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1. Temporal dynamics of the multi-omic response to endurance exercise training

Author

Bae, Dam, Dasari, Surendra, Dennis, Courtney, Evans, Charles R, Gaul, David A, Ilkayeva, Olga, Ivanova, Anna A, Kachman, Maureen T, Keshishian, Hasmik, Lanza, Ian R, Lira, Ana C, Muehlbauer, Michael J, Nair, Venugopalan D, Piehowski, Paul D, Rooney, Jessica L, Smith, Kevin S, Stowe, Cynthia L, Zhao, Bingqing, Clark, Natalie M, Jimenez-Morales, David, Lindholm, Malene E, Many, Gina M, Sanford, James A, Smith, Gregory R, Vetr, Nikolai G, Zhang, Tiantian, Almagro Armenteros, Jose J, Avila-Pacheco, Julian, Bararpour, Nasim, Ge, Yongchao, Hou, Zhenxin, Marwaha, Shruti, Presby, David M, Natarajan Raja, Archana, Savage, Evan M, Steep, Alec, Sun, Yifei, Wu, Si, Zhen, Jimmy, Bodine, Sue C, Esser, Karyn A, Goodyear, Laurie J, Schenk, Simon, Montgomery, Stephen B, Fernández, Facundo M, Sealfon, Stuart C, Snyder, Michael P, Adkins, Joshua N, Ashley, Euan, Burant, Charles F, Carr, Steven A, Clish, Clary B, Cutter, Gary, Gerszten, Robert E, Kraus, William E, Li, Jun Z, Miller, Michael E, Nair, K Sreekumaran, Newgard, Christopher, Ortlund, Eric A, Qian, Wei-Jun, Tracy, Russell, Walsh, Martin J, Wheeler, Matthew T, Dalton, Karen P, Hastie, Trevor, Hershman, Steven G, Samdarshi, Mihir, Teng, Christopher, Tibshirani, Rob, Cornell, Elaine, Gagne, Nicole, May, Sandy, Bouverat, Brian, Leeuwenburgh, Christiaan, Lu, Ching-ju, Pahor, Marco, Hsu, Fang-Chi, Rushing, Scott, Walkup, Michael P, Nicklas, Barbara, Rejeski, W Jack, Williams, John P, Xia, Ashley, Albertson, Brent G, Barton, Elisabeth R, Booth, Frank W, Caputo, Tiziana, Cicha, Michael, De Sousa, Luis Gustavo Oliveira, Farrar, Roger, Hevener, Andrea L, Hirshman, Michael F, Jackson, Bailey E, Ke, Benjamin G, Kramer, Kyle S, Lessard, Sarah J, Makarewicz, Nathan S, Marshall, Andrea G, and Nigro, Pasquale

Subjects
Health Sciences, Sports Science and Exercise, Prevention, Human Genome, Cardiovascular, Behavioral and Social Science, Genetics, Physical Activity, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Generic health relevance, Inflammatory and immune system, Good Health and Well Being, Animals, Female, Humans, Male, Rats, Acetylation, Blood, Cardiovascular Diseases, Databases, Factual, Endurance Training, Epigenome, Inflammatory Bowel Diseases, Internet, Lipidomics, Metabolome, Mitochondria, Multiomics, Non-alcoholic Fatty Liver Disease, Organ Specificity, Phosphorylation, Physical Conditioning, Animal, Physical Endurance, Proteome, Proteomics, Time Factors, Transcriptome, Ubiquitination, Wounds and Injuries, MoTrPAC Study Group, Lead Analysts, MoTrPAC Study Group, General Science & Technology
Abstract

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

Published
2024

2. Identification of proteins associated with type 2 diabetes risk in diverse racial and ethnic populations

Author

Liu, Shuai, Zhu, Jingjing, Zhong, Hua, Wu, Chong, Xue, Haoran, Darst, Burcu F., Guo, Xiuqing, Durda, Peter, Tracy, Russell P., Liu, Yongmei, Johnson, W. Craig, Taylor, Kent D., Manichaikul, Ani W., Goodarzi, Mark O., Gerszten, Robert E., Clish, Clary B., Chen, Yii-Der Ida, Highland, Heather, Haiman, Christopher A., Gignoux, Christopher R., Lange, Leslie, Conti, David V., Raffield, Laura M., Wilkens, Lynne, Marchand, Loïc Le, North, Kari E., Young, Kristin L., Loos, Ruth J., Buyske, Steve, Matise, Tara, Peters, Ulrike, Kooperberg, Charles, Reiner, Alexander P., Yu, Bing, Boerwinkle, Eric, Sun, Quan, Rooney, Mary R., Echouffo-Tcheugui, Justin B., Daviglus, Martha L., Qi, Qibin, Mancuso, Nicholas, Li, Changwei, Deng, Youping, Manning, Alisa, Meigs, James B., Rich, Stephen S., Rotter, Jerome I., and Wu, Lang

Published
2024
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3. Commensal consortia decolonize Enterobacteriaceae via ecological control

Author

Furuichi, Munehiro, Kawaguchi, Takaaki, Pust, Marie-Madlen, Yasuma-Mitobe, Keiko, Plichta, Damian R., Hasegawa, Naomi, Ohya, Takashi, Bhattarai, Shakti K., Sasajima, Satoshi, Aoto, Yoshimasa, Tuganbaev, Timur, Yaginuma, Mizuki, Ueda, Masahiro, Okahashi, Nobuyuki, Amafuji, Kimiko, Kiridoshi, Yuko, Sugita, Kayoko, Stražar, Martin, Avila-Pacheco, Julian, Pierce, Kerry, Clish, Clary B., Skelly, Ashwin N., Hattori, Masahira, Nakamoto, Nobuhiro, Caballero, Silvia, Norman, Jason M., Olle, Bernat, Tanoue, Takeshi, Suda, Wataru, Arita, Makoto, Bucci, Vanni, Atarashi, Koji, Xavier, Ramnik J., and Honda, Kenya

Published
2024
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4. Reverse metabolomics for the discovery of chemical structures from humans

Author

Gentry, Emily C, Collins, Stephanie L, Panitchpakdi, Morgan, Belda-Ferre, Pedro, Stewart, Allison K, Carrillo Terrazas, Marvic, Lu, Hsueh-han, Zuffa, Simone, Yan, Tingting, Avila-Pacheco, Julian, Plichta, Damian R, Aron, Allegra T, Wang, Mingxun, Jarmusch, Alan K, Hao, Fuhua, Syrkin-Nikolau, Mashette, Vlamakis, Hera, Ananthakrishnan, Ashwin N, Boland, Brigid S, Hemperly, Amy, Vande Casteele, Niels, Gonzalez, Frank J, Clish, Clary B, Xavier, Ramnik J, Chu, Hiutung, Baker, Erin S, Patterson, Andrew D, Knight, Rob, Siegel, Dionicio, and Dorrestein, Pieter C

Subjects
Medical Biochemistry and Metabolomics, Analytical Chemistry, Biomedical and Clinical Sciences, Chemical Sciences, Inflammatory Bowel Disease, Digestive Diseases, Crohn's Disease, Autoimmune Disease, Animals, Humans, Bifidobacterium, Bile Acids and Salts, CD4-Positive T-Lymphocytes, Clostridium, Cohort Studies, Crohn Disease, Enterococcus, Esters, Fatty Acids, Inflammatory Bowel Diseases, Metabolomics, Phenotype, Pregnane X Receptor, Reproducibility of Results, Tandem Mass Spectrometry, Amides, General Science & Technology
Abstract

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.

Published
2024

6. Broadcasters, receivers, functional groups of metabolites, and the link to heart failure by revealing metabolomic network connectivity

Author

Yazdani, Azam, Mendez-Giraldez, Raul, Yazdani, Akram, Wang, Rui-Sheng, Schaid, Daniel J., Kong, Sek Won, Hadi, M. Reza, Samiei, Ahmad, Samiei, Esmat, Wittenbecher, Clemens, Lasky-Su, Jessica, Clish, Clary B., Muehlschlegel, Jochen D., Marotta, Francesco, Loscalzo, Joseph, Mora, Samia, Chasman, Daniel I., Larson, Martin G., and Elsea, Sarah H.

Published
2024
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7. Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma

Author

Benson, Mark D, Eisman, Aaron S, Tahir, Usman A, Katz, Daniel H, Deng, Shuliang, Ngo, Debby, Robbins, Jeremy M, Hofmann, Alissa, Shi, Xu, Zheng, Shuning, Keyes, Michelle, Yu, Zhi, Gao, Yan, Farrell, Laurie, Shen, Dongxiao, Chen, Zsu-Zsu, Cruz, Daniel E, Sims, Mario, Correa, Adolfo, Tracy, Russell P, Durda, Peter, Taylor, Kent D, Liu, Yongmei, Johnson, W Craig, Guo, Xiuqing, Yao, Jie, Chen, Yii-Der Ida, Manichaikul, Ani W, Jain, Deepti, Yang, Qiong, Consortium, NHLBI Trans-Omics for Precision Medicine, Bouchard, Claude, Sarzynski, Mark A, Rich, Stephen S, Rotter, Jerome I, Wang, Thomas J, Wilson, James G, Clish, Clary B, Sarkar, Indra Neil, Natarajan, Pradeep, and Gerszten, Robert E

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Genetics, Medical Biochemistry and Metabolomics, Biotechnology, 2.1 Biological and endogenous factors, Humans, Animals, Mice, Proteomics, Metabolomics, Signal Transduction, Genome-Wide Association Study, Polymorphism, Single Nucleotide, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, GWAS, functional genomics, genome-wide association study, genomics, metabolomics, multi-omics, pathway discovery, proteomics, Endocrinology & Metabolism, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.

Published
2023

10. Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection

Author

Luo, Kai, Peters, Brandilyn A., Moon, Jee-Young, Xue, Xiaonan, Wang, Zheng, Usyk, Mykhaylo, Hanna, David B., Landay, Alan L., Schneider, Michael F., Gustafson, Deborah, Weber, Kathleen M., French, Audrey, Sharma, Anjali, Anastos, Kathryn, Wang, Tao, Brown, Todd, Clish, Clary B., Kaplan, Robert C., Knight, Rob, Burk, Robert D., and Qi, Qibin

Published
2024
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12. Plasma metabolite profile of legume consumption and future risk of type 2 diabetes and cardiovascular disease

Author

Margara-Escudero, Hernando J., Paz-Graniel, Indira, García-Gavilán, Jesús, Ruiz-Canela, Miguel, Sun, Qi, Clish, Clary B., Toledo, Estefania, Corella, Dolores, Estruch, Ramón, Ros, Emilio, Castañer, Olga, Arós, Fernando, Fiol, Miquel, Guasch-Ferré, Marta, Lapetra, José, Razquin, Cristina, Dennis, Courtney, Deik, Amy, Li, Jun, Gómez-Gracia, Enrique, Babio, Nancy, Martínez-González, Miguel A., Hu, Frank B., and Salas-Salvadó, Jordi

Published
2024
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14. Lac-Phe mediates the effects of metformin on food intake and body weight

Author

Xiao, Shuke, Li, Veronica L., Lyu, Xuchao, Chen, Xudong, Wei, Wei, Abbasi, Fahim, Knowles, Joshua W., Tung, Alan Sheng-Hwa, Deng, Shuliang, Tiwari, Gaurav, Shi, Xu, Zheng, Shuning, Farrell, Laurie, Chen, Zsu-Zsu, Taylor, Kent D., Guo, Xiuqing, Goodarzi, Mark O., Wood, Alexis C., Chen, Yii-Der Ida, Lange, Leslie A., Rich, Stephen S., Rotter, Jerome I., Clish, Clary B., Tahir, Usman A., Gerszten, Robert E., Benson, Mark D., and Long, Jonathan Z.

Published
2024
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15. Large scale proteomic studies create novel privacy considerations

Author

Hill, Andrew C, Guo, Claire, Litkowski, Elizabeth M, Manichaikul, Ani W, Yu, Bing, Konigsberg, Iain R, Gorbet, Betty A, Lange, Leslie A, Pratte, Katherine A, Kechris, Katerina J, DeCamp, Matthew, Coors, Marilyn, Ortega, Victor E, Rich, Stephen S, Rotter, Jerome I, Gerzsten, Robert E, Clish, Clary B, Curtis, Jeffrey L, Hu, Xiaowei, Obeidat, Ma-en, Morris, Melody, Loureiro, Joseph, Ngo, Debby, O’Neal, Wanda K, Meyers, Deborah A, Bleecker, Eugene R, Hobbs, Brian D, Cho, Michael H, Banaei-Kashani, Farnoush, and Bowler, Russell P

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Cardiovascular, Minority Health, Biotechnology, Atherosclerosis, Health Disparities, Human Genome, Generic health relevance, Humans, Proteome, Bayes Theorem, Privacy, Genome-Wide Association Study, Polymorphism, Single Nucleotide
Abstract

Privacy protection is a core principle of genomic but not proteomic research. We identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS), calculated continuous protein level genotype probabilities, and then applied a naïve Bayesian approach to link SomaScan 1.3K proteomes to genomes for 2812 independent subjects from COPDGene, JHS, SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) and Multi-Ethnic Study of Atherosclerosis (MESA). We correctly linked 90-95% of proteomes to their correct genome and for 95-99% we identify the 1% most likely links. The linking accuracy in subjects with African ancestry was lower (~ 60%) unless training included diverse subjects. With larger profiling (SomaScan 5K) in the Atherosclerosis Risk Communities (ARIC) correct identification was > 99% even in mixed ancestry populations. We also linked proteomes-to-proteomes and used the proteome only to determine features such as sex, ancestry, and first-degree relatives. When serial proteomes are available, the linking algorithm can be used to identify and correct mislabeled samples. This work also demonstrates the importance of including diverse populations in omics research and that large proteomic datasets (> 1000 proteins) can be accurately linked to a specific genome through pQTL knowledge and should not be considered unidentifiable.

Published
2023

16. Nontargeted and Targeted Metabolomic Profiling Reveals Novel Metabolite Biomarkers of Incident Diabetes in African Americans

Author

Chen, Zsu-Zsu, Pacheco, Julian Avila, Gao, Yan, Deng, Shuliang, Peterson, Bennet, Shi, Xu, Zheng, Shuning, Tahir, Usman A, Katz, Daniel H, Cruz, Daniel E, Ngo, Debby, Benson, Mark D, Robbins, Jeremy M, Guo, Xiuqing, del Rocio Sevilla Gonzalez, Magdalena, Manning, Alisa, Correa, Adolfo, Meigs, James B, Taylor, Kent D, Rich, Stephen S, Goodarzi, Mark O, Rotter, Jerome I, Wilson, James G, Clish, Clary B, and Gerszten, Robert E

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Diabetes, Clinical Research, Prevention, Metabolic and endocrine, Humans, Blood Glucose, Black or African American, Metabolomics, Biomarkers, Diabetes Mellitus, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Nontargeted metabolomics methods have increased potential to identify new disease biomarkers, but assessments of the additive information provided in large human cohorts by these less biased techniques are limited. To diversify our knowledge of diabetes-associated metabolites, we leveraged a method that measures 305 targeted or "known" and 2,342 nontargeted or "unknown" compounds in fasting plasma samples from 2,750 participants (315 incident cases) in the Jackson Heart Study (JHS)-a community cohort of self-identified African Americans-who are underrepresented in omics studies. We found 307 unique compounds (82 known) associated with diabetes after adjusting for age and sex at a false discovery rate of

Published
2022

17. Differences in Metabolomic Profiles Between Black and White Women and Risk of Coronary Heart Disease: an Observational Study of Women From Four US Cohorts

Author

Hu, Jie, Yao, Jie, Deng, Shuliang, Balasubramanian, Raji, Jiménez, Monik C, Li, Jun, Guo, Xiuqing, Cruz, Daniel E, Gao, Yan, Huang, Tianyi, Zeleznik, Oana A, Ngo, Debby, Liu, Simin, Rosal, Milagros C, Nassir, Rami, Paynter, Nina P, Albert, Christine M, Tracy, Russell P, Durda, Peter, Liu, Yongmei, Taylor, Kent D, Johnson, W Craig, Sun, Qi, Rimm, Eric B, Eliassen, A Heather, Rich, Stephen S, Rotter, Jerome I, Gerszten, Robert E, Clish, Clary B, and Rexrode, Kathryn M

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Heart Disease - Coronary Heart Disease, Atherosclerosis, Aging, Cardiovascular, Prevention, Clinical Research, Heart Disease, Good Health and Well Being, Amino Acids, Coronary Disease, Female, Hormones, Humans, Lipids, Risk Factors, United States, heart diseases, health status disparities, metabolomics, plasma, race, women, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundRacial differences in metabolomic profiles may reflect underlying differences in social determinants of health by self-reported race and may be related to racial disparities in coronary heart disease (CHD) among women in the United States. However, the magnitude of differences in metabolomic profiles between Black and White women in the United States has not been well-described. It also remains unknown whether such differences are related to differences in CHD risk.MethodsPlasma metabolomic profiles were analyzed using liquid chromatography-tandem mass spectrometry in the WHI-OS (Women's Health Initiative-Observational Study; 138 Black and 696 White women), WHI-HT trials (WHI-Hormone Therapy; 156 Black and 1138 White women), MESA (Multi-Ethnic Study of Atherosclerosis; 114 Black and 219 White women), JHS (Jackson Heart Study; 1465 Black women with 107 incident CHD cases), and NHS (Nurses' Health Study; 2506 White women with 136 incident CHD cases). First, linear regression models were used to estimate associations between self-reported race and 472 metabolites in WHI-OS (discovery); findings were replicated in WHI-HT and validated in MESA. Second, we used elastic net regression to construct a racial difference metabolomic pattern (RDMP) representing differences in the metabolomic patterns between Black and White women in the WHI-OS; the RDMP was validated in the WHI-HT and MESA. Third, using conditional logistic regressions in the WHI (717 CHD cases and 719 matched controls), we examined associations of metabolites with large differences in levels by race and the RDMP with risk of CHD, and the results were replicated in Black women from the JHS and White women from the NHS.ResultsOf the 472 tested metabolites, levels of 259 (54.9%) metabolites, mostly lipid metabolites and amino acids, significantly differed between Black and White women in both WHI-OS and WHI-HT after adjusting for baseline characteristics, socioeconomic status, lifestyle factors, baseline health conditions, and medication use (false discovery rate

Published
2022

18. Gut Microbiota, Plasma Metabolomic Profiles, and Carotid Artery Atherosclerosis in HIV Infection

Author

Wang, Zheng, Peters, Brandilyn A, Usyk, Mykhaylo, Xing, Jiaqian, Hanna, David B, Wang, Tao, Post, Wendy S, Landay, Alan L, Hodis, Howard N, Weber, Kathleen, French, Audrey, Golub, Elizabeth T, Lazar, Jason, Gustafson, Deborah, Kassaye, Seble, Aouizerat, Bradley, Haberlen, Sabina, Malvestutto, Carlos, Budoff, Matthew, Wolinsky, Steven M, Sharma, Anjali, Anastos, Kathryn, Clish, Clary B, Kaplan, Robert C, Burk, Robert D, and Qi, Qibin

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Atherosclerosis, HIV/AIDS, Infectious Diseases, Cardiovascular, Clinical Research, Prevention, Aetiology, 2.2 Factors relating to the physical environment, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Carotid Arteries, Carotid Artery Diseases, Carotid Stenosis, Cross-Sectional Studies, Female, Gastrointestinal Microbiome, HIV Infections, Humans, Lysophosphatidylcholines, Male, Plaque, Atherosclerotic, atherosclerosis, cardiovascular diseases, diglycerides, lipid metabolism, lipidomics, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundAlterations in gut microbiota and blood metabolomic profiles have been implicated in HIV infection and cardiovascular disease. However, it remains unclear whether alterations in gut microbiota may contribute to disrupted host blood metabolomic profiles in relation to atherosclerosis, especially in the context of HIV infection.MethodsWe analyzed cross-sectional associations between gut microbiota features and carotid artery plaque in 361 women with or at high risk of HIV (67% HIV+), and further integrated plaque-associated microbial features with plasma lipidomic/metabolomic profiles. Furthermore, in 737 women and men, we examined prospective associations of baseline gut bacteria-associated lipidomic and metabolomic profiles with incident carotid artery plaque over 7-year follow-up.ResultsWe found 2 potentially pathogenic bacteria, Fusobacterium and Proteus, were associated with carotid artery plaque; while the beneficial butyrate producer Odoribacter was inversely associated with plaque. Fusobacterium and Proteus were associated with multiple lipids/metabolites which were clustered into 8 modules in network. A module comprised of 9 lysophosphatidylcholines and lysophosphatidylethanolamines and a module comprised of 9 diglycerides were associated with increased risk of carotid artery plaque (risk ratio [95% CI], 1.34 [1.09-1.64] and 1.24 [1.02-1.51] per SD increment, respectively). Functional analyses identified bacterial enzymes in lipid metabolism associated with these plasma lipids. In particular, phospholipase A1 and A2 are the key enzymes in the reactions producing lysophosphatidylcholines and lysophosphatidylethanolamines.ConclusionsAmong individuals with or at high risk of HIV infection, we identified altered gut microbiota and related functional capacities in the lipid metabolism associated with disrupted plasma lipidomic profiles and carotid artery atherosclerosis.

Published
2022

19. Vaginal Lactobacillus fatty acid response mechanisms reveal a metabolite-targeted strategy for bacterial vaginosis treatment

Author

Zhu, Meilin, Frank, Matthew W., Radka, Christopher D., Jeanfavre, Sarah, Xu, Jiawu, Tse, Megan W., Pacheco, Julian Avila, Kim, Jae Sun, Pierce, Kerry, Deik, Amy, Hussain, Fatima Aysha, Elsherbini, Joseph, Hussain, Salina, Xulu, Nondumiso, Khan, Nasreen, Pillay, Vanessa, Mitchell, Caroline M., Dong, Krista L., Ndung'u, Thumbi, Clish, Clary B., Rock, Charles O., Blainey, Paul C., Bloom, Seth M., and Kwon, Douglas S.

Published
2024
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21. A Metabolomics Approach to Identify Metabolites Associated With Mortality in Patients Receiving Maintenance Hemodialysis

Author

Al Awadhi, Solaf, Myint, Leslie, Guallar, Eliseo, Clish, Clary B., Wulczyn, Kendra E., Kalim, Sahir, Thadhani, Ravi, Segev, Dorry L., McAdams DeMarco, Mara, Moe, Sharon M., Moorthi, Ranjani N., Hostetter, Thomas H., Himmelfarb, Jonathan, Meyer, Timothy W., Powe, Neil R., Tonelli, Marcello, Rhee, Eugene P., and Shafi, Tariq

Published
2024
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23. Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies

Author

Qi, Qibin, Li, Jun, Yu, Bing, Moon, Jee-Young, Chai, Jin C, Merino, Jordi, Hu, Jie, Ruiz-Canela, Miguel, Rebholz, Casey, Wang, Zheng, Usyk, Mykhaylo, Chen, Guo-Chong, Porneala, Bianca C, Wang, Wenshuang, Nguyen, Ngoc Quynh, Feofanova, Elena V, Grove, Megan L, Wang, Thomas J, Gerszten, Robert E, Dupuis, Josée, Salas-Salvadó, Jordi, Bao, Wei, Perkins, David L, Daviglus, Martha L, Thyagarajan, Bharat, Cai, Jianwen, Wang, Tao, Manson, JoAnn E, Martínez-González, Miguel A, Selvin, Elizabeth, Rexrode, Kathryn M, Clish, Clary B, Hu, Frank B, Meigs, James B, Knight, Rob, Burk, Robert D, Boerwinkle, Eric, and Kaplan, Robert C

Subjects
Obesity, Human Genome, Prevention, Genetics, Nutrition, Diabetes, 2.2 Factors relating to the physical environment, Aetiology, Metabolic and endocrine, Oral and gastrointestinal, Bacteria, Cohort Studies, Diabetes Mellitus, Type 2, Diet, Gastrointestinal Microbiome, Humans, Kynurenine, Lactase, Tryptophan, diabetes mellitus, dietary factors, genetics, Clinical Sciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology
Abstract

ObjectiveTryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.MethodWe analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites.ResultsTryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals.ConclusionHigher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

Published
2022

25. Metabolites Associated With Uremic Symptoms in Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

Author

Dember, Laura M., Landis, J. Richard, Townsend, Raymond R., Appel, Lawrence, Fink, Jeffrey, Rahman, Mahboob, Horwitz, Edward J., Taliercio, Jonathan J., Rao, Panduranga, Sondheimer, James H., Lash, James P., Chen, Jing, Go, Alan S., Parsa, Afshin, Rankin, Tracy, Wulczyn, Kendra E., Shafi, Tariq, Anderson, Amanda, Rincon-Choles, Hernan, Clish, Clary B., Denburg, Michelle, Feldman, Harold I., He, Jiang, Hsu, Chi-yuan, Kelly, Tanika, Kimmel, Paul L., Mehta, Rupal, Nelson, Robert G., Ramachandran, Vasan, Ricardo, Ana, Shah, Vallabh O., Srivastava, Anand, Xie, Dawei, Rhee, Eugene P., and Kalim, Sahir

Published
2024
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27. Metabolic liability for weight gain in early adulthood

Author

Murthy, Venkatesh L., Mosley, Jonathan D., Perry, Andrew S., Jacobs, David R., Jr., Tanriverdi, Kahraman, Zhao, Shilin, Sawicki, Konrad T., Carnethon, Mercedes, Wilkins, John T., Nayor, Matthew, Das, Saumya, Abel, E. Dale, Freedman, Jane E., Clish, Clary B., and Shah, Ravi V.

Published
2024
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30. Plasma metabolite profiles associated with the World Cancer Research Fund/American Institute for Cancer Research lifestyle score and future risk of cardiovascular disease and type 2 diabetes

Author

Rios, Santiago, García-Gavilán, Jesús F., Babio, Nancy, Paz-Graniel, Indira, Ruiz-Canela, Miguel, Liang, Liming, Clish, Clary B, Toledo, Estefania, Corella, Dolores, Estruch, Ramón, Ros, Emilio, Fitó, Montserrat, Arós, Fernando, Fiol, Miquel, Guasch-Ferré, Marta, Santos-Lozano, José M, Li, Jun, Razquin, Cristina, Martínez-González, Miguel Ángel, Hu, Frank B, and Salas-Salvadó, Jordi

Published
2023
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31. Gut microbiota, circulating inflammatory markers and metabolites, and carotid artery atherosclerosis in HIV infection

Author

Wang, Zheng, Peters, Brandilyn A., Bryant, MacKenzie, Hanna, David B., Schwartz, Tara, Wang, Tao, Sollecito, Christopher C., Usyk, Mykhaylo, Grassi, Evan, Wiek, Fanua, Peter, Lauren St., Post, Wendy S., Landay, Alan L., Hodis, Howard N., Weber, Kathleen M., French, Audrey, Golub, Elizabeth T., Lazar, Jason, Gustafson, Deborah, Sharma, Anjali, Anastos, Kathryn, Clish, Clary B., Burk, Robert D., Kaplan, Robert C., Knight, Rob, and Qi, Qibin

Published
2023
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33. Trans-ethnic genome-wide association study of blood metabolites in the Chronic Renal Insufficiency Cohort (CRIC) study

Author

Rhee, Eugene P, Surapaneni, Aditya, Zheng, Zihe, Zhou, Linda, Dutta, Diptavo, Arking, Dan E, Zhang, Jingning, Duong, ThuyVy, Chatterjee, Nilanjan, Luo, Shengyuan, Schlosser, Pascal, Mehta, Rupal, Waikar, Sushrut S, Saraf, Santosh L, Kelly, Tanika N, Hamm, Lee L, Rao, Panduranga S, Mathew, Anna V, Hsu, Chi-yuan, Parsa, Afshin, Vasan, Ramachandran S, Kimmel, Paul L, Clish, Clary B, Coresh, Josef, Feldman, Harold I, Grams, Morgan E, and Investigators, CKD Biomarkers Consortium and the Chronic Renal Insufficiency Cohort Study

Subjects
Human Genome, Genetics, Kidney Disease, Aetiology, 2.1 Biological and endogenous factors, Renal and urogenital, Cohort Studies, Ethnicity, Female, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, GWAS, metabolomics, trans-ethnic meta-analysis, CKD Biomarkers Consortium and the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators, Clinical Sciences, Urology & Nephrology
Abstract

Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate analyses in 822 White and 687 Black study participants. Trans-ethnic meta-analysis was then applied to improve fine-mapping of potential causal variants. Mean estimated glomerular filtration rate was 44.4 and 41.5 mL/min/1.73m2 in the White and Black participants, respectively. There were 45 significant metabolite associations at 19 loci, including novel associations at PYROXD2, PHYHD1, FADS1-3, ACOT2, MYRF, FAAH, and LIPC. The strength of associations was unchanged in models additionally adjusted for estimated glomerular filtration rate and proteinuria, consistent with a direct biochemical effect of gene products on associated metabolites. At several loci, trans-ethnic meta-analysis, which leverages differences in linkage disequilibrium across populations, reduced the number and/or genomic interval spanned by potentially causal single nucleotide polymorphisms compared to fine-mapping in the White participant cohort alone. Across all validated associations, we found strong concordance in effect sizes of the potentially causal single nucleotide polymorphisms between White and Black study participants. Thus, our study identifies novel genetic determinants of blood metabolites in chronic kidney disease, demonstrates the value of diverse cohorts to improve causal inference in metabolomics GWAS, and underscores the shared genetic basis of metabolism across race.

Published
2022

34. Human gut bacteria produce ΤΗ17-modulating bile acid metabolites

Author

Paik, Donggi, Yao, Lina, Zhang, Yancong, Bae, Sena, D’Agostino, Gabriel D, Zhang, Minghao, Kim, Eunha, Franzosa, Eric A, Avila-Pacheco, Julian, Bisanz, Jordan E, Rakowski, Christopher K, Vlamakis, Hera, Xavier, Ramnik J, Turnbaugh, Peter J, Longman, Randy S, Krout, Michael R, Clish, Clary B, Rastinejad, Fraydoon, Huttenhower, Curtis, Huh, Jun R, and Devlin, A Sloan

Subjects
Inflammatory Bowel Disease, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, Oral and gastrointestinal, Inflammatory and immune system, Bacteria, Bile Acids and Salts, Cell Differentiation, Gastrointestinal Tract, Humans, Inflammatory Bowel Diseases, Interleukin-17, Lithocholic Acid, Th17 Cells, General Science & Technology
Abstract

The microbiota modulates gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17A (TH17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits TH17 cell differentiation1. Although it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown, and it was unclear whether 3-oxoLCA and other immunomodulatory bile acids are associated with inflammatory pathologies in humans. Here we identify human gut bacteria and corresponding enzymes that convert the secondary bile acid lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Similar to 3-oxoLCA, isoLCA suppressed TH17 cell differentiation by inhibiting retinoic acid receptor-related orphan nuclear receptor-γt, a key TH17-cell-promoting transcription factor. The levels of both 3-oxoLCA and isoLCA and the 3α-hydroxysteroid dehydrogenase genes that are required for their biosynthesis were significantly reduced in patients with inflammatory bowel disease. Moreover, the levels of these bile acids were inversely correlated with the expression of TH17-cell-associated genes. Overall, our data suggest that bacterially produced bile acids inhibit TH17 cell function, an activity that may be relevant to the pathophysiology of inflammatory disorders such as inflammatory bowel disease.

Published
2022

35. Plasma lipidome and risk of atrial fibrillation: results from the PREDIMED trial

Author

Toledo, Estefania, Wittenbecher, Clemens, Razquin, Cristina, Ruiz-Canela, Miguel, Clish, Clary B., Liang, Liming, Alonso, Alvaro, Hernández-Alonso, Pablo, Becerra-Tomás, Nerea, Arós-Borau, Fernando, Corella, Dolores, Ros, Emilio, Estruch, Ramón, García-Rodríguez, Antonio, Fitó, Montserrat, Lapetra, José, Fiol, Miquel, Alonso-Gomez, Ángel M., Serra-Majem, Luis, Deik, Amy, Salas-Salvadó, Jordi, Hu, Frank B., and Martínez-González, Miguel A.

Published
2023
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36. Plasma metabolites of a healthy lifestyle in relation to mortality and longevity: Four prospective US cohort studies

Author

Tessier, Anne-Julie, Wang, Fenglei, Liang, Liming, Wittenbecher, Clemens, Haslam, Danielle E., Eliassen, A. Heather, Tobias, Deirdre K., Li, Jun, Zeleznik, Oana A., Ascherio, Alberto, Sun, Qi, Stampfer, Meir J., Grodstein, Francine, Rexrode, Kathryn M., Manson, JoAnn E., Balasubramanian, Raji, Clish, Clary B., Martínez-González, Miguel A., Chavarro, Jorge E., Hu, Frank B., and Guasch-Ferré, Marta

Published
2024
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38. Linking microbial genes to plasma and stool metabolites uncovers host-microbial interactions underlying ulcerative colitis disease course

Author

Schirmer, Melanie, Stražar, Martin, Avila-Pacheco, Julian, Rojas-Tapias, Daniel F., Brown, Eric M., Temple, Emily, Deik, Amy, Bullock, Kevin, Jeanfavre, Sarah, Pierce, Kerry, Jin, Shen, Invernizzi, Rachele, Pust, Marie-Madlen, Costliow, Zach, Mack, David R., Griffiths, Anne M., Walters, Thomas, Boyle, Brendan M., Kugathasan, Subra, Vlamakis, Hera, Hyams, Jeffrey, Denson, Lee, Clish, Clary B., and Xavier, Ramnik J.

Published
2024
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39. Plasma metabolite predictors of metabolic syndrome incidence and reversion

Author

Semnani-Azad, Zhila, Toledo, Estefanía, Babio, Nancy, Ruiz-Canela, Miguel, Wittenbecher, Clemens, Razquin, Cristina, Wang, Fenglei, Dennis, Courtney, Deik, Amy, Clish, Clary B., Corella, Dolores, Fitó, Montserrat, Estruch, Ramon, Arós, Fernando, Ros, Emilio, García-Gavilan, Jesús, Liang, Liming, Salas-Salvadó, Jordi, Martínez-González, Miguel A., Hu, Frank B., and Guasch-Ferré, Marta

Published
2024
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40. Lymphocyte activation gene-3-associated protein networks are associated with HDL-cholesterol and mortality in the Trans-omics for Precision Medicine program

Author

Manichaikul, Ani, Lin, Honghuang, Kang, Chansuk, Yang, Chaojie, Rich, Stephen S, Taylor, Kent D, Guo, Xiuqing, Rotter, Jerome I, Craig Johnson, W, Cornell, Elaine, Tracy, Russell P, Peter Durda, J, Liu, Yongmei, Vasan, Ramachandran S, Adrienne Cupples, L, Gerszten, Robert E, Clish, Clary B, Jain, Deepti, Conomos, Matthew P, Blackwell, Thomas, Papanicolaou, George J, and Rodriguez, Annabelle

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Heart Disease, Biotechnology, Human Genome, Heart Disease - Coronary Heart Disease, Clinical Research, Cardiovascular, Atherosclerosis, Aging, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Cholesterol, HDL, Chromatin, Humans, Lymphocyte Activation, Membrane Proteins, Precision Medicine, Biological sciences, Biomedical and clinical sciences
Abstract

Deficiency of the immune checkpoint lymphocyte activation gene-3 (LAG3) protein is significantly associated with both elevated HDL-cholesterol (HDL-C) and myocardial infarction risk. We determined the association of genetic variants within ±500 kb of LAG3 with plasma LAG3 and defined LAG3-associated plasma proteins with HDL-C and clinical outcomes. Whole genome sequencing and plasma proteomics were obtained from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study (FHS) cohorts as part of the Trans-Omics for Precision Medicine program. In situ Hi-C chromatin capture was performed in EBV-transformed cell lines isolated from four MESA participants. Genetic association analyses were performed in MESA using multivariate regression models, with validation in FHS. A LAG3-associated protein network was tested for association with HDL-C, coronary heart disease, and all-cause mortality. We identify an association between the LAG3 rs3782735 variant and plasma LAG3 protein. Proteomics analysis reveals 183 proteins significantly associated with LAG3 with four proteins associated with HDL-C. Four proteins discovered for association with all-cause mortality in FHS shows nominal associations in MESA. Chromatin capture analysis reveals significant cis interactions between LAG3 and C1S, LRIG3, TNFRSF1A, and trans interactions between LAG3 and B2M. A LAG3-associated protein network has significant associations with HDL-C and mortality.

Published
2022

41. Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals

Author

Tahir, Usman A, Katz, Daniel H, Avila-Pachecho, Julian, Bick, Alexander G, Pampana, Akhil, Robbins, Jeremy M, Yu, Zhi, Chen, Zsu-Zsu, Benson, Mark D, Cruz, Daniel E, Ngo, Debby, Deng, Shuliang, Shi, Xu, Zheng, Shuning, Eisman, Aaron S, Farrell, Laurie, Hall, Michael E, Correa, Adolfo, Tracy, Russell P, Durda, Peter, Taylor, Kent D, Liu, Yongmei, Johnson, W Craig, Guo, Xiuqing, Yao, Jie, Chen, Yii-Der Ida, Manichaikul, Ani W, Ruberg, Frederick L, Blaner, William S, Jain, Deepti, Bouchard, Claude, Sarzynski, Mark A, Rich, Stephen S, Rotter, Jerome I, Wang, Thomas J, Wilson, James G, Clish, Clary B, Natarajan, Pradeep, and Gerszten, Robert E

Subjects
Analytical Chemistry, Biological Sciences, Biomedical and Clinical Sciences, Chemical Sciences, Genetics, Medical Biochemistry and Metabolomics, Clinical Research, Orphan Drug, Biotechnology, Human Genome, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Black People, Cardiovascular Diseases, Genome-Wide Association Study, Humans, Metabolome, Metabolomics, Tandem Mass Spectrometry, NHLBI Trans-Omics for Precision Medicine 1 Consortium
Abstract

Integrating genetic information with metabolomics has provided new insights into genes affecting human metabolism. However, gene-metabolite integration has been primarily studied in individuals of European Ancestry, limiting the opportunity to leverage genomic diversity for discovery. In addition, these analyses have principally involved known metabolites, with the majority of the profiled peaks left unannotated. Here, we perform a whole genome association study of 2,291 metabolite peaks (known and unknown features) in 2,466 Black individuals from the Jackson Heart Study. We identify 519 locus-metabolite associations for 427 metabolite peaks and validate our findings in two multi-ethnic cohorts. A significant proportion of these associations are in ancestry specific alleles including findings in APOE, TTR and CD36. We leverage tandem mass spectrometry to annotate unknown metabolites, providing new insight into hereditary diseases including transthyretin amyloidosis and sickle cell disease. Our integrative omics approach leverages genomic diversity to provide novel insights into diverse cardiometabolic diseases.

Published
2022

42. Tryptophan metabolism, gut microbiota, and carotid artery plaque in women with and without HIV infection

Author

Luo, Kai, Wang, Zheng, Peters, Brandilyn A., Hanna, David B., Wang, Tao, Sollecito, Christopher C., Grassi, Evan, Wiek, Fanua, St. Peter, Lauren, Usyk, Mykhaylo, Post, Wendy S., Landay, Alan L., Hodis, Howard N., Weber, Kathleen M., French, Audrey, Topper, Elizabeth F., Lazar, Jason, Gustafson, Deborah, Sharma, Anjali, Anastos, Kathryn, Clish, Clary B., Knight, Rob, Kaplan, Robert C., Burk, Robert D., and Qi, Qibin

Published
2024
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43. ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits

Author

Singh, Charandeep, Jin, Byungchang, Shrestha, Nirajan, Markhard, Andrew L., Panda, Apekshya, Calvo, Sarah E., Deik, Amy, Pan, Xingxiu, Zuckerman, Austin L., Ben Saad, Amel, Corey, Kathleen E., Sjoquist, Julia, Osganian, Stephanie, AminiTabrizi, Roya, Rhee, Eugene P., Shah, Hardik, Goldberger, Olga, Mullen, Alan C., Cracan, Valentin, Clish, Clary B., Mootha, Vamsi K., and Goodman, Russell P.

Published
2024
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44. Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer

Author

Lee, Min-Sik, Dennis, Courtney, Naqvi, Insia, Dailey, Lucas, Lorzadeh, Alireza, Ye, George, Zaytouni, Tamara, Adler, Ashley, Hitchcock, Daniel S., Lin, Lin, Hoffman, Megan T., Bhuiyan, Aladdin M., Barth, Jaimie L., Machacek, Miranda E., Mino-Kenudson, Mari, Dougan, Stephanie K., Jadhav, Unmesh, Clish, Clary B., and Kalaany, Nada Y.

Published
2023
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45. Early cellular and molecular signatures correlate with severity of West Nile virus infection

Author

Lee, Ho-Joon, Zhao, Yujiao, Fleming, Ira, Mehta, Sameet, Wang, Xiaomei, Wyk, Brent Vander, Ronca, Shannon E., Kang, Heather, Chou, Chih-Hung, Fatou, Benoit, Smolen, Kinga K., Levy, Ofer, Clish, Clary B., Xavier, Ramnik J., Steen, Hanno, Hafler, David A., Love, J. Christopher, Shalek, Alex K., Guan, Leying, Murray, Kristy O., Kleinstein, Steven H., and Montgomery, Ruth R.

Published
2023
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47. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Author

Taliun, Daniel, Harris, Daniel N, Kessler, Michael D, Carlson, Jedidiah, Szpiech, Zachary A, Torres, Raul, Taliun, Sarah A Gagliano, Corvelo, André, Gogarten, Stephanie M, Kang, Hyun Min, Pitsillides, Achilleas N, LeFaive, Jonathon, Lee, Seung-been, Tian, Xiaowen, Browning, Brian L, Das, Sayantan, Emde, Anne-Katrin, Clarke, Wayne E, Loesch, Douglas P, Shetty, Amol C, Blackwell, Thomas W, Smith, Albert V, Wong, Quenna, Liu, Xiaoming, Conomos, Matthew P, Bobo, Dean M, Aguet, François, Albert, Christine, Alonso, Alvaro, Ardlie, Kristin G, Arking, Dan E, Aslibekyan, Stella, Auer, Paul L, Barnard, John, Barr, R Graham, Barwick, Lucas, Becker, Lewis C, Beer, Rebecca L, Benjamin, Emelia J, Bielak, Lawrence F, Blangero, John, Boehnke, Michael, Bowden, Donald W, Brody, Jennifer A, Burchard, Esteban G, Cade, Brian E, Casella, James F, Chalazan, Brandon, Chasman, Daniel I, Chen, Yii-Der Ida, Cho, Michael H, Choi, Seung Hoan, Chung, Mina K, Clish, Clary B, Correa, Adolfo, Curran, Joanne E, Custer, Brian, Darbar, Dawood, Daya, Michelle, de Andrade, Mariza, DeMeo, Dawn L, Dutcher, Susan K, Ellinor, Patrick T, Emery, Leslie S, Eng, Celeste, Fatkin, Diane, Fingerlin, Tasha, Forer, Lukas, Fornage, Myriam, Franceschini, Nora, Fuchsberger, Christian, Fullerton, Stephanie M, Germer, Soren, Gladwin, Mark T, Gottlieb, Daniel J, Guo, Xiuqing, Hall, Michael E, He, Jiang, Heard-Costa, Nancy L, Heckbert, Susan R, Irvin, Marguerite R, Johnsen, Jill M, Johnson, Andrew D, Kaplan, Robert, Kardia, Sharon LR, Kelly, Tanika, Kelly, Shannon, Kenny, Eimear E, Kiel, Douglas P, Klemmer, Robert, Konkle, Barbara A, Kooperberg, Charles, Köttgen, Anna, Lange, Leslie A, Lasky-Su, Jessica, Levy, Daniel, Lin, Xihong, Lin, Keng-Han, Liu, Chunyu, and Loos, Ruth JF

Subjects
Genetics, Biotechnology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, Good Health and Well Being, Cytochrome P-450 CYP2D6, Genetic Variation, Genome, Human, Genomics, Haplotypes, Heterozygote, Humans, INDEL Mutation, Loss of Function Mutation, Mutagenesis, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Population Density, Precision Medicine, Quality Control, Sample Size, United States, Whole Genome Sequencing, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, General Science & Technology
Abstract

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Published
2021

48. MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis

Author

Phadnis, Vaishnavi V., Snider, Jamie, Varadharajan, Venkateshwari, Ramachandiran, Iyappan, Deik, Amy A., Lai, Zon Weng, Kunchok, Tenzin, Eaton, Elinor Ng, Sebastiany, Carolin, Lyakisheva, Anna, Vaccaro, Kyle D., Allen, Juliet, Yao, Zhong, Wong, Victoria, Geng, Betty, Weiskopf, Kipp, Clish, Clary B., Brown, J. Mark, Stagljar, Igor, Weinberg, Robert A., and Henry, Whitney S.

Published
2023
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49. Screening in serum-derived medium reveals differential response to compounds targeting metabolism

Author

Abbott, Keene L., Ali, Ahmed, Casalena, Dominick, Do, Brian T., Ferreira, Raphael, Cheah, Jaime H., Soule, Christian K., Deik, Amy, Kunchok, Tenzin, Schmidt, Daniel R., Renner, Steffen, Honeder, Sophie E., Wu, Michelle, Chan, Sze Ham, Tseyang, Tenzin, Stoltzfus, Andrew T., Michel, Sarah L.J., Greaves, Daniel, Hsu, Peggy P., Ng, Christopher W., Zhang, Chelsea J., Farsidjani, Ali, Kent, Johnathan R., Madariaga, Maria Lucia L., Gramatikov, Iva Monique T., Matheson, Nicholas J., Lewis, Caroline A., Clish, Clary B., Rees, Matthew G., Roth, Jennifer A., Griner, Lesley Mathews, Muir, Alexander, Auld, Douglas S., and Vander Heiden, Matthew G.

Published
2023
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