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11 results on '"Jai G. Broome"'

1. Whole-exome sequence analysis of anthropometric traits illustrates challenges in identifying effects of rare genetic variants

Author

Kristin L. Young, Virginia Fisher, Xuan Deng, Jennifer A. Brody, Misa Graff, Elise Lim, Bridget M. Lin, Hanfei Xu, Najaf Amin, Ping An, Stella Aslibekyan, Alison E. Fohner, Bertha Hidalgo, Petra Lenzini, Robert Kraaij, Carolina Medina-Gomez, Ivana Prokić, Fernando Rivadeneira, Colleen Sitlani, Ran Tao, Jeroen van Rooij, Di Zhang, Jai G. Broome, Erin J. Buth, Benjamin D. Heavner, Deepti Jain, Albert V. Smith, Kathleen Barnes, Meher Preethi Boorgula, Sameer Chavan, Dawood Darbar, Mariza De Andrade, Xiuqing Guo, Jeffrey Haessler, Marguerite R. Irvin, Rita R. Kalyani, Sharon L.R. Kardia, Charles Kooperberg, Wonji Kim, Rasika A. Mathias, Merry-Lynn McDonald, Braxton D. Mitchell, Patricia A. Peyser, Elizabeth A. Regan, Susan Redline, Alexander P. Reiner, Stephen S. Rich, Jerome I. Rotter, Jennifer A. Smith, Scott Weiss, Kerri L. Wiggins, Lisa R. Yanek, Donna Arnett, Nancy L. Heard-Costa, Suzanne Leal, Danyu Lin, Barbara McKnight, Michael Province, Cornelia M. van Duijn, Kari E. North, L. Adrienne Cupples, Ching-Ti Liu, Epidemiology, and Internal Medicine

Subjects
Anthropometry, central obesity, Quantitative Trait Loci, Human Genome, Cell Cycle Proteins, body mass index, Good Health and Well Being, Clinical Research, Genetics, Molecular Medicine, Humans, Intercellular Signaling Peptides and Proteins, 2.1 Biological and endogenous factors, Exome, Generic health relevance, Aetiology, exome sequencing, Genetics (clinical), Genome-Wide Association Study, height, Biotechnology
Abstract

Anthropometric traits, measuring body size and shape, are highly heritable and significant clinical risk factors for cardiometabolic disorders. These traits have been extensively studied in genome-wide association studies (GWASs), with hundreds of genome-wide significant loci identified. We performed a whole-exome sequence analysis of the genetics of height, body mass index (BMI) and waist/hip ratio (WHR). We meta-analyzed single-variant and gene-based associations of whole-exome sequence variation with height, BMI, and WHR in up to 22,004 individuals, and we assessed replication of our findings in up to 16,418 individuals from 10 independent cohorts from Trans-Omics for Precision Medicine (TOPMed). We identified four trait associations with single-nucleotide variants (SNVs; two for height and two for BMI) and replicated the LECT2 gene association with height. Our expression quantitative trait locus (eQTL) analysis within previously reported GWAS loci implicated CEP63 and RFT1 as potential functional genes for known height loci. We further assessed enrichment of SNVs, which were monogenic or syndromic variants within loci associated with our three traits. This led to the significant enrichment results for height, whereas we observed no Bonferroni-corrected significance for all SNVs. With a sample size of ∼20,000 whole-exome sequences in our discovery dataset, our findings demonstrate the importance of genomic sequencing in genetic association studies, yet they also illustrate the challenges in identifying effects of rare genetic variants.

Published
2023
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2. Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program

Author

Nicholas L. Smith, James A. Perry, Cecelia A. Laurie, Nancy J. Cox, Gonçalo R. Abecasis, Jerome I. Rotter, Laura Almasy, Zhe Wang, Michelle Daya, Yun Li, Eric Jorgenson, Adolfo Correa, Jai G. Broome, Nancy Min, Lisa R. Yanek, Alanna C. Morrison, Lynette Ekunwe, Debby Ngo, Victor E. Ortega, Klaudia Walter, John Blangero, Laura M. Raffield, Corey Cox, Terri H. Beaty, Deborah A. Meyers, Hua Tang, Marsha M. Wheeler, Kari E. North, Xue Zhong, Yann Ilboudo, Andrew D. Johnson, Caitlin P. McHugh, Jeffrey R. O'Connell, Ming-Huei Chen, Russell P. Tracy, Ramachandran S. Vasan, Nathan Pankratz, Joshua P. Lewis, Dawn L. DeMeo, Linda M. Polfus, Leslie A. Lange, Nancy L. Heard-Costa, Robert C. Kaplan, Meher Preethi Boorgula, Robert E. Gerszten, Albert V. Smith, Paul L. Auer, Sameer Chavan, Jennifer A. Brody, Charles Kooperberg, Michael Preuss, David C. Glahn, Rasika A. Mathias, Paul S. de Vries, Jonathon Rosen, Anna V. Mikhaylova, Joe Zein, Eric Boerwinkle, Nathalie Chami, Kathleen C. Barnes, Joanne E. Curran, Edwin K. Silverman, Matthew P. Conomos, Stephen S. Rich, Nicole Soranzo, Heather M. Highland, Michael H. Cho, Donald M. Lloyd-Jones, Myriam Fornage, Guillaume Lettre, Tyne W Miller-Fleming, Kathleen A. Ryan, Thomas W. Blackwell, Bruce M. Psaty, Lewis C. Becker, Nauder Faraday, Hélène Choquet, Alexander P. Reiner, Adam S. Butterworth, Kousik Kundu, Deepti Jain, Timothy A. Thornton, Brian D. Hobbs, Braxton D. Mitchell, Jee-Young Moon, Lifang Hou, Ani Manichaikul, Praveen Surendran, Suraj S. Nongmaithem, Quan Sun, Bingshan Li, Deborah A. Nickerson, and Ruth J. F. Loos

Subjects
Proteome, Quantitative Trait Loci, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Dermatitis, Atopic, Pulmonary Disease, Chronic Obstructive, Leukocytes, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), X chromosome, Genetic association, Whole genome sequencing, Autosome, Whole Genome Sequencing, Genome, Human, Monocyte, Prognosis, Asthma, United Kingdom, United States, Phenotype, medicine.anatomical_structure, National Heart, Lung, and Blood Institute (U.S.), Biomarkers, Imputation (genetics), Genome-Wide Association Study
Abstract

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

Published
2021
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3. Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative

Author

Nauder Faraday, Brian D. Hobbs, Quan Sun, Michael Preuss, Ani Manichaikul, Eric Jorgenson, Ming-Huei Chen, Eric Boerwinkle, Florian Thibord, Arunoday Bhan, Alanna C. Morrison, Ramachandran S. Vasan, Nathan Pankratz, Charles Kooperberg, Deborah A. Nickerson, Joshua P. Lewis, Hélène Choquet, Jee-Young Moon, Jeffrey R. O'Connell, Marsha M. Wheeler, Albert V. Smith, Russell P. Tracy, Nathalie Chami, Ruth J. F. Loos, Alexander P. Reiner, Nicholas L. Smith, Gonçalo R. Abecasis, Laura M. Raffield, Amarise Little, Nancy L. Heard-Costa, Andrew D. Johnson, David C. Glahn, Rasika A. Mathias, Adam S. Butterworth, John Blangero, Joanne E. Curran, Timothy A. Thornton, Laura Almasy, Jerome I. Rotter, Nancy Min, Lisa R. Yanek, Donald M. Lloyd-Jones, Zhe Wang, Matthew P. Conomos, Myriam Fornage, Hua Tang, Lewis C. Becker, Lynette Ekunwe, Cecelia A. Laurie, Adolfo Correa, Jai G. Broome, Terri H. Beaty, Jennifer A. Brody, Caitlin P. McHugh, Yao Hu, Braxton D. Mitchell, Lifang Hou, Yun Li, Kathleen A. Ryan, Paul L. Auer, Stephen S. Rich, Kari E. North, Thomas W. Blackwell, Bruce M. Psaty, Deepti Jain, Paul S Vries, Praveen Surendran, Butterworth, Adam [0000-0002-6915-9015], and Apollo - University of Cambridge Repository

Subjects
Blood Platelets, Platelet disorder, Population, Genome-wide association study, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Medical and Health Sciences, Genome, 03 medical and health sciences, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, 0302 clinical medicine, Clinical Research, and Blood Institute (U.S.), Genetics, Humans, 2.1 Biological and endogenous factors, Polymorphism, Precision Medicine, Aetiology, Mean platelet volume, education, Hemostatic function, Lung, Molecular Biology, Genetics (clinical), 030304 developmental biology, Blood Platelet Disorders, Genetics & Heredity, 0303 health sciences, education.field_of_study, Human Genome, Single Nucleotide, National Heart, Hematology, General Medicine, Biological Sciences, United States, 3. Good health, Phenotype, Good Health and Well Being, 030220 oncology & carcinogenesis, General Article, National Heart, Lung, and Blood Institute (U.S.), Genome-Wide Association Study, Biotechnology
Abstract

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI’s Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

Published
2021
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4. Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program

Author

Adolfo Correa, Jai G. Broome, Chunyan Ren, Kari E. North, Nancy L. Heard-Costa, Yao Yao, Brian D. Hobbs, Mary Cushman, Leslie A. Lange, Daniel E. Bauer, Xiuwen Zheng, Braxton D. Mitchell, Yun Li, Quan Sun, Sébastian Méric de Bellefon, Terri H. Beaty, Paul S. de Vries, Ruth J. F. Loos, Adrienne M. Stilp, Albert V. Smith, Paul L. Auer, Deepti Jain, Lifang Hou, Robert C. Kaplan, Jee-Young Moon, Michael Preuss, Stephen S. Rich, Guillaume Lettre, Nicole Soranzo, Eric Boerwinkle, Kousik Kundu, Laura Almasy, Marsha M. Wheeler, Thomas W. Blackwell, Nancy Min, Nicholas L. Smith, Bruce M. Psaty, Lisa R. Yanek, Joanne E. Curran, Stacey Gabriel, Kathleen A. Ryan, Alanna C. Morrison, Lynette Ekunwe, Caitlin P. McHugh, Laura M. Raffield, Adam S. Butterworth, Deborah A. Nickerson, Ravindranath Duggirala, Gonçalo R. Abecasis, John Lane, Hélène Choquet, Andrew D. Johnson, Nauder Faraday, Russell T. Walton, Praveen Surendran, Jennifer A. Brody, Yao Hu, Alexander P. Reiner, Jerome I. Rotter, Donald M. Lloyd-Jones, Cathy C. Laurie, Zhe Wang, Hua Tang, Charles Kooperberg, Eric Jorgenson, Jeffrey R. O'Connell, Shuquan Rao, Nathalie Chami, Rasika A. Mathias, Matthew P. Conomos, Myriam Fornage, Ramachandran S. Vasan, Nathan Pankratz, Joshua P. Lewis, Lewis C. Becker, Benjamin P. Kleinstiver, Cecelia A. Laurie, Ming-Huei Chen, and John Blangero

Subjects
Adult, Male, Quality Control, 0301 basic medicine, Erythrocytes, Population, Datasets as Topic, Genome-wide association study, Biology, Quantitative trait locus, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Indel, education, Gene, Genetics (clinical), Aged, Genetic association, Gene Editing, Whole genome sequencing, education.field_of_study, Genetic Variation, Reproducibility of Results, Correction, Middle Aged, United States, Genetic architecture, HEK293 Cells, Phenotype, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, National Heart, Lung, and Blood Institute (U.S.), Chromosomes, Human, Pair 16, Genome-Wide Association Study
Abstract

Summary Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380 ), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

Published
2021
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5. Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

Author

George Hindy, Peter Dornbos, Mark D. Chaffin, Dajiang J. Liu, Minxian Wang, Margaret Sunitha Selvaraj, David Zhang, Joseph Park, Carlos A. Aguilar-Salinas, Lucinda Antonacci-Fulton, Diego Ardissino, Donna K. Arnett, Stella Aslibekyan, Gil Atzmon, Christie M. Ballantyne, Francisco Barajas-Olmos, Nir Barzilai, Lewis C. Becker, Lawrence F. Bielak, Joshua C. Bis, John Blangero, Eric Boerwinkle, Lori L. Bonnycastle, Erwin Bottinger, Donald W. Bowden, Matthew J. Bown, Jennifer A. Brody, Jai G. Broome, Noël P. Burtt, Brian E. Cade, Federico Centeno-Cruz, Edmund Chan, Yi-Cheng Chang, Yii-Der I. Chen, Ching-Yu Cheng, Won Jung Choi, Rajiv Chowdhury, Cecilia Contreras-Cubas, Emilio J. Córdova, Adolfo Correa, L. Adrienne Cupples, Joanne E. Curran, John Danesh, Paul S. de Vries, Ralph A. DeFronzo, Harsha Doddapaneni, Ravindranath Duggirala, Susan K. Dutcher, Patrick T. Ellinor, Leslie S. Emery, Jose C. Florez, Myriam Fornage, Barry I. Freedman, Valentin Fuster, Ma. Eugenia Garay-Sevilla, Humberto García-Ortiz, Soren Germer, Richard A. Gibbs, Christian Gieger, Benjamin Glaser, Clicerio Gonzalez, Maria Elena Gonzalez-Villalpando, Mariaelisa Graff, Sarah E. Graham, Niels Grarup, Leif C. Groop, Xiuqing Guo, Namrata Gupta, Sohee Han, Craig L. Hanis, Torben Hansen, Jiang He, Nancy L. Heard-Costa, Yi-Jen Hung, Mi Yeong Hwang, Marguerite R. Irvin, Sergio Islas-Andrade, Gail P. Jarvik, Hyun Min Kang, Sharon L.R. Kardia, Tanika Kelly, Eimear E. Kenny, Alyna T. Khan, Bong-Jo Kim, Ryan W. Kim, Young Jin Kim, Heikki A. Koistinen, Charles Kooperberg, Johanna Kuusisto, Soo Heon Kwak, Markku Laakso, Leslie A. Lange, Jiwon Lee, Juyoung Lee, Seonwook Lee, Donna M. Lehman, Rozenn N. Lemaitre, Allan Linneberg, Jianjun Liu, Ruth J.F. Loos, Steven A. Lubitz, Valeriya Lyssenko, Ronald C.W. Ma, Lisa Warsinger Martin, Angélica Martínez-Hernández, Rasika A. Mathias, Stephen T. McGarvey, Ruth McPherson, James B. Meigs, Thomas Meitinger, Olle Melander, Elvia Mendoza-Caamal, Ginger A. Metcalf, Xuenan Mi, Karen L. Mohlke, May E. Montasser, Jee-Young Moon, Hortensia Moreno-Macías, Alanna C. Morrison, Donna M. Muzny, Sarah C. Nelson, Peter M. Nilsson, Jeffrey R. O’Connell, Marju Orho-Melander, Lorena Orozco, Colin N.A. Palmer, Nicholette D. Palmer, Cheol Joo Park, Kyong Soo Park, Oluf Pedersen, Juan M. Peralta, Patricia A. Peyser, Wendy S. Post, Michael Preuss, Bruce M. Psaty, Qibin Qi, D.C. Rao, Susan Redline, Alexander P. Reiner, Cristina Revilla-Monsalve, Stephen S. Rich, Nilesh Samani, Heribert Schunkert, Claudia Schurmann, Daekwan Seo, Jeong-Sun Seo, Xueling Sim, Rob Sladek, Kerrin S. Small, Wing Yee So, Adrienne M. Stilp, E. Shyong Tai, Claudia H.T. Tam, Kent D. Taylor, Yik Ying Teo, Farook Thameem, Brian Tomlinson, Michael Y. Tsai, Tiinamaija Tuomi, Jaakko Tuomilehto, Teresa Tusié-Luna, Miriam S. Udler, Rob M. van Dam, Ramachandran S. Vasan, Karine A. Viaud Martinez, Fei Fei Wang, Xuzhi Wang, Hugh Watkins, Daniel E. Weeks, James G. Wilson, Daniel R. Witte, Tien-Yin Wong, Lisa R. Yanek, Sekar Kathiresan, Daniel J. Rader, Jerome I. Rotter, Michael Boehnke, Mark I. McCarthy, Cristen J. Willer, Pradeep Natarajan, Jason A. Flannick, Amit V. Khera, Gina M. Peloso, NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, Clinicum, Department of Medicine, HUS Internal Medicine and Rehabilitation, University of Helsinki, and Department of Public Health

Subjects
APOC3, Blood Glucose, Multifactorial Inheritance, gene-based association, Polymorphism, Single Nucleotide, Article, Open Reading Frames, ANGPTL3, lipid, OF-FUNCTION MUTATIONS, BINDING, Databases, Genetic, SEQUENCE VARIANTS, Genetics, Humans, Exome, Genetic Predisposition to Disease, SINUSOIDAL ENDOTHELIAL-CELLS, Genetics (clinical), Alleles, RISK, IDENTIFICATION, 1184 Genetics, developmental biology, physiology, association, cholesterol, Genetic Variation, Computational Biology, Molecular Sequence Annotation, PERILIPIN, Lipid Metabolism, Lipids, Genetics, Population, Phenotype, Diabetes Mellitus, Type 2, Liver, Case-Control Studies, exome sequencing, TRIGLYCERIDES, Genome-Wide Association Study
Abstract

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels. This work was supported by a grant from the Swedish Research Council (2016-06830) and grants from the National Heart, Lung, and Blood Institute (NHLBI): R01HL142711 and R01HL127564. Please refer to the supplemental information for the full acknowledgements. Sí

Published
2022
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6. eSCAN: scan regulatory regions for aggregate association testing using whole-genome sequencing data

Author

Yingxi, Yang, Quan, Sun, Le, Huang, Jai G, Broome, Adolfo, Correa, Alexander, Reiner, Laura M, Raffield, Yuchen, Yang, and Yun, Li

Subjects
Genome, Whole Genome Sequencing, Problem Solving Protocol, Genomics, Regulatory Sequences, Nucleic Acid, Molecular Biology, Information Systems, Genome-Wide Association Study
Abstract

Multiple statistical methods for aggregate association testing have been developed for whole-genome sequencing (WGS) data. Many aggregate variants in a given genomic window and ignore existing knowledge to define test regions, resulting in many identified regions not clearly linked to genes, and thus, limiting biological understanding. Functional information from new technologies (such as Hi-C and its derivatives), which can help link enhancers to their effector genes, can be leveraged to predefine variant sets for aggregate testing in WGS data. Here, we propose the eSCAN (scan the enhancers) method for genome-wide assessment of enhancer regions in sequencing studies, combining the advantages of dynamic window selection in SCANG (SCAN the Genome), a previously developed method, with the advantages of incorporating putative regulatory regions from annotation. eSCAN, by searching in putative enhancers, increases statistical power and aids mechanistic interpretation, as demonstrated by extensive simulation studies. We also apply eSCAN for blood cell traits using NHLBI Trans-Omics for Precision Medicine WGS data. Results from real data analysis show that eSCAN is able to capture more significant signals, and these signals are of shorter length (indicating higher resolution fine-mapping capability) and drive association of larger regions detected by other methods.

Published
2021

7. Rare coding variants in 35 genes associate with circulating lipid levels – a multi-ancestry analysis of 170,000 exomes

Author

Marju Orho-Melander, Humberto García-Ortiz, Xueling Sim, Amp-T D-Genes, Cheol Joo Park, Gina M. Peloso, Jason Flannick, Brian Tomlinson, Hyun Min Kang, Emilio J. Cordova, Stephen S. Rich, Richard A. Gibbs, Angélica Martínez-Hernández, Lorena Orozco, Harsha Doddapaneni, Lisa R. Yanek, Jiwon Lee, Namrata Gupta, Valeriya Lyssenko, Sohee Han, James B. Meigs, Bong-Jo Kim, Bruce M. Psaty, Leslie S. Emery, Kerrin S. Small, Pradeep Natarajan, May E. Montasser, Christian Gieger, Sharon L.R. Kardia, Sarah C. Nelson, Craig L. Hanis, Heikki A. Koistinen, María Elena González-Villalpando, Edmund Chan, Michael Y. Tsai, Benjamin Glaser, Thomas Meitinger, Matthew J. Bown, Mariaelisa Graff, John Danesh, Sekar Kathiresan, Tiinamaija Tuomi, Ramachandran S. Vasan, Gil Atzmon, Alyna T. Khan, Diego Ardissino, Yii-Der Ida Chen, David Zhang, Rob M. van Dam, Wendy S. Post, Barry I. Freedman, D. C. Rao, Michael Preuss, Donna M. Lehman, L. Adrienne Cupples, Colin N. A. Palmer, Claudia H. T. Tam, Hortensia Moreno-Macías, Markku Laakso, Peter Dornbos, Teresa Tusié-Luna, Stella Aslibekyan, Marguerite R. Irvin, Daniel J. Rader, Jee-Young Moon, Eimear E. Kenny, Lisa W. Martin, Jennifer A. Brody, Amit Khera, Erwin P. Bottinger, Sarah E. Graham, Myriam Fornage, Ruth McPherson, Nancy L. Heard-Costa, Michael Boehnke, Clicerio Gonzalez, Ryan W. Kim, Yi-Cheng Chang, Peter M. Nilsson, Yik Ying Teo, Robert Sladek, Cristen J. Willer, Fei Fei Wang, Donna K. Arnett, Mark Chaffin, Karine A. Viaud Martinez, Alanna C. Morrison, Leslie A. Lange, Ravindranath Duggirala, Donna M. Muzny, Kent D. Taylor, Niels Grarup, Soren Germer, Patricia A. Peyser, Brian E. Cade, Lewis C. Becker, Steven A. Lubitz, Nicholette D. Palmer, Susan K. Dutcher, Ronald C.W. Ma, Xuenan Mi, Xiuqing Guo, Hugh Watkins, Eric Boerwinkle, Qibin Qi, Johanna Kuusisto, Christie M. Ballantyne, Tanika N. Kelly, Rajiv Chowdhury, Elvia Mendoza-Caamal, Wing-Yee So, Tien Yin Wong, Torben Hansen, Cecilia Contreras-Cubas, Jeong-Sun Seo, Mi Yeong Hwang, Daekwan Seo, Dajiang J. Liu, Cristina Revilla-Monsalve, Paul S. de Vries, Daniel R. Witte, Yi-Jen Hung, Olle Melander, Karen L. Mohlke, Lucinda Antonacci-Fulton, Francisco Barajas-Olmos, Soo Heon Kwak, Daniel E. Weeks, Claudia Schurmann, Ginger A. Metcalf, Young-Jin Kim, Adrienne M. Stilp, Lori L. Bonnycastle, John Blangero, Ralph A. DeFronzo, Donald W. Bowden, Rasika A. Mathias, Oluf Pedersen, Rozenn N. Lemaitre, Stephen T. McGarvey, Heribert Schunkert, Jaakko Tuomilehto, Farook Thameem, Valentin Fuster, Joshua C. Bis, George Hindy, Allan Linneberg, James G. Wilson, Kyong Soo Park, Sergio A. Islas-Andrade, Ching-Yu Cheng, Won Jung Choi, Minxian X. Wang, Xuzhi Wang, Adolfo Correa, Jai G. Broome, Gail P. Jarvik, Alexander P. Reiner, E. Shyong Tai, Juyoung Lee, Mark I. McCarthy, Nilesh J. Samani, Susan Redline, Carlos A. Aguilar-Salinas, Jerome I. Rotter, Ma. Eugenia Garay-Sevilla, Jiang He, Patrick T. Ellinor, Joseph Park, Joanne E. Curran, Nir Barzilai, Federico Centeno-Cruz, Seonwook Lee, Lawrence F. Bielak, Jianjun Liu, Charles Kooperberg, Juan M. Peralta, Jose C. Florez, Leif Groop, Noël P. Burtt, Margaret Sunitha Selvaraj, Jeffrey R. O'Connell, and Ruth J. F. Loos

Subjects
Genetics, 0303 health sciences, education.field_of_study, Population, Single-nucleotide polymorphism, Genome-wide association study, Biology, DNA sequencing, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, SNP, education, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels. Ten of these: ALB, SRSF2, JAK2, CREB3L3, TMEM136, VARS, NR1H3, PLA2G12A, PPARG and STAB1 have not been implicated for lipid levels using rare coding variation in population-based samples. We prioritize 32 genes identified in array-based genome-wide association study (GWAS) loci based on gene-based associations, of which three: EVI5, SH2B3, and PLIN1, had no prior evidence of rare coding variant associations. Most of the associated genes showed evidence of association in multiple ancestries. Also, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes, and for genes closest to GWAS index single nucleotide polymorphisms (SNP). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

Published
2020
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8. Whole genome sequencing association analysis of quantitative red blood cell phenotypes: the NHLBI TOPMed program

Author

Paul L. Auer, Laura Almasy, Jerome I. Rotter, Nancy Min, Lisa R. Yanek, Shuquan Rao, Hua Tang, Zhe Wang, Stacey Gabriel, Jee-Young Moon, Nancy L. Heard-Costa, Adam S. Butterworth, Ravindranath Duggirala, Cathy C. Laurie, Hélène Choquet, Ruth J. F. Loos, Alanna C. Morrison, Eric Jorgenson, Charles Kooperberg, Rasika A. Mathias, Laura M. Raffield, Nicholas L. Smith, Andrew D. Johnson, Matthew P. Conomos, Lynette Ekunwe, Donald M. Lloyd-Jones, Gonçalo R. Abecasis, Robert C. Kaplan, Myriam Fornage, Daniel E. Bauer, Nathalie Chami, Lewis C. Becker, Leslie A. Lange, Ming-Huei Chen, Brian D. Hobbs, Paul S. de Vries, Terri H. Beaty, Cecelia A. Laurie, Eric Boerwinkle, Michael Preuss, Adrienne M. Stilp, Jeffrey R. O'Connell, Kousik Kundu, Joanne E. Curran, Mary Cushman, Kari E. North, Xiuwen Zheng, John Blangero, Sébastian Méric de Bellefon, Ramachandran S. Vasan, Nathan Pankratz, Praveen Surendran, Joshua P. Lewis, Kathleen A. Ryan, Jennifer A. Brody, Deepti Jain, Braxton D. Mitchell, Marsha M. Wheeler, Lifang Hou, Deborah A. Nickerson, Guillaume Lettre, Alexander P. Reiner, Albert V. Smith, Stephen S. Rich, Nicole Soranzo, Adolfo Correa, Jai G. Broome, Nauder Faraday, Thomas W. Blackwell, Bruce M. Psaty, Quan Sun, Yun Li, Caitlin P. McHugh, Yao Hu, and John Lane

Subjects
Genetics, Whole genome sequencing, education.field_of_study, Population, Genome-wide association study, Quantitative trait locus, Biology, Genetic architecture, symbols.namesake, Mendelian inheritance, symbols, Indel, education, Genetic association
Abstract

Whole genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these newly discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3bp indel p.Lys2169del (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis [OMIM 194380], associated with higher MCHC. In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically-diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

Published
2020
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9. Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Author

Pradeep Natarajan, Akhil Pampana, Sarah E. Graham, Sanni E. Ruotsalainen, James A. Perry, Paul S. de Vries, Jai G. Broome, James P. Pirruccello, Michael C. Honigberg, Krishna Aragam, Brooke Wolford, Jennifer A. Brody, Lucinda Antonacci-Fulton, Moscati Arden, Stella Aslibekyan, Themistocles L. Assimes, Christie M. Ballantyne, Lawrence F. Bielak, Joshua C. Bis, Brian E. Cade, Ron Do, Harsha Doddapaneni, Leslie S. Emery, Yi-Jen Hung, Marguerite R. Irvin, Alyna T. Khan, Leslie Lange, Jiwon Lee, Rozenn N. Lemaitre, Lisa W. Martin, Ginger Metcalf, May E. Montasser, Jee-Young Moon, Donna Muzny, Jeffrey R. O’Connell, Nicholette D. Palmer, Juan M. Peralta, Patricia A. Peyser, Adrienne M. Stilp, Michael Tsai, Fei Fei Wang, Daniel E. Weeks, Lisa R. Yanek, James G. Wilson, Goncalo Abecasis, Donna K. Arnett, Lewis C. Becker, John Blangero, Eric Boerwinkle, Donald W. Bowden, Yi-Cheng Chang, Yii-Der I. Chen, Won Jung Choi, Adolfo Correa, Joanne E. Curran, Mark J. Daly, Susan K. Dutcher, Patrick T. Ellinor, Myriam Fornage, Barry I. Freedman, Stacey Gabriel, Soren Germer, Richard A. Gibbs, Jiang He, Kristian Hveem, Gail P. Jarvik, Robert C. Kaplan, Sharon L. R. Kardia, Eimear Kenny, Ryan W. Kim, Charles Kooperberg, Cathy C. Laurie, Seonwook Lee, Don M. Lloyd-Jones, Ruth J. F. Loos, Steven A. Lubitz, Rasika A. Mathias, Karine A. Viaud Martinez, Stephen T. McGarvey, Braxton D. Mitchell, Deborah A. Nickerson, Kari E. North, Aarno Palotie, Cheol Joo Park, Bruce M. Psaty, D. C. Rao, Susan Redline, Alexander P. Reiner, Daekwan Seo, Jeong-Sun Seo, Albert V. Smith, Russell P. Tracy, Ramachandran S. Vasan, Sekar Kathiresan, L. Adrienne Cupples, Jerome I. Rotter, Alanna C. Morrison, Stephen S. Rich, Samuli Ripatti, Cristen Willer, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, FinnGen, Gina M. Peloso, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Department of Public Health, Biostatistics Helsinki, Department of Clinical Chemistry and Hematology, Doctoral Programme in Social Sciences, HYKS erva, Päijät-Häme Welfare Consortium, Department of Medicine, HUS Inflammation Center, Clinicum, HUS Heart and Lung Center, Marja-Riitta Taskinen Research Group, Tiinamaija Tuomi Research Group, HUS Abdominal Center, Department of Oncology, Heikki Joensuu / Principal Investigator, HUS Comprehensive Cancer Center, Department of Medical and Clinical Genetics, Lauri Antti Aaltonen / Principal Investigator, HUS Head and Neck Center, Silmäklinikka, Department of Dermatology, Allergology and Venereology, Department of Food and Nutrition, Medicum, Data Science Genetic Epidemiology Lab, HUSLAB, Department of Mathematics and Statistics, University Management, Biosciences, Pregnancy and Genes, and HUS Gynecology and Obstetrics

Subjects
0301 basic medicine, Male, Apolipoprotein B, General Physics and Astronomy, Blood lipids, Adipose tissue, Genome-wide association study, 030204 cardiovascular system & hematology, Genome-wide association studies, PCSK9, 0302 clinical medicine, Subcutaneous Tissue, GENETIC-VARIANTS, Phenomics, X chromosome, RISK, Multidisciplinary, biology, 1184 Genetics, developmental biology, physiology, Middle Aged, Lipids, X-CHROMOSOME, CORONARY-ARTERY-DISEASE, Female, medicine.medical_specialty, CHOLESTEROL/APOLIPOPROTEIN-B RATIO, APOLIPOPROTEIN-B, Genotype, Science, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Diabetes mellitus, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele, Eye Proteins, Genetic Association Studies, Chromosomes, Human, X, DENSITY-LIPOPROTEIN-CHOLESTEROL, Whole Genome Sequencing, business.industry, Cardiometabolic Risk Factors, FAT DISTRIBUTION, General Chemistry, Cardiovascular genetics, medicine.disease, 030104 developmental biology, Endocrinology, Gene Expression Regulation, Genetic Loci, biology.protein, business
Abstract

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids., The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

Published
2020

10. Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Author

Cashell E. Jaquish, Craig P. Hersh, Emily Barron-Casella, Larry Phillips, James S. Pankow, JoAnn E. Manson, Mariza de Andrade, Vivien A. Sheehan, Norann A. Zaghloul, Yongmei Liu, Sergei Nekhai, Russell P. Tracy, Bruce S. Weir, Pankaj Qasba, Adrienne M. Stilp, Tasha E. Fingerlin, Heather M. Ochs-Balcom, L. Adrienne Cupples, Rongze Yang, David A. Schwartz, Shannon Kelly, Scott E. Devine, Tanja Smith, G.L. Kinney, Beverly Snively, Kent D. Taylor, Manolis Kellis, Ruth J. F. Loos, Seth A. Ament, Kathleen C. Barnes, Robert C. Kaplan, Ulrich Broeckel, Hemant K. Tiwari, Karin F. Hoth, Peter Durda, Julie L. Mikulla, Charles B. Eaton, Cotton Seed, Merry Lynn McDonald, Eric Boerwinkle, Josh Smith, Honghuang Lin, Ingrid B. Borecki, Jeffrey L. Curtis, Emelia J. Benjamin, Kenneth Rice, Sharon L.R. Kardia, Nicholas L. Smith, Coleen M. Damcott, Jeffrey Haessler, Kimberly L. Jones, Elaine Cornell, Nona Sotoodehnia, Adolfo Correa, Rich Johnston, C. Charles Gu, Chii Min Hwu, Peter C. Anderson, Lesley F. Tinker, Colleen Davis, R. Graham Barr, Scott T. Weiss, Leanna Farnam, Chao Hsiung, Brian Silver, Patrick F. McArdle, Lisa W. Martin, Yii-Der Ida Chen, John Barnard, Holly Kramer, Sekar Kathiresan, Gonçalo R. Abecasis, Barry Make, Michael C. Mahaney, Marco V Perez, Donna K. Arnett, Mark Chaffin, Xiuqing Guo, Joshua C. Bis, Pamela Russell, Paul L. Auer, James G. Wilson, Marilyn J. Telen, David K. Levine, Jennifer A. Smith, Christopher Scheller, Meher Preethi Boorgula, Aakrosh Ratan, Kari E. North, Dan E. Arking, Elizabeth A. Regan, Margaret G. Parker, Andres Metspalu, Jai G. Broome, Daniel Taliun, Lynette Ekunwe, Alyna T. Khan, Hao Mei, Dhananjay Vaidya, Ellen M. Schmidt, Stanford Mwasongwe, Joshua P. Lewis, Stacey Gabriel, Christine E. Seidman, Margery Gass, Deborah A. Nickerson, Nicola L. Hawley, Rebecca L. Beer, Afshin Parsa, Steven L. Salzberg, Terri H. Beaty, Stella Aslibekyan, Girish N. Nadkarni, Wei Zhao, David L. Tirschwell, Karen Bunting, Dawn L. DeMeo, Laura J. Rasmussen-Torvik, Julia Powers Becker, Dmitry Prokopenko, Karen Schwander, Bruce D. Gelb, Stephanie Krauter, Laura M. Raffield, Michael E. Hall, Frank C. Sciurba, Lauren Margolin, Nora Franceschini, Daniel N. Harris, Seyedeh M. Zekavat, Dawood Darbar, Keng-Han Lin, Haley Huston, Steven A. Lubitz, Andrea Ganna, Carole Sztalryd, Cathy C. Laurie, Christy Chang, James E. Hixson, Steven A. McCarroll, Barbara A. Konkle, Michael D. Kessler, Scott I. Vrieze, Yingze Zhang, Sarah Ruuska, George J. Papanicolaou, Weiniu Gan, Maris Alver, Elizabeth A. Streeten, Fei Fei Wang, Lu-Chen Weng, Braxton D. Mitchell, Lee-Ming Chuang, Sean P. David, Wei-Min Chen, Susan R. Heckbert, Ryan D. Hernandez, Andrew D. Johnson, Cristen J. Willer, Ani Manichaikul, Jonathan M. Bloom, Timothy D. O’Connor, Sylvia Smoller, Marguerite R. Irvin, Seung Hoan Choi, Ida Surakka, Veikko Salomaa, Diane M. Becker, Ron Do, W. Craig Johnson, Cecelia A. Laurie, Meryl S. LeBoff, Aniket Shetty, Tõnu Esko, Michael C. Zody, Xiaoqi Geng, Da Wei Gong, Snow Xueyan Zhao, Esteban G. Burchard, Xiuwen Zheng, Cara L. Carty, Alexander P. Reiner, Tim Assimes, Deborah A. Meyers, Mina K. Chung, Harald H H Göring, Benjamin M. Neale, Pradeep Natarajan, Yan Gao, Stephen S. Rich, Yun Ju Sung, Susan K. Dutcher, Ferdouse Begum, Stephanie M. Gogarten, John Blangero, Jonathan Cardwell, Kayleen Williams, Rakhi P. Naik, Amol C. Shetty, Sayantan Das, Myriam Fornage, May E. Montasser, Michelle Daya, Edwin K. Silverman, Daniel E. Weeks, Laura J. Kaufman, Dimitrios Avramopoulos, Michael Y. Tsai, Christine M. Albert, Vijay G. Sankaran, Jeffrey R. O'Connell, Thomas W. Blackwell, Stephen T. McGarvey, Robert M. Reed, Leslie A. Lange, Qing Duan, Bruce M. Psaty, Leslie S. Emery, Bertha Hidalgo, Jennifer A. Brody, L. Keoki Williams, Soren Germer, Zhaohui S. Qin, Deepti Jain, Deborah Applebaum-Bowden, Carla Wilson, Degui Zhi, Christoph Lange, Elliott Hong, L.F. Bielak, Wen Jane Lee, Yue Guan, Tarik Walker, Rebecca D. Jackson, Charles R. Farber, Mark J. Daly, Stephanie M. Fullerton, John E. Hokanson, Karol E. Watson, James Luo, Richard Casaburi, Seunggeun Lee, Jill M. Johnsen, Margaret A. Taub, Ryan L. Minster, Ravi Duggirala, Susan K. Mathai, Yun Li, Quenna Wong, Matthew Flickinger, Huichun Xu, Susan Redline, Ulrike Peters, Ivana V. Yang, Jesse M. Engreitz, Sanni Ruotsalainen, Sean K. McFarland, Avram D Walts, Patricia A. Peyser, Allison E. Ashley-Koch, Lewis C. Becker, Nicholette Palmer Allred, James A. Perry, Jody S. Sylvia, Tamar Sofer, Vasan S. Ramachandran, Laura Almasy, Matthew J. Budoff, Ranjan Deka, David M. Herrington, Simeon I. Taylor, Daniel Levy, Chaojie Yang, Sameer Chavan, Kathleen A. Ryan, Josyf C. Mychaleckyj, Ingo Ruczinski, Sebastian Zoellner, Michael Preuss, Tim Poterba, Wendy S. Post, Amber L. Beitelshees, Ben Heavner, Carolina Roselli, Namiko Abe, Jonathon LeFaive, Mark T. Gladwin, Brian Custer, Robert B. Wallace, Simin Liu, Michael H. Cho, Robert E. Handsaker, Dabeeru C. Rao, Bo Juen Chen, Wayne Hui Heng Sheu, Xiang Zhou, Marcos Bezerra, Solomon K. Musani, Eimear E. Kenny, James F. Casella, Kathryn L. Lunetta, Nancy Min, Nicholas Rafaels, Lisa R. Yanek, Min A. Jhun, David C. Glahn, Rasika A. Mathias, Mollie A. Minear, Russell P. Bowler, Jason Ernst, Carolyn J. Crandall, Sara Penchev, Alvaro Alonso, Timothy A. Thornton, Toni I. Pollin, Charles Kooperberg, Ethan M. Lange, Juan M. Peralta, Pramod Anugu, Lucinda Fulton, Adam A. Szpiro, Michael R. DeBaun, M. Benjamin Shoemaker, Sam Phillips, Dan M. Roden, Mao Fu, Daniel I. Chasman, James D. Crapo, Hua Tang, Gina M. Peloso, Hyun Min Kang, Samuli Ripatti, Phuwanat Sakornsakolpat, Christopher R. Gignoux, Peter VandeHaar, Jerome I. Rotter, Dandi Qiao, Emily S. Wan, Shabnam Salimi, Kevin Sandow, Jiang He, Patrick T. Ellinor, Joanne E. Curran, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Clinicum, Doctoral Programme in Population Health, Department of Public Health, and Complex Disease Genetics

Subjects
0301 basic medicine, Apolipoprotein B, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular, Lipoprotein particle, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, GENETIC-VARIANTS, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, Aetiology, lcsh:Science, African Continental Ancestry Group, Genetics, Multidisciplinary, Genome, biology, CHOLESTEROL, Adaptor Proteins, Lipoprotein(a), Single Nucleotide, NHLBI TOPMed Lipids Working Group, 3142 Public health care science, environmental and occupational health, 3. Good health, Cholesterol, Heart Disease, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, RARE VARIANTS, lipids (amino acids, peptides, and proteins), LOW-FREQUENCY, Human, DNA Copy Number Variations, Science, Quantitative Trait Loci, European Continental Ancestry Group, Black People, POPULATION-SCALE, Quantitative trait locus, Article, White People, General Biochemistry, Genetics and Molecular Biology, LDL, Structural variation, 03 medical and health sciences, COMPONENTS-ANALYSIS, RISK-FACTOR, Humans, CORONARY-HEART-DISEASE, Polymorphism, Whole Genome Sequencing, Prevention, Human Genome, General Chemistry, Atherosclerosis, Vesicular Transport, Good Health and Well Being, 030104 developmental biology, chemistry, biology.protein, lcsh:Q, 3111 Biomedicine, Lipoprotein, Genome-Wide Association Study
Abstract

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans., Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

Published
2018
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11. Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Author

Dan M. Roden, Hemant K. Tiwari, Eric A. Whitsel, Arden Moscati, Russell P. Tracy, Robert C. Kaplan, Hongsheng Gui, Joshua C. Bis, Brian Custer, Michael H. Cho, David A. Schwartz, Eric Boerwinkle, Kari E. North, Kent D. Taylor, May E. Montasser, Mariza de Andrade, Jai G. Broome, Hongyu Zhao, Alexander P. Reiner, L. Keoki Williams, James G. Wilson, Erik L. Bao, Kristin G. Ardlie, Jee-Young Moon, Laura M. Raffield, Susan R. Heckbert, Stella Aslibekyan, Lawrence F. Bielak, Stephen S. Rich, Bala Bharathi Burugula, Kyle Chang, Pradeep Natarajan, Paul L. Auer, Marsha M. Wheeler, Scott T. Weiss, Andrew D. Johnson, Marguerite R. Irvin, Ruth J. F. Loos, Esteban G. Burchard, Sebastian M. Armasu, Thomas W. Blackwell, Bruce M. Psaty, Tanika N. Kelly, Ida Yii-Der Chen, Siddhartha Jaiswal, Tasha E. Fingerlin, Myriam Fornage, Jiang He, Patrick T. Ellinor, Mindy D. Szeto, Edwin K. Silverman, Daniel E. Weeks, Nicholas L. Smith, Peter Durda, Donna K. Arnett, John A. Heit, James S. Floyd, Barry I. Freedman, Stephen T. McGarvey, Matthew Leventhal, Sharon L.R. Kardia, Joanne E. Curran, Joseph Nasser, Angel C.Y. Mak, Deborah A. Meyers, Gonçalo R. Abecasis, Lewis C. Becker, Satish K. Nandakumar, Jacob O. Kitzman, Xiuqing Guo, Ivana V. Yang, Benjamin L. Ebert, James E. Hixson, Jesse M. Engreitz, Christopher J. Gibson, Eric S. Lander, Amy E. Lin, Jennifer A. Smith, Seyedeh M. Zekavat, Daniel Levy, Sekar Kathiresan, Charles Kooperberg, Jerome I. Rotter, Xiaotian Liao, Fei Fei Wang, Cathy C. Laurie, Nicholette D. Palmer, Ramachandran S. Vasan, Barbara A. Konkle, Jessica Lasky-Su, Ethan M. Lange, Leslie A. Lange, Juan M. Peralta, Jiwon Lee, Eimear E. Kenny, JoAnn E. Manson, Patricia A. Peyser, Priyadarshini Kachroo, Albert V. Smith, Brian E. Cade, Bruce D. Levy, Vijay G. Sankaran, Yongmei Liu, Nicholas Rafaels, Stephanie M. Gogarten, John Blangero, Alexander G. Bick, Joshua S. Weinstock, François Aguet, Steven A. Lubitz, Lenore J. Launer, Quenna Wong, M. Benjamin Shoemaker, L. Adrienne Cupples, Susan Redline, Paul Scheet, Michelle Daya, Sally E. Wenzel, Charles P. Fulco, Dabeeru C. Rao, Rasika A. Mathias, Cecelia A. Laurie, Jill M. Johnsen, Margaret A. Taub, Braxton D. Mitchell, Lifang Hou, Erin J Buth, Pinkal Desai, Ester Cerdeira Sabino, Donald W. Bowden, Kathleen C. Barnes, Adolfo Correa, Wayne Huey-Herng Sheu, and Dawood Darbar

Subjects
0301 basic medicine, Adult, Male, alpha Karyopherins, Somatic cell, Black People, Locus (genetics), Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Germline, Article, Dioxygenases, Tripartite Motif Proteins, 03 medical and health sciences, 0302 clinical medicine, Proto-Oncogene Proteins, Genetic variation, Humans, Genetic Predisposition to Disease, Cell Self Renewal, Precision Medicine, Germ-Line Mutation, Aged, Genetics, Aged, 80 and over, Multidisciplinary, Whole Genome Sequencing, Genome, Human, Intracellular Signaling Peptides and Proteins, Middle Aged, Hematopoietic Stem Cells, Human genetics, United States, DNA-Binding Proteins, Haematopoiesis, 030104 developmental biology, Phenotype, Africa, Female, Stem cell, Clonal Hematopoiesis, National Heart, Lung, and Blood Institute (U.S.)
Abstract

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2–4 and coronary heart disease5—this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Published
2019

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