@article {118, title = {Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand and Gene-By-Air-Pollution Interaction.}, journal = {Genetics}, volume = {215}, year = {2020}, month = {2020 07}, pages = {869-886}, abstract = {

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 {\texttimes} 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.

}, issn = {1943-2631}, doi = {10.1534/genetics.120.303231}, author = {Mak, Angel C Y and Sajuthi, Satria and Joo, Jaehyun and Xiao, Shujie and Sleiman, Patrick M and White, Marquitta J and Lee, Eunice Y and Saef, Benjamin and Hu, Donglei and Gui, Hongsheng and Keys, Kevin L and Lurmann, Fred and Jain, Deepti and Abecasis, Gon{\c c}alo and Kang, Hyun Min and Nickerson, Deborah A and Germer, Soren and Zody, Michael C and Winterkorn, Lara and Reeves, Catherine and Huntsman, Scott and Eng, Celeste and Salazar, Sandra and Oh, Sam S and Gilliland, Frank D and Chen, Zhanghua and Kumar, Rajesh and Mart{\'\i}nez, Fernando D and Wu, Ann Chen and Ziv, Elad and Hakonarson, Hakon and Himes, Blanca E and Williams, L Keoki and Seibold, Max A and Burchard, Esteban G} } @article {54, title = {Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 Sep}, pages = {2135-2144}, abstract = {

PURPOSE: To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs.

METHODS: DNA sequence coverage data are normalized within each sample and subsequently exonic CNVs are identified in a batch of samples, when the target log ratio of the sample to the batch median exceeds defined thresholds. The quality of exonic CNV calls is assessed by C-scores (Z-like scores) using thresholds derived from gold standard samples and simulation studies. We integrate an ExonQC threshold to lower FDR and compare performance with alternate software (VisCap).

RESULTS: Thirteen CNVs were used as a truth set to validate Atlas-CNV and compared with VisCap. We demonstrated FDR reduction in validation, simulation, and 10,926 eMERGESeq samples without sensitivity loss. Sixty-four multiexon and 29 single-exon CNVs with high C-scores were assessed by~Multiplex Ligation-dependent Probe Amplification (MLPA).

CONCLUSION: Atlas-CNV is validated as a method to identify exonic CNVs in targeted sequencing data generated in the clinical laboratory. The ExonQC and C-score assignment can reduce FDR (identification of targets with high variance) and improve calling accuracy of single-exon CNVs respectively. We propose guidelines and criteria to identify high confidence single-exon CNVs.

}, issn = {1530-0366}, doi = {10.1038/s41436-019-0475-4}, author = {Chiang, Theodore and Liu, Xiuping and Wu, Tsung-Jung and Hu, Jianhong and Sedlazeck, Fritz J and White, Simon and Schaid, Daniel and Andrade, Mariza de and Jarvik, Gail P and Crosslin, David and Stanaway, Ian and Carrell, David S and Connolly, John J and Hakonarson, Hakon and Groopman, Emily E and Gharavi, Ali G and Fedotov, Alexander and Bi, Weimin and Leduc, Magalie S and Murdock, David R and Jiang, Yunyun and Meng, Linyan and Eng, Christine M and Wen, Shu and Yang, Yaping and Muzny, Donna M and Boerwinkle, Eric and Salerno, William and Venner, Eric and Gibbs, Richard A} } @article {42, title = {Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.}, journal = {Am J Respir Crit Care Med}, volume = {197}, year = {2018}, month = {2018 Jun 15}, pages = {1552-1564}, abstract = {

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 {\texttimes} 10) and suggestive (P < 7.06 {\texttimes} 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.

}, issn = {1535-4970}, doi = {10.1164/rccm.201712-2529OC}, author = {Mak, Angel C Y and White, Marquitta J and Eckalbar, Walter L and Szpiech, Zachary A and Oh, Sam S and Pino-Yanes, Maria and Hu, Donglei and Goddard, Pag{\'e} and Huntsman, Scott and Galanter, Joshua and Wu, Ann Chen and Himes, Blanca E and Germer, Soren and Vogel, Julia M and Bunting, Karen L and Eng, Celeste and Salazar, Sandra and Keys, Kevin L and Liberto, Jennifer and Nuckton, Thomas J and Nguyen, Thomas A and Torgerson, Dara G and Kwok, Pui-Yan and Levin, Albert M and Celed{\'o}n, Juan C and Forno, Erick and Hakonarson, Hakon and Sleiman, Patrick M and Dahlin, Amber and Tantisira, Kelan G and Weiss, Scott T and Serebrisky, Denise and Brigino-Buenaventura, Emerita and Farber, Harold J and Meade, Kelley and Lenoir, Michael A and Avila, Pedro C and Sen, Saunak and Thyne, Shannon M and Rodriguez-Cintron, William and Winkler, Cheryl A and Moreno-Estrada, Andr{\'e}s and Sandoval, Karla and Rodriguez-Santana, Jose R and Kumar, Rajesh and Williams, L Keoki and Ahituv, Nadav and Ziv, Elad and Seibold, Max A and Darnell, Robert B and Zaitlen, Noah and Hernandez, Ryan D and Burchard, Esteban G} }