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Your search keyword '"Laura M Raffield"' showing total 6 results
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6 results on '"Laura M Raffield"'

1. Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium

Author

Bridget M Lin, Kelsey E Grinde, Jennifer A Brody, Charles E Breeze, Laura M Raffield, Josyf C Mychaleckyj, Timothy A Thornton, James A Perry, Leslie J Baier, Lisa de las Fuentes, Xiuqing Guo, Benjamin D Heavner, Robert L Hanson, Yi-Jen Hung, Huijun Qian, Chao A Hsiung, Shih-Jen Hwang, Margaret R Irvin, Deepti Jain, Tanika N Kelly, Sayuko Kobes, Leslie Lange, James P Lash, Yun Li, Xiaoming Liu, Xuenan Mi, Solomon K Musani, George J Papanicolaou, Afshin Parsa, Alex P Reiner, Shabnam Salimi, Wayne H-H Sheu, Alan R Shuldiner, Kent D Taylor, Albert V Smith, Jennifer A Smith, Adrienne Tin, Dhananjay Vaidya, Robert B Wallace, Kenichi Yamamoto, Saori Sakaue, Koichi Matsuda, Yoichiro Kamatani, Yukihide Momozawa, Lisa R Yanek, Betsi A Young, Wei Zhao, Yukinori Okada, Gonzalo Abecasis, Bruce M Psaty, Donna K Arnett, Eric Boerwinkle, Jianwen Cai, Ida Yii-Der Chen, Adolfo Correa, L Adrienne Cupples, Jiang He, Sharon LR Kardia, Charles Kooperberg, Rasika A Mathias, Braxton D Mitchell, Deborah A Nickerson, Steve T Turner, Vasan S Ramachandran, Jerome I Rotter, Daniel Levy, Holly J Kramer, Anna Köttgen, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Kidney Working Group, Stephen S Rich, Dan-Yu Lin, Sharon R Browning, and Nora Franceschini

Subjects
Whole genome sequencing, Kidney traits, Rare variants, Ancestry-specific variants, Medicine, Medicine (General), R5-920
Abstract

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants. Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity. Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10−11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10−9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10−9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10−9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10−9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants. Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

Published
2021
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2. Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

Author

Torben Hansen, Marie-Pierre Dubé, Frank J. A. van Rooij, Todd L. Edwards, Michele K. Evans, Tõnu Esko, Paul Elliott, Leslie A. Lange, Kjell Nikus, Jette Bork-Jensen, Caterina Vacchi-Suzzi, Mika Kähönen, John M. Starr, Jennifer A. Brody, Ethan M. Lange, Christopher J. O'Donnell, John D. Eicher, Marju Orho-Melander, Kent D. Taylor, Vilmundur Gudnason, Yingchang Lu, Betina H. Thuesen, Amber A. Burt, Lisa R. Yanek, Andreas Greinacher, Leo-Pekka Lyytikäinen, Albert V. Smith, Eric Boerwinkle, Ming-Huei Chen, Paul L. Auer, Laura M. Raffield, Ani Manichaikul, Kenneth Rice, Frank Schmidt, Evangelos Evangelou, Russell P. Tracy, Nathalie Chami, Ayush Giri, Jussi Hernesniemi, Andrew D. Johnson, Ruth J. F. Loos, Sekar Kathiresan, Salman M. Tajuddin, Nina Mononen, Emma Raitoharju, Dawn M. Waterworth, James G. Wilson, Linda M. Polfus, Akihiro Nomura, Tamara B. Harris, Guillaume Lettre, Astrid Petersmann, Marguerite R. Irvin, Jerome I. Rotter, Alexander P. Reiner, Niels Grarup, Latisha Love-Gregory, Claudia Schurmann, Michelle L. O'Donoghue, Ursula M. Schick, Raha Pazoki, Lars Wallentin, Anne-Claire Vergnaud, Nauder Faraday, W. David Hill, Cornelia M. van Duijn, Nathan Pankratz, Rasika A. Mathias, Joel N. Hirschhorn, Jin Li, Santhi K. Ganesh, Tim Kacprowski, Traci M. Bartz, Mike A. Nalls, Samuel Lessard, Albert Hofman, Reedik Mägi, Ioanna Tzoulaki, Myriam Fornage, Evelin Mihailov, He Gao, Lewis C. Becker, Lenore J. Launer, Fernando Rivadeneira, Deborah A. Nickerson, Simon de Denus, Andrew J. Slater, Allan Linneberg, Andres Metspalu, Oluf Pedersen, Olli T. Raitakari, Harvey D. White, Yongmei Liu, Heather M. Highland, Bruce M. Psaty, Melissa A. Richard, Neil A. Zakai, Olle Melander, David R. Crosslin, Gunnar Engström, Ian J. Deary, Digna R. Velez Edwards, David C. Liewald, Mary Cushman, Erwin P. Bottinger, Eric S. Torstenson, Alan B. Zonderman, Nada A. Abumrad, Diane M. Becker, Terho Lehtimäki, Caroline Hayward, James S. Floyd, Alexander Teumer, Epidemiology, and Internal Medicine

Subjects
0301 basic medicine, Hemolytic anemia, Erythrocyte Indices, Erythrocytes, Genotype, Quantitative Trait Loci, Mean corpuscular hemoglobin, 030204 cardiovascular system & hematology, Biology, Allelic Imbalance, Article, 03 medical and health sciences, Hemoglobins, 0302 clinical medicine, Sideroblastic anemia, Gene Frequency, Pleiotropy, hemic and lymphatic diseases, Genetics, medicine, Humans, Genetics(clinical), Erythropoiesis, Exome, Allele frequency, Mean corpuscular volume, Genetics (clinical), Genetics & Heredity, Medical And Health Sciences, medicine.diagnostic_test, ta1184, Genetic Variation, Genetic Pleiotropy, Biological Sciences, ta3121, medicine.disease, 3. Good health, Minor allele frequency, Black or African American, 030104 developmental biology, Hematocrit
Abstract

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

Published
2016
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3. Genome-wide study investigating effector genes and polygenic prediction for kidney function in persons with ancestry from Africa and the Americas

Author

Odessica Hughes, Amy R. Bentley, Charles E. Breeze, Francois Aguet, Xiaoguang Xu, Girish Nadkarni, Quan Sun, Bridget M. Lin, Thomas Gilliland, Mariah C. Meyer, Jiawen Du, Laura M. Raffield, Holly Kramer, Robert W. Morton, Mateus H. Gouveia, Elizabeth G. Atkinson, Adan Valladares-Salgado, Niels Wacher-Rodarte, Nicole D. Dueker, Xiuqing Guo, Yang Hai, Adebowale Adeyemo, Lyle G. Best, Jianwen Cai, Guanjie Chen, Michael Chong, Ayo Doumatey, James Eales, Mark O. Goodarzi, Eli Ipp, Marguerite Ryan Irvin, Minzhi Jiang, Alana C. Jones, Charles Kooperberg, Jose E. Krieger, Ethan M. Lange, Matthew B. Lanktree, James P. Lash, Paulo A. Lotufo, Ruth J.F. Loos, Vy Thi Ha My, Jesús Peralta-Romero, Lihong Qi, Leslie J. Raffel, Stephen S. Rich, Erik J. Rodriquez, Eduardo Tarazona-Santos, Kent D. Taylor, Jason G. Umans, Jia Wen, Bessie A. Young, Zhi Yu, Ying Zhang, Yii-Der Ida Chen, Tanja Rundek, Jerome I. Rotter, Miguel Cruz, Myriam Fornage, Maria Fernanda Lima-Costa, Alexandre C. Pereira, Guillaume Paré, Pradeep Natarajan, Shelley A. Cole, April P. Carson, Leslie A. Lange, Yun Li, Eliseo J. Perez-Stable, Ron Do, Fadi J. Charchar, Maciej Tomaszewski, Josyf C. Mychaleckyj, Charles Rotimi, Andrew P. Morris, and Nora Franceschini

Subjects
kidney function, chronic kidney disease, genome-wide association study, multi-ancestry, admixed populations, eGFR, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract

Summary: Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p

Published
2024
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4. From GWAS variant to function: A study of ∼148,000 variants for blood cell traits

Author

Quan Sun, Cheynna A. Crowley, Le Huang, Jia Wen, Jiawen Chen, Erik L. Bao, Paul L. Auer, Guillaume Lettre, Alexander P. Reiner, Vijay G. Sankaran, Laura M. Raffield, and Yun Li

Subjects
genome-wide association studies, variant to function, functional annotations, experimental validations, blood cell traits, Genetics, QH426-470
Abstract

Summary: Genome-wide association studies (GWASs) have identified hundreds of thousands of genetic variants associated with complex diseases and traits. However, most variants are noncoding and not clearly linked to genes, making it challenging to interpret these GWAS signals. We present a systematic variant-to-function study, prioritizing the most likely functional elements of the genome for experimental follow-up, for >148,000 variants identified for hematological traits. Specifically, we developed VAMPIRE: Variant Annotation Method Pointing to Interesting Regulatory Effects, an interactive web application implemented in R Shiny. This tool efficiently integrates and displays information from multiple complementary sources, including epigenomic signatures from blood-cell-relevant tissues or cells, functional and conservation summary scores, variant impact on protein and gene expression, chromatin conformation information, as well as publicly available GWAS and phenome-wide association study (PheWAS) results. Leveraging data generated from independently performed functional validation experiments, we demonstrate that our prioritized variants, genes, or variant-gene links are significantly more likely to be experimentally validated. This study not only has important implications for systematic and efficient revelation of functional mechanisms underlying GWAS variants for hematological traits but also provides a prototype that can be adapted to many other complex traits, paving the path for efficient variant-to-function (V2F) analyses.

Published
2022
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5. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Author

Margaret A. Taub, Matthew P. Conomos, Rebecca Keener, Kruthika R. Iyer, Joshua S. Weinstock, Lisa R. Yanek, John Lane, Tyne W. Miller-Fleming, Jennifer A. Brody, Laura M. Raffield, Caitlin P. McHugh, Deepti Jain, Stephanie M. Gogarten, Cecelia A. Laurie, Ali Keramati, Marios Arvanitis, Albert V. Smith, Benjamin Heavner, Lucas Barwick, Lewis C. Becker, Joshua C. Bis, John Blangero, Eugene R. Bleecker, Esteban G. Burchard, Juan C. Celedón, Yen Pei C. Chang, Brian Custer, Dawood Darbar, Lisa de las Fuentes, Dawn L. DeMeo, Barry I. Freedman, Melanie E. Garrett, Mark T. Gladwin, Susan R. Heckbert, Bertha A. Hidalgo, Marguerite R. Irvin, Talat Islam, W. Craig Johnson, Stefan Kaab, Lenore Launer, Jiwon Lee, Simin Liu, Arden Moscati, Kari E. North, Patricia A. Peyser, Nicholas Rafaels, Christine Seidman, Daniel E. Weeks, Fayun Wen, Marsha M. Wheeler, L. Keoki Williams, Ivana V. Yang, Wei Zhao, Stella Aslibekyan, Paul L. Auer, Donald W. Bowden, Brian E. Cade, Zhanghua Chen, Michael H. Cho, L. Adrienne Cupples, Joanne E. Curran, Michelle Daya, Ranjan Deka, Celeste Eng, Tasha E. Fingerlin, Xiuqing Guo, Lifang Hou, Shih-Jen Hwang, Jill M. Johnsen, Eimear E. Kenny, Albert M. Levin, Chunyu Liu, Ryan L. Minster, Take Naseri, Mehdi Nouraie, Muagututi‘a Sefuiva Reupena, Ester C. Sabino, Jennifer A. Smith, Nicholas L. Smith, Jessica Lasky-Su, James G. Taylor, VI, Marilyn J. Telen, Hemant K. Tiwari, Russell P. Tracy, Marquitta J. White, Yingze Zhang, Kerri L. Wiggins, Scott T. Weiss, Ramachandran S. Vasan, Kent D. Taylor, Moritz F. Sinner, Edwin K. Silverman, M. Benjamin Shoemaker, Wayne H.-H. Sheu, Frank Sciurba, David A. Schwartz, Jerome I. Rotter, Daniel Roden, Susan Redline, Benjamin A. Raby, Bruce M. Psaty, Juan M. Peralta, Nicholette D. Palmer, Sergei Nekhai, Courtney G. Montgomery, Braxton D. Mitchell, Deborah A. Meyers, Stephen T. McGarvey, Angel C.Y. Mak, Ruth J.F. Loos, Rajesh Kumar, Charles Kooperberg, Barbara A. Konkle, Shannon Kelly, Sharon L.R. Kardia, Robert Kaplan, Jiang He, Hongsheng Gui, Frank D. Gilliland, Bruce D. Gelb, Myriam Fornage, Patrick T. Ellinor, Mariza de Andrade, Adolfo Correa, Yii-Der Ida Chen, Eric Boerwinkle, Kathleen C. Barnes, Allison E. Ashley-Koch, Donna K. Arnett, Christine Albert, Cathy C. Laurie, Goncalo Abecasis, Deborah A. Nickerson, James G. Wilson, Stephen S. Rich, Daniel Levy, Ingo Ruczinski, Abraham Aviv, Thomas W. Blackwell, Timothy Thornton, Jeff O’Connell, Nancy J. Cox, James A. Perry, Mary Armanios, Alexis Battle, Nathan Pankratz, Alexander P. Reiner, and Rasika A. Mathias

Subjects
telomeres, telomere length genetics, trans-population genome-wide association study, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract

Summary: Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.

Published
2022
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6. Association of mitochondrial DNA copy number with cardiometabolic diseases

Author

Xue Liu, Ryan J. Longchamps, Kerri L. Wiggins, Laura M. Raffield, Lawrence F. Bielak, Wei Zhao, Achilleas Pitsillides, Thomas W. Blackwell, Jie Yao, Xiuqing Guo, Nuzulul Kurniansyah, Bharat Thyagarajan, Nathan Pankratz, Stephen S. Rich, Kent D. Taylor, Patricia A. Peyser, Susan R. Heckbert, Sudha Seshadri, L. Adrienne Cupples, Eric Boerwinkle, Megan L. Grove, Nicholas B. Larson, Jennifer A. Smith, Ramachandran S. Vasan, Tamar Sofer, Annette L. Fitzpatrick, Myriam Fornage, Jun Ding, Adolfo Correa, Goncalo Abecasis, Bruce M. Psaty, James G. Wilson, Daniel Levy, Jerome I. Rotter, Joshua C. Bis, Claudia L. Satizabal, Dan E. Arking, and Chunyu Liu

Subjects
mitochondrial DNA copy number, cardiometabolic disease, whole-genome sequencing, whole-exom sequencing, aging, white blood cell counts, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract

Summary: Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole-blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: each additional 10 years of age was associated with a 0.03 SD higher level of mtDNA CN (p = 0.0014) among younger participants (younger than 65 years) versus a 0.14 SD lower level of mtDNA CN (p = 1.82 × 10−13) among older participants (65 years and older). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity (p = 5.6 × 10−238), hypertension (p = 2.8 × 10−50), diabetes (p = 3.6 × 10−7), and hyperlipidemia (p = 6.3 × 10−56). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

Published
2021
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