11 results on '"Farber, Emily"'
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2. Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci
- Author
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Hodonsky, Chani J., Turner, Adam W., Khan, Mohammad Daud, Barrientos, Nelson B., Methorst, Ruben, Ma, Lijiang, Lopez, Nicolas G., Mosquera, Jose Verdezoto, Auguste, Gaëlle, Farber, Emily, Ma, Wei Feng, Wong, Doris, Onengut-Gumuscu, Suna, Kavousi, Maryam, Peyser, Patricia A., van der Laan, Sander W., Leeper, Nicholas J., Kovacic, Jason C., Björkegren, Johan L.M., Miller, Clint L., Hodonsky, Chani J., Turner, Adam W., Khan, Mohammad Daud, Barrientos, Nelson B., Methorst, Ruben, Ma, Lijiang, Lopez, Nicolas G., Mosquera, Jose Verdezoto, Auguste, Gaëlle, Farber, Emily, Ma, Wei Feng, Wong, Doris, Onengut-Gumuscu, Suna, Kavousi, Maryam, Peyser, Patricia A., van der Laan, Sander W., Leeper, Nicholas J., Kovacic, Jason C., Björkegren, Johan L.M., and Miller, Clint L.
- Abstract
Genome-wide association studies (GWASs) have identified hundreds of risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWASs, and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotypes to identify quantitative trait loci for expression (eQTLs) and splicing (sQTLs) in coronary arteries from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary artery; 19% exhibited cell-type-specific expression. Colocalization revealed subgroups of eGenes unique to CAD and blood pressure GWAS. Fine-mapping highlighted additional eGenes, including TBX20 and IL5. We also identified sQTLs for 1,690 genes, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing to accurately identify disease-relevant isoform expression. Our work provides a patient-derived coronary artery eQTL resource and exemplifies the need for diverse study populations and multifaceted approaches to characterize gene regulation in disease processes.
- Published
- 2024
3. Integrative multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci
- Author
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CDL Onderzoek Pasterkamp, Circulatory Health, Hodonsky, Chani J, Turner, Adam W, Khan, Mohammad Daud, Barrientos, Nelson B, Methorst, Ruben, Ma, Lijiang, Lopez, Nicolas G, Mosquera, Jose Verdezoto, Auguste, Gaëlle, Farber, Emily, Ma, Wei Feng, Wong, Doris, Onengut-Gumuscu, Suna, Kavousi, Maryam, Peyser, Patricia A, van der Laan, Sander W, Leeper, Nicholas J, Kovacic, Jason C, Björkegren, Johan L M, Miller, Clint L, CDL Onderzoek Pasterkamp, Circulatory Health, Hodonsky, Chani J, Turner, Adam W, Khan, Mohammad Daud, Barrientos, Nelson B, Methorst, Ruben, Ma, Lijiang, Lopez, Nicolas G, Mosquera, Jose Verdezoto, Auguste, Gaëlle, Farber, Emily, Ma, Wei Feng, Wong, Doris, Onengut-Gumuscu, Suna, Kavousi, Maryam, Peyser, Patricia A, van der Laan, Sander W, Leeper, Nicholas J, Kovacic, Jason C, Björkegren, Johan L M, and Miller, Clint L
- Published
- 2023
4. Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes.
- Author
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Robertson, Catherine C, Robertson, Catherine C, Inshaw, Jamie RJ, Onengut-Gumuscu, Suna, Chen, Wei-Min, Santa Cruz, David Flores, Yang, Hanzhi, Cutler, Antony J, Crouch, Daniel JM, Farber, Emily, Bridges, S Louis, Edberg, Jeffrey C, Kimberly, Robert P, Buckner, Jane H, Deloukas, Panos, Divers, Jasmin, Dabelea, Dana, Lawrence, Jean M, Marcovina, Santica, Shah, Amy S, Greenbaum, Carla J, Atkinson, Mark A, Gregersen, Peter K, Oksenberg, Jorge R, Pociot, Flemming, Rewers, Marian J, Steck, Andrea K, Dunger, David B, Type 1 Diabetes Genetics Consortium, Wicker, Linda S, Concannon, Patrick, Todd, John A, Rich, Stephen S, Robertson, Catherine C, Robertson, Catherine C, Inshaw, Jamie RJ, Onengut-Gumuscu, Suna, Chen, Wei-Min, Santa Cruz, David Flores, Yang, Hanzhi, Cutler, Antony J, Crouch, Daniel JM, Farber, Emily, Bridges, S Louis, Edberg, Jeffrey C, Kimberly, Robert P, Buckner, Jane H, Deloukas, Panos, Divers, Jasmin, Dabelea, Dana, Lawrence, Jean M, Marcovina, Santica, Shah, Amy S, Greenbaum, Carla J, Atkinson, Mark A, Gregersen, Peter K, Oksenberg, Jorge R, Pociot, Flemming, Rewers, Marian J, Steck, Andrea K, Dunger, David B, Type 1 Diabetes Genetics Consortium, Wicker, Linda S, Concannon, Patrick, Todd, John A, and Rich, Stephen S
- Abstract
We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10-8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. Using chromatin-accessibility profiling of CD4+ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.
- Published
- 2021
5. Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes.
- Author
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Robertson, Catherine C, Robertson, Catherine C, Inshaw, Jamie RJ, Onengut-Gumuscu, Suna, Chen, Wei-Min, Santa Cruz, David Flores, Yang, Hanzhi, Cutler, Antony J, Crouch, Daniel JM, Farber, Emily, Bridges, S Louis, Edberg, Jeffrey C, Kimberly, Robert P, Buckner, Jane H, Deloukas, Panos, Divers, Jasmin, Dabelea, Dana, Lawrence, Jean M, Marcovina, Santica, Shah, Amy S, Greenbaum, Carla J, Atkinson, Mark A, Gregersen, Peter K, Oksenberg, Jorge R, Pociot, Flemming, Rewers, Marian J, Steck, Andrea K, Dunger, David B, Type 1 Diabetes Genetics Consortium, Wicker, Linda S, Concannon, Patrick, Todd, John A, Rich, Stephen S, Robertson, Catherine C, Robertson, Catherine C, Inshaw, Jamie RJ, Onengut-Gumuscu, Suna, Chen, Wei-Min, Santa Cruz, David Flores, Yang, Hanzhi, Cutler, Antony J, Crouch, Daniel JM, Farber, Emily, Bridges, S Louis, Edberg, Jeffrey C, Kimberly, Robert P, Buckner, Jane H, Deloukas, Panos, Divers, Jasmin, Dabelea, Dana, Lawrence, Jean M, Marcovina, Santica, Shah, Amy S, Greenbaum, Carla J, Atkinson, Mark A, Gregersen, Peter K, Oksenberg, Jorge R, Pociot, Flemming, Rewers, Marian J, Steck, Andrea K, Dunger, David B, Type 1 Diabetes Genetics Consortium, Wicker, Linda S, Concannon, Patrick, Todd, John A, and Rich, Stephen S
- Abstract
We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10-8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. Using chromatin-accessibility profiling of CD4+ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.
- Published
- 2021
6. Genetic Regulation of Atherosclerosis-Relevant Phenotypes in Human Vascular Smooth Muscle Cells
- Author
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CDL Onderzoek Pasterkamp, Child Health, Infection & Immunity, Circulatory Health, Experimentele Afd. Cardiologie 1, Aherrahrou, Rédouane, Guo, Liang, Nagraj, Vijay Peter, Aguhob, Aaron Andrew, Hinkle, Jameson, Chen, Lisa, Soh, Joon Yuhl, Lue, Dillon, Alencar, Gabriel F, Boltjes, Arjan, van der Laan, Sander W, Farber, Emily, Fuller, Daniela, Anane-Wae, Rita, Akingbesote, Ngozi D, Manichaikul, Ani W, Ma, Lijiang, Kaikkonen, Minna U, Björkegren, Johan Lm, Onengut-Gumuscu, Suna, Pasterkamp, Gerard, Miller, Clint L, Owens, Gary K, Finn, Aloke V, Navab, Mohamad, Fogelman, Alan M, Berliner, Judith A, Civelek, Mete, CDL Onderzoek Pasterkamp, Child Health, Infection & Immunity, Circulatory Health, Experimentele Afd. Cardiologie 1, Aherrahrou, Rédouane, Guo, Liang, Nagraj, Vijay Peter, Aguhob, Aaron Andrew, Hinkle, Jameson, Chen, Lisa, Soh, Joon Yuhl, Lue, Dillon, Alencar, Gabriel F, Boltjes, Arjan, van der Laan, Sander W, Farber, Emily, Fuller, Daniela, Anane-Wae, Rita, Akingbesote, Ngozi D, Manichaikul, Ani W, Ma, Lijiang, Kaikkonen, Minna U, Björkegren, Johan Lm, Onengut-Gumuscu, Suna, Pasterkamp, Gerard, Miller, Clint L, Owens, Gary K, Finn, Aloke V, Navab, Mohamad, Fogelman, Alan M, Berliner, Judith A, and Civelek, Mete
- Published
- 2020
7. Type 1 Diabetes Risk in African-Ancestry Participants and Utility of an Ancestry-Specific Genetic Risk Score.
- Author
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Onengut-Gumuscu, Suna, Onengut-Gumuscu, Suna, Chen, Wei-Min, Robertson, Catherine C, Bonnie, Jessica K, Farber, Emily, Zhu, Zhennan, Oksenberg, Jorge R, Brant, Steven R, Bridges, S Louis, Edberg, Jeffrey C, Kimberly, Robert P, Gregersen, Peter K, Rewers, Marian J, Steck, Andrea K, Black, Mary H, Dabelea, Dana, Pihoker, Catherine, Atkinson, Mark A, Wagenknecht, Lynne E, Divers, Jasmin, Bell, Ronny A, SEARCH for Diabetes in Youth, Type 1 Diabetes Genetics Consortium, Erlich, Henry A, Concannon, Patrick, Rich, Stephen S, Onengut-Gumuscu, Suna, Onengut-Gumuscu, Suna, Chen, Wei-Min, Robertson, Catherine C, Bonnie, Jessica K, Farber, Emily, Zhu, Zhennan, Oksenberg, Jorge R, Brant, Steven R, Bridges, S Louis, Edberg, Jeffrey C, Kimberly, Robert P, Gregersen, Peter K, Rewers, Marian J, Steck, Andrea K, Black, Mary H, Dabelea, Dana, Pihoker, Catherine, Atkinson, Mark A, Wagenknecht, Lynne E, Divers, Jasmin, Bell, Ronny A, SEARCH for Diabetes in Youth, Type 1 Diabetes Genetics Consortium, Erlich, Henry A, Concannon, Patrick, and Rich, Stephen S
- Abstract
ObjectiveGenetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS.Research design and methodsWe generated single nucleotide polymorphism (SNP) data with the ImmunoChip on 1,021 African-ancestry participants with type 1 diabetes and 2,928 control participants. HLA class I and class II alleles were imputed using SNP2HLA. Logistic regression models were used to identify genome-wide significant (P < 5.0 × 10-8) SNPs associated with type 1 diabetes in the African-ancestry samples and validate SNPs associated with risk in known European-ancestry loci (P < 2.79 × 10-5).ResultsAfrican-specific (HLA-DQA1*03:01-HLA-DQB1*02:01) and known European-ancestry HLA haplotypes (HLA-DRB1*03:01-HLA-DQA1*05:01-HLA-DQB1*02:01, HLA-DRB1*04:01-HLA-DQA1*03:01-HLA-DQB1*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts.ConclusionsGenetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.
- Published
- 2019
8. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers
- Author
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Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Ward, Lucas D., Kundaje, Anshul, Kellis, Manolis, Onengut-Gumuscu, Suna, Chen, Wei-Min, Burren, Oliver, Farber, Emily, Szpak, Michal, Schofield, Ellen, Achuthan, Premanand, Guo, Hui, Stevens, Helen, Deloukas, Panos, Wallace, Chris, Concannon, Patrick, Cooper, Nick J., Quinlan, Aaron R., Mychaleckyj, Josyf C., Bonnie, Jessica K., Fortune, Mary D., Walker, Neil M., Daly, Mark J., Barrett, Jeffrey C., Cooper, Jason D., Todd, John A., Rich, Stephen S., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Ward, Lucas D., Kundaje, Anshul, Kellis, Manolis, Onengut-Gumuscu, Suna, Chen, Wei-Min, Burren, Oliver, Farber, Emily, Szpak, Michal, Schofield, Ellen, Achuthan, Premanand, Guo, Hui, Stevens, Helen, Deloukas, Panos, Wallace, Chris, Concannon, Patrick, Cooper, Nick J., Quinlan, Aaron R., Mychaleckyj, Josyf C., Bonnie, Jessica K., Fortune, Mary D., Walker, Neil M., Daly, Mark J., Barrett, Jeffrey C., Cooper, Jason D., Todd, John A., and Rich, Stephen S.
- Abstract
Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10[superscript −8]). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34[superscript +] stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.
- Published
- 2016
9. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.
- Author
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Onengut-Gumuscu, Suna, Chen, Wei-Min, Burren, Oliver, Cooper, Nick J, Quinlan, Aaron R, Mychaleckyj, Josyf C, Farber, Emily, Bonnie, Jessica K, Szpak, Michal, Schofield, Ellen, Achuthan, Premanand, Guo, Hui, Fortune, Mary D, Stevens, Helen, Walker, Neil M, Ward, Lucas D, Kundaje, Anshul, Kellis, Manolis, Daly, Mark J, Barrett, Jeffrey C, Cooper, Jason D, Deloukas, Panos, Todd, John A, Wallace, Chris, Concannon, Patrick, Rich, Stephen S, Onengut-Gumuscu, Suna, Chen, Wei-Min, Burren, Oliver, Cooper, Nick J, Quinlan, Aaron R, Mychaleckyj, Josyf C, Farber, Emily, Bonnie, Jessica K, Szpak, Michal, Schofield, Ellen, Achuthan, Premanand, Guo, Hui, Fortune, Mary D, Stevens, Helen, Walker, Neil M, Ward, Lucas D, Kundaje, Anshul, Kellis, Manolis, Daly, Mark J, Barrett, Jeffrey C, Cooper, Jason D, Deloukas, Panos, Todd, John A, Wallace, Chris, Concannon, Patrick, and Rich, Stephen S
- Abstract
Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.
- Published
- 2015
- Full Text
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10. Activating the synthesis of progerin, the mutant prelamin A in Hutchinson-Gilford progeria syndrome, with antisense oligonucleotides.
- Author
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Fong, Loren G, Fong, Loren G, Vickers, Timothy A, Farber, Emily A, Choi, Christine, Yun, Ui Jeong, Hu, Yan, Yang, Shao H, Coffinier, Catherine, Lee, Roger, Yin, Liya, Davies, Brandon SJ, Andres, Douglas A, Spielmann, H Peter, Bennett, C Frank, Young, Stephen G, Fong, Loren G, Fong, Loren G, Vickers, Timothy A, Farber, Emily A, Choi, Christine, Yun, Ui Jeong, Hu, Yan, Yang, Shao H, Coffinier, Catherine, Lee, Roger, Yin, Liya, Davies, Brandon SJ, Andres, Douglas A, Spielmann, H Peter, Bennett, C Frank, and Young, Stephen G
- Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is caused by point mutations that increase utilization of an alternate splice donor site in exon 11 of LMNA (the gene encoding lamin C and prelamin A). The alternate splicing reduces transcripts for wild-type prelamin A and increases transcripts for a truncated prelamin A (progerin). Here, we show that antisense oligonucleotides (ASOs) against exon 11 sequences downstream from the exon 11 splice donor site promote alternate splicing in both wild-type and HGPS fibroblasts, increasing the synthesis of progerin. Indeed, wild-type fibroblasts transfected with these ASOs exhibit progerin levels similar to (or greater than) those in fibroblasts from HGPS patients. This progerin was farnesylated, as judged by metabolic labeling studies. The synthesis of progerin in wild-type fibroblasts was accompanied by the same nuclear shape and gene-expression perturbations observed in HGPS fibroblasts. An ASO corresponding to the 5' portion of intron 11 also promoted alternate splicing. In contrast, an ASO against exon 11 sequences 5' to the alternate splice site reduced alternate splicing in HGPS cells and modestly lowered progerin levels. Thus, different ASOs can be used to increase or decrease 'HGPS splicing'. ASOs represent a new and powerful tool for recreating HGPS pathophysiology in wild-type cells.
- Published
- 2009
11. Activating the synthesis of progerin, the mutant prelamin A in Hutchinson-Gilford progeria syndrome, with antisense oligonucleotides.
- Author
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Fong, Loren G, Fong, Loren G, Vickers, Timothy A, Farber, Emily A, Choi, Christine, Yun, Ui Jeong, Hu, Yan, Yang, Shao H, Coffinier, Catherine, Lee, Roger, Yin, Liya, Davies, Brandon SJ, Andres, Douglas A, Spielmann, H Peter, Bennett, C Frank, Young, Stephen G, Fong, Loren G, Fong, Loren G, Vickers, Timothy A, Farber, Emily A, Choi, Christine, Yun, Ui Jeong, Hu, Yan, Yang, Shao H, Coffinier, Catherine, Lee, Roger, Yin, Liya, Davies, Brandon SJ, Andres, Douglas A, Spielmann, H Peter, Bennett, C Frank, and Young, Stephen G
- Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is caused by point mutations that increase utilization of an alternate splice donor site in exon 11 of LMNA (the gene encoding lamin C and prelamin A). The alternate splicing reduces transcripts for wild-type prelamin A and increases transcripts for a truncated prelamin A (progerin). Here, we show that antisense oligonucleotides (ASOs) against exon 11 sequences downstream from the exon 11 splice donor site promote alternate splicing in both wild-type and HGPS fibroblasts, increasing the synthesis of progerin. Indeed, wild-type fibroblasts transfected with these ASOs exhibit progerin levels similar to (or greater than) those in fibroblasts from HGPS patients. This progerin was farnesylated, as judged by metabolic labeling studies. The synthesis of progerin in wild-type fibroblasts was accompanied by the same nuclear shape and gene-expression perturbations observed in HGPS fibroblasts. An ASO corresponding to the 5' portion of intron 11 also promoted alternate splicing. In contrast, an ASO against exon 11 sequences 5' to the alternate splice site reduced alternate splicing in HGPS cells and modestly lowered progerin levels. Thus, different ASOs can be used to increase or decrease 'HGPS splicing'. ASOs represent a new and powerful tool for recreating HGPS pathophysiology in wild-type cells.
- Published
- 2009
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