola-Ayele, Fasil, Tayo, Bamidele O., Ware, Erin B., Gu, C. Charles, Lu, Yingchang, Yao, Jie, Zhao, Wei, Smith, Jennifer A., Hellwege, Jacklyn N., Guo, Xiuqing, Edwards, Todd L., Loos, Ruth J. F., Arnett, Donna K., Fornage, Myriam, Rotimi, Charles, Kardia, Sharon L. R., Cooper, Richard S., Rao, D. C., Ehret, Georg, Chakravarti, Aravinda, and Zhu, Xiaofeng

Published
2019
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44. Alcohol Use and Mortality Among Older Couples in the United States: Evidence of Individual and Partner Effects.

Author

Birditt, Kira S, Turkelson, Angela, Polenick, Courtney A, Cranford, James A, Smith, Jennifer A, Ware, Erin B, and Blow, Frederic C

Subjects
MORTALITY of people with alcoholism, ALCOHOLISM, SURVEYS, SPOUSES, ALCOHOL drinking, QUESTIONNAIRES, RESEARCH funding, OLD age
Abstract

Background and Objectives Spouses with concordant (i.e. similar) drinking behaviors often report better quality marriages and are married longer compared with those who report discordant drinking behaviors. Less is known regarding whether concordant or discordant patterns have implications for health, as couples grow older. The present study examined whether drinking patterns among older couples are associated with mortality over time. Research Design and Methods The Health and Retirement Study (HRS) is a nationally representative sample of individuals and their partners (married/cohabiting) over age 50 in the United States, in which participants completed surveys every 2 years. Participants included 4,656 married/cohabiting different-sex couples (9,312 individuals) who completed at least 3 waves of the HRS from 1996 to 2016. Participants reported whether they drank alcohol at all in the last 3 months, and if so, the average amount they drank per week. Mortality data were from 2016. Results Analyses revealed concordant drinking spouses (both indicated they drank in the last 3 months) survived longer than discordant drinking spouses (1 partner drinks and the other does not) and concordant nondrinking spouses. Analysis of average drinks per week showed a quadratic association with mortality such that light drinking predicted better survival rates among individuals and their partners compared with abstaining and heavy drinking. Further, similar levels of drinking in terms of the amount of drinking were associated with greater survival, particularly among wives. Discussion and Implications This study moves the field forward by showing that survival varies as a function of one's own and one's partner's drinking. [ABSTRACT FROM AUTHOR]

Published
2024
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45. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author

Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inês, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D’Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmantas, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathias, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niels, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kees, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charles, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian’an, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., McCarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O’Connel, Jeffrey R., O’Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Markus, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H.-H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Panos, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., and Loos, Ruth J. F.

Published
2018
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46. The Mediating Role of Systemic Inflammation and Moderating Role of Race/Ethnicity in Racialized Disparities in Incident Dementia: A Decomposition Analysis

Author

Higgins Tejera, César, primary, Ware, Erin B., additional, Hicken, Margaret T., additional, Kobayashi, Lindsay C., additional, Wang, Herong, additional, Adkins-Jackson, Paris B., additional, Blostein, Freida, additional, Zawistowski, Matthew, additional, Mukherjee, Bhramar, additional, and Bakulski, Kelly M., additional

Published
2023
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47. Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

Author

de las Fuentes, Lisa, Schwander, Karen L., Brown, Michael R., Bentley, Amy R., Winkler, Thomas W., Sung, Yun Ju, Munroe, Patricia B., Miller, Clint L., Aschard, Hugo, Aslibekyan, Stella, Bartz, Traci M., Bielak, Lawrence F., Chai, Jin Fang, Cheng, Ching Yu, Dorajoo, Rajkumar, Feitosa, Mary F., Guo, Xiuqing, Hartwig, Fernando P., Horimoto, Andrea, Kolčić, Ivana, Lim, Elise, Liu, Yongmei, Manning, Alisa K., Marten, Jonathan, Musani, Solomon K., Noordam, Raymond, Padmanabhan, Sandosh, Rankinen, Tuomo, Richard, Melissa A., Ridker, Paul M., Smith, Albert V., Vojinovic, Dina, Zonderman, Alan B., Alver, Maris, Boissel, Mathilde, Christensen, Kaare, Freedman, Barry I., Gao, Chuan, Giulianini, Franco, Harris, Sarah E., He, Meian, Hsu, Fang Chi, Kühnel, Brigitte, Laguzzi, Federica, Li, Xiaoyin, Lyytikäinen, Leo Pekka, Nolte, Ilja M., Poveda, Alaitz, Rauramaa, Rainer, Riaz, Muhammad, Robino, Antonietta, Sofer, Tamar, Takeuchi, Fumihiko, Tayo, Bamidele O., van der Most, Peter J., Verweij, Niek, Ware, Erin B., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhan, Yiqiang, Amin, Najaf, Arking, Dan E., Ballantyne, Christie, Boerwinkle, Eric, Brody, Jennifer A., Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Chai, Xiaoran, Chen, Yii Der Ida, Chen, Xu, Chitrala, Kumaraswamy Naidu, Concas, Maria Pina, de Faire, Ulf, de Mutsert, Renée, de Silva, H. Janaka, de Vries, Paul S., Do, Ahn, Faul, Jessica D., Fisher, Virginia, Floyd, James S., Forrester, Terrence, Friedlander, Yechiel, Girotto, Giorgia, Gu, C. Charles, Hallmans, Göran, Heikkinen, Sami, Heng, Chew Kiat, Homuth, Georg, Hunt, Steven, Ikram, M. Arfan, Jacobs, David R., Kavousi, Maryam, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon Puay, Komulainen, Pirjo, Langefeld, Carl D., Liang, Jingjing, Liu, Kiang, Liu, Jianjun, Lohman, Kurt, Mägi, Reedik, Manichaikul, Ani W., McKenzie, Colin A., Meitinger, Thomas, Milaneschi, Yuri, Nauck, Matthias, Nelson, Christopher P., O’Connell, Jeffrey R., Palmer, Nicholette D., Pereira, Alexandre C., Perls, Thomas, Peters, Annette, Polašek, Ozren, Raitakari, Olli T., Rice, Kenneth, Rice, Treva K., Rich, Stephen S., Sabanayagam, Charumathi, Schreiner, Pamela J., Shu, Xiao Ou, Sidney, Stephen, Sims, Mario, Smith, Jennifer A., Starr, John M., Strauch, Konstantin, Tai, E. Shyong, Taylor, Kent D., Tsai, Michael Y., Uitterlinden, André G., van Heemst, Diana, Waldenberger, Melanie, Wang, Ya Xing, Wei, Wen Bin, Wilson, Gregory, Xuan, Deng, Yao, Jie, Yu, Caizheng, Yuan, Jian Min, Zhao, Wei, Becker, Diane M., Bonnefond, Amélie, Bowden, Donald W., Cooper, Richard S., Deary, Ian J., Divers, Jasmin, Esko, Tõnu, Franks, Paul W., Froguel, Philippe, Gieger, Christian, Jonas, Jost B., Kato, Norihiro, Lakka, Timo A., Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K.E., North, Kari E., Ntalla, Ioanna, Penninx, Brenda, Samani, Nilesh J., Snieder, Harold, Spedicati, Beatrice, van der Harst, Pim, Völzke, Henry, Wagenknecht, Lynne E., Weir, David R., Wojczynski, Mary K., Wu, Tangchun, Zheng, Wei, Zhu, Xiaofeng, Bouchard, Claude, Chasman, Daniel I., Evans, Michele K., Fox, Ervin R., Gudnason, Vilmundur, Hayward, Caroline, Horta, Bernardo L., Kardia, Sharon L.R., Krieger, Jose Eduardo, Mook-Kanamori, Dennis O., Peyser, Patricia A., Province, Michael M., Psaty, Bruce M., Rudan, Igor, Sim, Xueling, Smith, Blair H., van Dam, Rob M., van Duijn, Cornelia M., Wong, Tien Yin, Arnett, Donna K., Rao, Dabeeru C., Gauderman, James, Liu, Ching Ti, Morrison, Alanna C., Rotter, Jerome I., Fornage, Myriam, de las Fuentes, Lisa, Schwander, Karen L., Brown, Michael R., Bentley, Amy R., Winkler, Thomas W., Sung, Yun Ju, Munroe, Patricia B., Miller, Clint L., Aschard, Hugo, Aslibekyan, Stella, Bartz, Traci M., Bielak, Lawrence F., Chai, Jin Fang, Cheng, Ching Yu, Dorajoo, Rajkumar, Feitosa, Mary F., Guo, Xiuqing, Hartwig, Fernando P., Horimoto, Andrea, Kolčić, Ivana, Lim, Elise, Liu, Yongmei, Manning, Alisa K., Marten, Jonathan, Musani, Solomon K., Noordam, Raymond, Padmanabhan, Sandosh, Rankinen, Tuomo, Richard, Melissa A., Ridker, Paul M., Smith, Albert V., Vojinovic, Dina, Zonderman, Alan B., Alver, Maris, Boissel, Mathilde, Christensen, Kaare, Freedman, Barry I., Gao, Chuan, Giulianini, Franco, Harris, Sarah E., He, Meian, Hsu, Fang Chi, Kühnel, Brigitte, Laguzzi, Federica, Li, Xiaoyin, Lyytikäinen, Leo Pekka, Nolte, Ilja M., Poveda, Alaitz, Rauramaa, Rainer, Riaz, Muhammad, Robino, Antonietta, Sofer, Tamar, Takeuchi, Fumihiko, Tayo, Bamidele O., van der Most, Peter J., Verweij, Niek, Ware, Erin B., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhan, Yiqiang, Amin, Najaf, Arking, Dan E., Ballantyne, Christie, Boerwinkle, Eric, Brody, Jennifer A., Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Chai, Xiaoran, Chen, Yii Der Ida, Chen, Xu, Chitrala, Kumaraswamy Naidu, Concas, Maria Pina, de Faire, Ulf, de Mutsert, Renée, de Silva, H. Janaka, de Vries, Paul S., Do, Ahn, Faul, Jessica D., Fisher, Virginia, Floyd, James S., Forrester, Terrence, Friedlander, Yechiel, Girotto, Giorgia, Gu, C. Charles, Hallmans, Göran, Heikkinen, Sami, Heng, Chew Kiat, Homuth, Georg, Hunt, Steven, Ikram, M. Arfan, Jacobs, David R., Kavousi, Maryam, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon Puay, Komulainen, Pirjo, Langefeld, Carl D., Liang, Jingjing, Liu, Kiang, Liu, Jianjun, Lohman, Kurt, Mägi, Reedik, Manichaikul, Ani W., McKenzie, Colin A., Meitinger, Thomas, Milaneschi, Yuri, Nauck, Matthias, Nelson, Christopher P., O’Connell, Jeffrey R., Palmer, Nicholette D., Pereira, Alexandre C., Perls, Thomas, Peters, Annette, Polašek, Ozren, Raitakari, Olli T., Rice, Kenneth, Rice, Treva K., Rich, Stephen S., Sabanayagam, Charumathi, Schreiner, Pamela J., Shu, Xiao Ou, Sidney, Stephen, Sims, Mario, Smith, Jennifer A., Starr, John M., Strauch, Konstantin, Tai, E. Shyong, Taylor, Kent D., Tsai, Michael Y., Uitterlinden, André G., van Heemst, Diana, Waldenberger, Melanie, Wang, Ya Xing, Wei, Wen Bin, Wilson, Gregory, Xuan, Deng, Yao, Jie, Yu, Caizheng, Yuan, Jian Min, Zhao, Wei, Becker, Diane M., Bonnefond, Amélie, Bowden, Donald W., Cooper, Richard S., Deary, Ian J., Divers, Jasmin, Esko, Tõnu, Franks, Paul W., Froguel, Philippe, Gieger, Christian, Jonas, Jost B., Kato, Norihiro, Lakka, Timo A., Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K.E., North, Kari E., Ntalla, Ioanna, Penninx, Brenda, Samani, Nilesh J., Snieder, Harold, Spedicati, Beatrice, van der Harst, Pim, Völzke, Henry, Wagenknecht, Lynne E., Weir, David R., Wojczynski, Mary K., Wu, Tangchun, Zheng, Wei, Zhu, Xiaofeng, Bouchard, Claude, Chasman, Daniel I., Evans, Michele K., Fox, Ervin R., Gudnason, Vilmundur, Hayward, Caroline, Horta, Bernardo L., Kardia, Sharon L.R., Krieger, Jose Eduardo, Mook-Kanamori, Dennis O., Peyser, Patricia A., Province, Michael M., Psaty, Bruce M., Rudan, Igor, Sim, Xueling, Smith, Blair H., van Dam, Rob M., van Duijn, Cornelia M., Wong, Tien Yin, Arnett, Donna K., Rao, Dabeeru C., Gauderman, James, Liu, Ching Ti, Morrison, Alanna C., Rotter, Jerome I., and Fornage, Myriam

Abstract

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods:A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue.Discussion: Genome-wide interaction analysis of educational a

Published
2023

48. GWAS Meta-Analysis of Suicide Attempt:Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors

Author

Docherty, Anna R., Mullins, Niamh, Ashley-Koch, Allison E., Qin, Xuejun, Coleman, Jonathan R.I., Shabalin, Andrey, Kang, Joo Eun, Murnyak, Balasz, Wendt, Frank, Adams, Mark, Campos, Adrian I., DiBlasi, Emily, Fullerton, Janice M., Kranzler, Henry R., Bakian, Amanda V., Monson, Eric T., Rentería, Miguel E., Walss-Bass, Consuelo, Andreassen, Ole A., Behera, Chittaranjan, Bulik, Cynthia M., Edenberg, Howard J., Kessler, Ronald C., John Mann, J., Nurnberger, John I., Pistis, Giorgio, Streit, Fabian, Ursano, Robert J., Polimanti, Renato, Dennis, Michelle, Garrett, Melanie, Hair, Lauren, Harvey, Philip, Hauser, Elizabeth R., Hauser, Michael A., Huffman, Jennifer, Jacobson, Daniel, Madduri, Ravi, McMahon, Benjamin, Oslin, David W., Trafton, Jodie, Awasthi, Swapnil, Berrettini, Wade H., Bohus, Martin, Chang, Xiao, Chen, Hsi Chung, Chen, Wei J., Christensen, Erik D.M.D., Crow, Scott, Duriez, Philibert, Edwards, Alexis C., Fernández-Aranda, Fernando, Galfalvy, Hanga, Gandal, Michael, Gorwood, Philip, Guo, Yiran, Hafferty, Jonathan D., Hakonarson, Hakon, Halmi, Katherine A., Hishimoto, Akitoyo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Kim, Minsoo, Klump, Kelly L., Levey, Daniel F., Li, Dong, Liao, Shih Cheng, Lieb, Klaus, Lilenfeld, Lisa, Marshall, Christian R., Mitchell, James E., Okazaki, Satoshi, Otsuka, Ikuo, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Ripke, Stephan, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Starnawska, Anna, Strober, Michael, Su, Mei Hsin, Thornton, Laura M., Treasure, Janet, Ware, Erin B., Watson, Hunna J., Witt, Stephanie H., Blake Woodside, D., Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Appadurai, Vivek, Artigas, María Soler, Van Der Auwera, Sandra, Helena Azevedo, M., Bass, Nicholas, Bau, Claiton H.D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Corvin, Aiden, Craddock, Nicholas, Djurovic, Srdjan, Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Gatt, Justine M., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamshere, Marian L., Hartmann, Annette M., Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Krebs, Marie Odile, Landén, Mikael, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Mehta, Divya, Melle, Ingrid, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Nievergelt, Caroline, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W.J.H., Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J.S., Trzaskowski, MacIej, Tsuang, Ming T., Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T.R., Weickert, Cynthia Shannon, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Demontis, Ditte, Erlangsen, Annette, Gelernter, Joel, Glatt, Stephen J., Hougaard, David M., Hwu, Hai Gwo, Kuo, Po Hsiu, Lewis, Cathryn M., Li, Qingqin S., Liu, Chih Min, Martin, Nicholas G., McIntosh, Andrew M., Medland, Sarah E., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Willour, Virginia, Coon, Hilary, Beckham, Jean C., Kimbrel, Nathan A., Ruderfer, Douglas M., Docherty, Anna R., Mullins, Niamh, Ashley-Koch, Allison E., Qin, Xuejun, Coleman, Jonathan R.I., Shabalin, Andrey, Kang, Joo Eun, Murnyak, Balasz, Wendt, Frank, Adams, Mark, Campos, Adrian I., DiBlasi, Emily, Fullerton, Janice M., Kranzler, Henry R., Bakian, Amanda V., Monson, Eric T., Rentería, Miguel E., Walss-Bass, Consuelo, Andreassen, Ole A., Behera, Chittaranjan, Bulik, Cynthia M., Edenberg, Howard J., Kessler, Ronald C., John Mann, J., Nurnberger, John I., Pistis, Giorgio, Streit, Fabian, Ursano, Robert J., Polimanti, Renato, Dennis, Michelle, Garrett, Melanie, Hair, Lauren, Harvey, Philip, Hauser, Elizabeth R., Hauser, Michael A., Huffman, Jennifer, Jacobson, Daniel, Madduri, Ravi, McMahon, Benjamin, Oslin, David W., Trafton, Jodie, Awasthi, Swapnil, Berrettini, Wade H., Bohus, Martin, Chang, Xiao, Chen, Hsi Chung, Chen, Wei J., Christensen, Erik D.M.D., Crow, Scott, Duriez, Philibert, Edwards, Alexis C., Fernández-Aranda, Fernando, Galfalvy, Hanga, Gandal, Michael, Gorwood, Philip, Guo, Yiran, Hafferty, Jonathan D., Hakonarson, Hakon, Halmi, Katherine A., Hishimoto, Akitoyo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Kim, Minsoo, Klump, Kelly L., Levey, Daniel F., Li, Dong, Liao, Shih Cheng, Lieb, Klaus, Lilenfeld, Lisa, Marshall, Christian R., Mitchell, James E., Okazaki, Satoshi, Otsuka, Ikuo, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Ripke, Stephan, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Starnawska, Anna, Strober, Michael, Su, Mei Hsin, Thornton, Laura M., Treasure, Janet, Ware, Erin B., Watson, Hunna J., Witt, Stephanie H., Blake Woodside, D., Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Appadurai, Vivek, Artigas, María Soler, Van Der Auwera, Sandra, Helena Azevedo, M., Bass, Nicholas, Bau, Claiton H.D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Corvin, Aiden, Craddock, Nicholas, Djurovic, Srdjan, Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Gatt, Justine M., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamshere, Marian L., Hartmann, Annette M., Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Krebs, Marie Odile, Landén, Mikael, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Mehta, Divya, Melle, Ingrid, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Nievergelt, Caroline, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W.J.H., Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J.S., Trzaskowski, MacIej, Tsuang, Ming T., Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T.R., Weickert, Cynthia Shannon, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Demontis, Ditte, Erlangsen, Annette, Gelernter, Joel, Glatt, Stephen J., Hougaard, David M., Hwu, Hai Gwo, Kuo, Po Hsiu, Lewis, Cathryn M., Li, Qingqin S., Liu, Chih Min, Martin, Nicholas G., McIntosh, Andrew M., Medland, Sarah E., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Willour, Virginia, Coon, Hilary, Beckham, Jean C., Kimbrel, Nathan A., and Ruderfer, Douglas M.

Abstract

Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide asso-ciation studies (GWASs) recently discovered and cross- validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic co-horts from both studies to conduct the largest GWAS meta- analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry ad-mixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and ge-netic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10–8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10–80). Significant brain tissue gene expression and drug set en-richment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major de-pressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical pheno-types. These findings provide insight into genetic fa, Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and crossvalidated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS metaanalysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attemp

Published
2023

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