9 results on '"Geisinger-Regeneron DiscovEHR Collaboration"'
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2. GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms
- Author
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Lucas D. Ward, Ho-Chou Tu, Chelsea B. Quenneville, Shira Tsour, Alexander O. Flynn-Carroll, Margaret M. Parker, Aimee M. Deaton, Patrick A. J. Haslett, Luca A. Lotta, Niek Verweij, Manuel A. R. Ferreira, Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, Aris Baras, Gregory Hinkle, and Paul Nioi
- Subjects
Science - Abstract
Circulating liver enzymes, like alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are highly heritable and predictive of disease. Here, the authors perform a genome-wide association study on ALT and AST, revealing a rare variant in SLC30A10 associated with elevated ALT and AST.
- Published
- 2021
- Full Text
- View/download PDF
3. Genome‐wide association analysis of serum alanine and aspartate aminotransferase, and the modifying effects of BMI in 388k European individuals
- Author
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Chuan Gao, Anthony Marcketta, Joshua D. Backman, Colm O'Dushlaine, Jeffrey Staples, Manuel Allen Revez Ferreira, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Tooraj Mirshahi, null Regeneron Genetics Center, null Geisinger Regeneron Discovehr Collaboration, Aris Baras, Gonçalo Abecasis, Alan R. Shuldiner, Cristopher V. Van Hout, and Shane McCarthy
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ALT ,Epidemiology ,interaction ,Physiology ,Genome-wide association study ,digestive system ,Body Mass Index ,03 medical and health sciences ,Liver disease ,Genome-Wide Association Analysis ,medicine ,Humans ,GWAS ,Aspartate Aminotransferases ,AST ,Research Articles ,Genetics (clinical) ,030304 developmental biology ,Genetic association ,Alanine ,0303 health sciences ,business.industry ,030305 genetics & heredity ,Alanine Transaminase ,medicine.disease ,digestive system diseases ,Genetic architecture ,Minor allele frequency ,liver disease ,business ,Body mass index ,Genome-Wide Association Study ,Research Article - Abstract
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are biomarkers for liver health. Here we report the largest genome‐wide association analysis to date of serum ALT and AST levels in over 388k people of European ancestry from UK biobank and DiscovEHR. Eleven million imputed markers with a minor allele frequency (MAF) ≥ 0.5% were analyzed. Overall, 300 ALT and 336 AST independent genome‐wide significant associations were identified. Among them, 81 ALT and 61 AST associations are reported for the first time. Genome‐wide interaction study identified 9 ALT and 12 AST independent associations significantly modified by body mass index (BMI), including several previously reported potential liver disease therapeutic targets, for example, PNPLA3, HSD17B13, and MARC1. While further work is necessary to understand the effect of ALT and AST‐associated variants on liver disease, the weighted burden of significant BMI‐modified signals is significantly associated with liver disease outcomes. In summary, this study identifies genetic associations which offer an important step forward in understanding the genetic architecture of serum ALT and AST levels. Significant interactions between BMI and genetic loci not only highlight the important role of adiposity in liver damage but also shed light on the genetic etiology of liver disease in obese individuals.
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- 2021
4. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation
- Author
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Vujkovic, Marijana, Ramdas, Shweta, Lorenz, Kim M, Guo, Xiuqing, Darlay, Rebecca, Cordell, Heather J, He, Jing, Gindin, Yevgeniy, Chung, Chuhan, Myers, Robert P, Schneider, Carolin V, Park, Joseph, Lee, Kyung Min, Serper, Marina, Carr, Rotonya M, Kaplan, David E, Haas, Mary E, MacLean, Matthew T, Witschey, Walter R, Zhu, Xiang, Tcheandjieu, Catherine, Kember, Rachel L, Kranzler, Henry R, Verma, Anurag, Giri, Ayush, Klarin, Derek M, Sun, Yan V, Huang, Jie, Huffman, Jennifer E, Creasy, Kate Townsend, Hand, Nicholas J, Liu, Ching-Ti, Long, Michelle T, Yao, Jie, Budoff, Matthew, Tan, Jingyi, Li, Xiaohui, Lin, Henry J, Chen, Yii-Der Ida, Taylor, Kent D, Chang, Ruey-Kang, Krauss, Ronald M, Vilarinho, Silvia, Brancale, Joseph, Nielsen, Jonas B, Locke, Adam E, Jones, Marcus B, Verweij, Niek, Baras, Aris, Reddy, K Rajender, Neuschwander-Tetri, Brent A, Schwimmer, Jeffrey B, Sanyal, Arun J, Chalasani, Naga, Ryan, Kathleen A, Mitchell, Braxton D, Gill, Dipender, Wells, Andrew D, Manduchi, Elisabetta, Saiman, Yedidya, Mahmud, Nadim, Miller, Donald R, Reaven, Peter D, Phillips, Lawrence S, Muralidhar, Sumitra, DuVall, Scott L, Lee, Jennifer S, Assimes, Themistocles L, Pyarajan, Saiju, Cho, Kelly, Edwards, Todd L, Damrauer, Scott M, Wilson, Peter W, Gaziano, J Michael, O'Donnell, Christopher J, Khera, Amit V, Grant, Struan FA, Brown, Christopher D, Tsao, Philip S, Saleheen, Danish, Lotta, Luca A, Bastarache, Lisa, Anstee, Quentin M, Daly, Ann K, Meigs, James B, Rotter, Jerome I, Lynch, Julie A, Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, EPoS Consortium, VA Million Veteran Program, Rader, Daniel J, Voight, Benjamin F, and Chang, Kyong-Mi
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Liver Disease ,Chronic Liver Disease and Cirrhosis ,Human Genome ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Alpha-Ketoglutarate-Dependent Dioxygenase FTO ,Alanine Transaminase ,Lipase ,Single Nucleotide ,Protein Serine-Threonine Kinases ,Biological Sciences ,Regeneron Genetics Center ,Medical and Health Sciences ,EPoS Consortium ,Non-alcoholic Fatty Liver Disease ,VA Million Veteran Program ,Genetics ,Geisinger-Regeneron DiscovEHR Collaboration ,Humans ,2.1 Biological and endogenous factors ,Polymorphism ,Aetiology ,Digestive Diseases ,Genome-Wide Association Study ,Developmental Biology - Abstract
Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P
- Published
- 2022
5. Genome‐wide association analysis of serum alanine and aspartate aminotransferase, and the modifying effects of BMI in 388k European individuals.
- Author
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Gao, Chuan, Marcketta, Anthony, Backman, Joshua D., O'Dushlaine, Colm, Staples, Jeffrey, Ferreira, Manuel Allen Revez, Lotta, Luca A., Overton, John D., Reid, Jeffrey G., Mirshahi, Tooraj, Regeneron Genetics Center, Geisinger Regeneron Discovehr Collaboration, Baras, Aris, Abecasis, Gonçalo, Shuldiner, Alan R., Van Hout, Cristopher V., and McCarthy, Shane
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- 2021
- Full Text
- View/download PDF
6. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program
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Klarin, Derek, Damrauer, Scott M, Cho, Kelly, Sun, Yan V, Teslovich, Tanya M, Honerlaw, Jacqueline, Gagnon, David R, DuVall, Scott L, Li, Jin, Peloso, Gina M, Chaffin, Mark, Small, Aeron M, Huang, Jie, Tang, Hua, Lynch, Julie A, Ho, Yuk-Lam, Liu, Dajiang J, Emdin, Connor A, Li, Alexander H, Huffman, Jennifer E, Lee, Jennifer S, Natarajan, Pradeep, Chowdhury, Rajiv, Saleheen, Danish, Vujkovic, Marijana, Baras, Aris, Pyarajan, Saiju, Di Angelantonio, Emanuele, Neale, Benjamin M, Naheed, Aliya, Khera, Amit V, Danesh, John, Chang, Kyong-Mi, Abecasis, Gonçalo, Willer, Cristen, Dewey, Frederick E, Carey, David J, Global Lipids Genetics Consortium, Myocardial Infarction Genetics (MIGen) Consortium, Geisinger-Regeneron DiscovEHR Collaboration, VA Million Veteran Program, Concato, John, Gaziano, J Michael, O'Donnell, Christopher J, Tsao, Philip S, Kathiresan, Sekar, Rader, Daniel J, Wilson, Peter WF, Assimes, Themistocles L, Gagnon, David R [0000-0002-6367-3179], Chaffin, Mark [0000-0002-1234-5562], Emdin, Connor A [0000-0002-2385-8259], Huffman, Jennifer E [0000-0002-9672-2491], Vujkovic, Marijana [0000-0003-4924-5714], Neale, Benjamin M [0000-0003-1513-6077], Willer, Cristen [0000-0001-5645-4966], Kathiresan, Sekar [0000-0002-6724-032X], Assimes, Themistocles L [0000-0003-2349-0009], and Apollo - University of Cambridge Repository
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Male ,Genotype ,Black People ,Hispanic or Latino ,Middle Aged ,Lipid Metabolism ,Lipids ,Polymorphism, Single Nucleotide ,White People ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Ethnicity ,Humans ,Female ,Aged ,Genome-Wide Association Study ,Veterans - Abstract
The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).
- Published
- 2018
7. Clinical and Molecular Prevalence of Lipodystrophy in an Unascertained Large Clinical Care Cohort.
- Author
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Gonzaga-Jauregui, Claudia, Wenzhen Ge, Staples, Jeffrey, Van Hout, Cristopher, Yadav, Ashish, Colonie, Ryan, Leader, Joseph B., Kirchner, H. Lester, Murray, Michael F., Reid, Jeffrey G., Carey, David J., Overton, John D., Shuldiner, Alan R., Gottesman, Omri, Gao, Steve, Gromada, Jesper, Baras, Aris, Altarejos, Judith, Ge, Wenzhen, and Geisinger-Regeneron DiscovEHR collaboration
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LIPODYSTROPHY ,ELECTRONIC health records ,DYSLIPIDEMIA ,METABOLIC disorders ,GENETIC disorders ,DISEASE prevalence - Abstract
Lipodystrophies are a group of disorders characterized by absence or loss of adipose tissue and abnormal fat distribution, commonly accompanied by metabolic dysregulation. Although considered rare disorders, their prevalence in the general population is not well understood. We aimed to evaluate the clinical and genetic prevalence of lipodystrophy disorders in a large clinical care cohort. We interrogated the electronic health record (EHR) information of >1.3 million adults from the Geisinger Health System for lipodystrophy diagnostic codes. We estimate a clinical prevalence of disease of 1 in 20,000 individuals. We performed genetic analyses in individuals with available genomic data to identify variants associated with inherited lipodystrophies and examined their EHR for comorbidities associated with lipodystrophy. We identified 16 individuals carrying the p.R482Q pathogenic variant in LMNA associated with Dunnigan familial partial lipodystrophy. Four had a clinical diagnosis of lipodystrophy, whereas the remaining had no documented clinical diagnosis despite having accompanying metabolic abnormalities. We observed a lipodystrophy-associated variant carrier frequency of 1 in 3,082 individuals in our cohort with substantial burden of metabolic dysregulation. We estimate a genetic prevalence of disease of ∼1 in 7,000 in the general population. Partial lipodystrophy is an underdiagnosed condition. and its prevalence, as defined molecularly, is higher than previously reported. Genetically guided stratification of patients with common metabolic disorders, like diabetes and dyslipidemia, is an important step toward precision medicine. [ABSTRACT FROM AUTHOR]
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- 2020
- Full Text
- View/download PDF
8. Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets
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Wain, LV, Shrine, N, Artigas, MS, Erzurumluoglu, AM, Noyvert, B, Bossini-Castillo, L, Obeidat, M, Henry, AP, Portelli, MA, Hall, RJ, Billington, CK, Rimington, TL, Fenech, AG, John, C, Blake, T, Jackson, VE, Allen, RJ, Prins, BP, Understanding Society Scientific Group, Campbell, A, Porteous, DJ, Jarvelin, M-R, Wielscher, M, James, AL, Hui, J, Wareham, NJ, Zhao, JH, Wilson, JF, Joshi, PK, Stubbe, B, Rawal, R, Schulz, H, Imboden, M, Probst-Hensch, NM, Karrasch, S, Gieger, C, Deary, IJ, Harris, SE, Marten, J, Rudan, I, Enroth, S, Gyllensten, U, Kerr, SM, Polasek, O, Kähönen, M, Surakka, I, Vitart, V, Hayward, C, Lehtimäki, T, Raitakari, OT, Evans, DM, Henderson, AJ, Pennell, CE, Wang, CA, Sly, PD, Wan, ES, Busch, R, Hobbs, BD, Litonjua, AA, Sparrow, DW, Gulsvik, A, Bakke, PS, Crapo, JD, Beaty, TH, Hansel, NN, Mathias, RA, Ruczinski, I, Barnes, KC, Bossé, Y, Joubert, P, Van Den Berge, M, Brandsma, C-A, Paré, PD, Sin, DD, Nickle, DC, Hao, K, Gottesman, O, Dewey, FE, Bruse, SE, Carey, DJ, Kirchner, HL, Geisinger-Regeneron DiscovEHR Collaboration, Jonsson, S, Thorleifsson, G, Jonsdottir, I, Gislason, T, Stefansson, K, Schurmann, C, Nadkarni, G, Bottinger, EP, Loos, RJF, Walters, RG, Chen, Z, Millwood, IY, Vaucher, J, Kurmi, OP, Li, L, Hansell, AL, Brightling, C, Zeggini, E, Cho, MH, Silverman, EK, Sayers, I, Trynka, G, Morris, AP, Strachan, DP, Hall, IP, and Tobin, MD
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Adult ,Aged, 80 and over ,Male ,Middle Aged ,Polymorphism, Single Nucleotide ,Asthma ,respiratory tract diseases ,3. Good health ,Epigenesis, Genetic ,Pulmonary Disease, Chronic Obstructive ,Genetic Loci ,Risk Factors ,Humans ,Female ,Genetic Predisposition to Disease ,Lung ,Alleles ,Aged ,Genome-Wide Association Study - Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10‾⁴⁹), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.
9. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program
- Author
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Klarin, Derek, Damrauer, Scott M, Cho, Kelly, Sun, Yan V, Teslovich, Tanya M, Honerlaw, Jacqueline, Gagnon, David R, DuVall, Scott L, Li, Jin, Peloso, Gina M, Chaffin, Mark, Small, Aeron M, Huang, Jie, Tang, Hua, Lynch, Julie A, Ho, Yuk-Lam, Liu, Dajiang J, Emdin, Connor A, Li, Alexander H, Huffman, Jennifer E, Lee, Jennifer S, Natarajan, Pradeep, Chowdhury, Rajiv, Saleheen, Danish, Vujkovic, Marijana, Baras, Aris, Pyarajan, Saiju, Di Angelantonio, Emanuele, Neale, Benjamin M, Naheed, Aliya, Khera, Amit V, Danesh, John, Chang, Kyong-Mi, Abecasis, Gonçalo, Willer, Cristen, Dewey, Frederick E, Carey, David J, Global Lipids Genetics Consortium, Myocardial Infarction Genetics (MIGen) Consortium, Geisinger-Regeneron DiscovEHR Collaboration, VA Million Veteran Program, Concato, John, Gaziano, J Michael, O'Donnell, Christopher J, Tsao, Philip S, Kathiresan, Sekar, Rader, Daniel J, Wilson, Peter WF, and Assimes, Themistocles L
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Male ,Genotype ,Black People ,Hispanic or Latino ,Middle Aged ,16. Peace & justice ,Lipid Metabolism ,Lipids ,Polymorphism, Single Nucleotide ,White People ,3. Good health ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Ethnicity ,Humans ,Female ,Aged ,Genome-Wide Association Study ,Veterans - Abstract
The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).
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