%0 Journal Article %J Nature %D 2020 %T Inherited causes of clonal haematopoiesis in 97,691 whole genomes. %A Bick, Alexander G %A Weinstock, Joshua S %A Nandakumar, Satish K %A Fulco, Charles P %A Bao, Erik L %A Zekavat, Seyedeh M %A Szeto, Mindy D %A Liao, Xiaotian %A Leventhal, Matthew J %A Nasser, Joseph %A Chang, Kyle %A Laurie, Cecelia %A Burugula, Bala Bharathi %A Gibson, Christopher J %A Lin, Amy E %A Taub, Margaret A %A Aguet, François %A Ardlie, Kristin %A Mitchell, Braxton D %A Barnes, Kathleen C %A Moscati, Arden %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Silverman, Edwin K %A Weiss, Scott T %A Palmer, Nicholette D %A Vasan, Ramachandran S %A Burchard, Esteban G %A Kardia, Sharon L R %A He, Jiang %A Kaplan, Robert C %A Smith, Nicholas L %A Arnett, Donna K %A Schwartz, David A %A Correa, Adolfo %A de Andrade, Mariza %A Guo, Xiuqing %A Konkle, Barbara A %A Custer, Brian %A Peralta, Juan M %A Gui, Hongsheng %A Meyers, Deborah A %A McGarvey, Stephen T %A Chen, Ida Yii-Der %A Shoemaker, M Benjamin %A Peyser, Patricia A %A Broome, Jai G %A Gogarten, Stephanie M %A Wang, Fei Fei %A Wong, Quenna %A Montasser, May E %A Daya, Michelle %A Kenny, Eimear E %A North, Kari E %A Launer, Lenore J %A Cade, Brian E %A Bis, Joshua C %A Cho, Michael H %A Lasky-Su, Jessica %A Bowden, Donald W %A Cupples, L Adrienne %A Mak, Angel C Y %A Becker, Lewis C %A Smith, Jennifer A %A Kelly, Tanika N %A Aslibekyan, Stella %A Heckbert, Susan R %A Tiwari, Hemant K %A Yang, Ivana V %A Heit, John A %A Lubitz, Steven A %A Johnsen, Jill M %A Curran, Joanne E %A Wenzel, Sally E %A Weeks, Daniel E %A Rao, Dabeeru C %A Darbar, Dawood %A Moon, Jee-Young %A Tracy, Russell P %A Buth, Erin J %A Rafaels, Nicholas %A Loos, Ruth J F %A Durda, Peter %A Liu, Yongmei %A Hou, Lifang %A Lee, Jiwon %A Kachroo, Priyadarshini %A Freedman, Barry I %A Levy, Daniel %A Bielak, Lawrence F %A Hixson, James E %A Floyd, James S %A Whitsel, Eric A %A Ellinor, Patrick T %A Irvin, Marguerite R %A Fingerlin, Tasha E %A Raffield, Laura M %A Armasu, Sebastian M %A Wheeler, Marsha M %A Sabino, Ester C %A Blangero, John %A Williams, L Keoki %A Levy, Bruce D %A Sheu, Wayne Huey-Herng %A Roden, Dan M %A Boerwinkle, Eric %A Manson, JoAnn E %A Mathias, Rasika A %A Desai, Pinkal %A Taylor, Kent D %A Johnson, Andrew D %A Auer, Paul L %A Kooperberg, Charles %A Laurie, Cathy C %A Blackwell, Thomas W %A Smith, Albert V %A Zhao, Hongyu %A Lange, Ethan %A Lange, Leslie %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Scheet, Paul %A Kitzman, Jacob O %A Lander, Eric S %A Engreitz, Jesse M %A Ebert, Benjamin L %A Reiner, Alexander P %A Jaiswal, Siddhartha %A Abecasis, Gonçalo %A Sankaran, Vijay G %A Kathiresan, Sekar %A Natarajan, Pradeep %K Adult %K Africa %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K alpha Karyopherins %K Cell Self Renewal %K Clonal Hematopoiesis %K DNA-Binding Proteins %K Female %K Genetic Predisposition to Disease %K Genome, Human %K Germ-Line Mutation %K Hematopoietic Stem Cells %K Humans %K Intracellular Signaling Peptides and Proteins %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Precision Medicine %K Proto-Oncogene Proteins %K Tripartite Motif Proteins %K United States %K Whole Genome Sequencing %X

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. 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 cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). 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.

%B Nature %V 586 %P 763-768 %8 2020 10 %G eng %N 7831 %1 https://www.ncbi.nlm.nih.gov/pubmed/33057201?dopt=Abstract %R 10.1038/s41586-020-2819-2 %0 Journal Article %J Genetics %D 2020 %T Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand and Gene-By-Air-Pollution Interaction. %A Mak, Angel C Y %A Sajuthi, Satria %A Joo, Jaehyun %A Xiao, Shujie %A Sleiman, Patrick M %A White, Marquitta J %A Lee, Eunice Y %A Saef, Benjamin %A Hu, Donglei %A Gui, Hongsheng %A Keys, Kevin L %A Lurmann, Fred %A Jain, Deepti %A Abecasis, Gonçalo %A Kang, Hyun Min %A Nickerson, Deborah A %A Germer, Soren %A Zody, Michael C %A Winterkorn, Lara %A Reeves, Catherine %A Huntsman, Scott %A Eng, Celeste %A Salazar, Sandra %A Oh, Sam S %A Gilliland, Frank D %A Chen, Zhanghua %A Kumar, Rajesh %A Martínez, Fernando D %A Wu, Ann Chen %A Ziv, Elad %A Hakonarson, Hakon %A Himes, Blanca E %A Williams, L Keoki %A Seibold, Max A %A Burchard, Esteban G %X

Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole-genome sequencing data from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV on chromosome 12 in 867 African American children with asthma ( = 1.26 × 10, β = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded nine variants as the most likely candidates responsible for the association with FEV Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with (KIT ligand, also known as ), and their minor alleles were associated with increased expression of the gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure ( = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV, possibly mediated through , in African American children with asthma. This is the first study that has identified a genetic association between lung function and , which has established a role in orchestrating allergic inflammation in asthma.

%B Genetics %V 215 %P 869-886 %8 2020 07 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/32327564?dopt=Abstract %R 10.1534/genetics.120.303231 %0 Journal Article %J Am J Respir Crit Care Med %D 2018 %T Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma. %A Mak, Angel C Y %A White, Marquitta J %A Eckalbar, Walter L %A Szpiech, Zachary A %A Oh, Sam S %A Pino-Yanes, Maria %A Hu, Donglei %A Goddard, Pagé %A Huntsman, Scott %A Galanter, Joshua %A Wu, Ann Chen %A Himes, Blanca E %A Germer, Soren %A Vogel, Julia M %A Bunting, Karen L %A Eng, Celeste %A Salazar, Sandra %A Keys, Kevin L %A Liberto, Jennifer %A Nuckton, Thomas J %A Nguyen, Thomas A %A Torgerson, Dara G %A Kwok, Pui-Yan %A Levin, Albert M %A Celedón, Juan C %A Forno, Erick %A Hakonarson, Hakon %A Sleiman, Patrick M %A Dahlin, Amber %A Tantisira, Kelan G %A Weiss, Scott T %A Serebrisky, Denise %A Brigino-Buenaventura, Emerita %A Farber, Harold J %A Meade, Kelley %A Lenoir, Michael A %A Avila, Pedro C %A Sen, Saunak %A Thyne, Shannon M %A Rodriguez-Cintron, William %A Winkler, Cheryl A %A Moreno-Estrada, Andrés %A Sandoval, Karla %A Rodriguez-Santana, Jose R %A Kumar, Rajesh %A Williams, L Keoki %A Ahituv, Nadav %A Ziv, Elad %A Seibold, Max A %A Darnell, Robert B %A Zaitlen, Noah %A Hernandez, Ryan D %A Burchard, Esteban G %X

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.

OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.

METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.

MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10) and suggestive (P < 7.06 × 10) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings.

CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

%B Am J Respir Crit Care Med %V 197 %P 1552-1564 %8 2018 Jun 15 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/29509491?dopt=Abstract %R 10.1164/rccm.201712-2529OC