Publications by authors named "Angel C Y Mak"

34 Publications

Racial/Ethnic differences in eligibility for asthma biologics among pediatric populations.

J Allergy Clin Immunol 2021 Sep 15. Epub 2021 Sep 15.

Department of Medicine, University of California San Francisco, San Francisco, CA, United States of America; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, United States of America.

Background: Asthma is a heterogenous disease. Clinical blood parameters differ by race/ethnicity and are used to distinguish asthma subtypes and inform therapies. Differences in subtypes may explain population-specific trends in asthma outcomes. However, these differences in racial/ethnic minority pediatric populations are unclear.

Objective: Investigate the association of blood parameters and asthma subtypes with asthma outcomes and examine population-specific eligibility for biologic therapies in minority pediatric populations.

Methods: Using data from two asthma case-control studies of pediatric minority populations, we performed case-control (N=3,738) and case only (N=2,743) logistic regressions to quantify the association of blood parameters and asthma subtypes with asthma outcomes. Heterogeneity of these associations was tested using an interaction term between race/ethnicity and each exposure. Differences in therapeutic eligibility were investigated using chi-squared tests.

Results: Race/ethnicity modified the association between total immunoglobulin E (IgE) and asthma exacerbations. Elevated IgE was associated with worse asthma outcomes in Puerto Ricans. Allergic asthma was associated with worse outcomes in Mexican Americans whereas eosinophilic asthma was associated with worse outcomes in Puerto Ricans. A lower proportion of Puerto Ricans met dosing criteria for allergic asthma-directed biologic therapy than other groups. A higher proportion of Puerto Ricans qualified for eosinophilic asthma-directed biologic therapy than African Americans.

Conclusion: We found population-specific associations between blood parameters and asthma subtypes with asthma outcomes. Our findings suggest that eligibility for asthma biologic therapies differs across pediatric racial/ethnic populations. These findings call for more studies in diverse populations for equitable treatment of minority patients with asthma.
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http://dx.doi.org/10.1016/j.jaci.2021.09.005DOI Listing
September 2021

Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Genetics 2021 May;218(1)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
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http://dx.doi.org/10.1093/genetics/iyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128395PMC
May 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Native American Ancestry and Air Pollution Interact to Impact Bronchodilator Response in Puerto Rican Children with Asthma.

Ethn Dis 2021 21;31(1):77-88. Epub 2021 Jan 21.

Department of Medicine, University of California, San Francisco, CA.

Objective: Asthma is the most common chronic disease in children. Short-acting bronchodilator medications are the most commonly prescribed asthma treatment worldwide, regardless of disease severity. Puerto Rican children display the highest asthma morbidity and mortality of any US population. Alarmingly, Puerto Rican children with asthma display poor bronchodilator drug response (BDR). Reduced BDR may explain, in part, the increased asthma morbidity and mortality observed in Puerto Rican children with asthma. Gene-environment interactions may explain a portion of the heritability of BDR. We aimed to identify gene-environment interactions associated with BDR in Puerto Rican children with asthma.

Setting: Genetic, environmental, and psycho-social data from the Genes-environments and Admixture in Latino Americans (GALA II) case-control study.

Participants: Our discovery dataset consisted of 658 Puerto Rican children with asthma; our replication dataset consisted of 514 Mexican American children with asthma.

Main Outcome Measures: We assessed the association of pairwise interaction models with BDR using ViSEN (Visualization of Statistical Epistasis Networks).

Results: We identified a non-linear interaction between Native American genetic ancestry and air pollution significantly associated with BDR in Puerto Rican children with asthma. This interaction was robust to adjustment for age and sex but was not significantly associated with BDR in our replication population.

Conclusions: Decreased Native American ancestry coupled with increased air pollution exposure was associated with increased BDR in Puerto Rican children with asthma. Our study acknowledges BDR's phenotypic complexity, and emphasizes the importance of integrating social, environmental, and biological data to further our understanding of complex disease.
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http://dx.doi.org/10.18865/ed.31.1.77DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843041PMC
January 2021

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

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

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.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium.

Nat Commun 2020 10 12;11(1):5139. Epub 2020 Oct 12.

Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.
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http://dx.doi.org/10.1038/s41467-020-18781-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550582PMC
October 2020

Integrative genomic analysis in African American children with asthma finds three novel loci associated with lung function.

Genet Epidemiol 2021 Mar 29;45(2):190-208. Epub 2020 Sep 29.

Department of Medicine, University of California, San Francisco, California, USA.

Bronchodilator (BD) drugs are commonly prescribed for treatment and management of obstructive lung function present with diseases such as asthma. Administration of BD medication can partially or fully restore lung function as measured by pulmonary function tests. The genetics of baseline lung function measures taken before BD medication have been extensively studied, and the genetics of the BD response itself have received some attention. However, few studies have focused on the genetics of post-BD lung function. To address this gap, we analyzed lung function phenotypes in 1103 subjects from the Study of African Americans, Asthma, Genes, and Environment, a pediatric asthma case-control cohort, using an integrative genomic analysis approach that combined genotype, locus-specific genetic ancestry, and functional annotation information. We integrated genome-wide association study (GWAS) results with an admixture mapping scan of three pulmonary function tests (forced expiratory volume in 1 s [FEV ], forced vital capacity [FVC], and FEV /FVC) taken before and after albuterol BD administration on the same subjects, yielding six traits. We identified 18 GWAS loci, and five additional loci from admixture mapping, spanning several known and novel lung function candidate genes. Most loci identified via admixture mapping exhibited wide variation in minor allele frequency across genotyped global populations. Functional fine-mapping revealed an enrichment of epigenetic annotations from peripheral blood mononuclear cells, fetal lung tissue, and lung fibroblasts. Our results point to three novel potential genetic drivers of pre- and post-BD lung function: ADAMTS1, RAD54B, and EGLN3.
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http://dx.doi.org/10.1002/gepi.22365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902343PMC
March 2021

Mapping the 17q12-21.1 Locus for Variants Associated with Early-Onset Asthma in African Americans.

Am J Respir Crit Care Med 2021 02;203(4):424-436

Department of Internal Medicine, Center for Individualized and Genomic Medicine Research and.

The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants. To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals. We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) ( = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) ( = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) ( = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant. The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms. A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.
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http://dx.doi.org/10.1164/rccm.202006-2623OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885840PMC
February 2021

Genome-wide association study reveals a novel locus for asthma with severe exacerbations in diverse populations.

Pediatr Allergy Immunol 2021 01 14;32(1):106-115. Epub 2020 Sep 14.

Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, San Cristóbal de La Laguna, Tenerife, Spain.

Background: Severe asthma exacerbations are a major cause of asthma morbidity and increased healthcare costs. Several studies have shown racial and ethnic differences in asthma exacerbation rates. We aimed to identify genetic variants associated with severe exacerbations in two high-risk populations for asthma.

Methods: A genome-wide association study of asthma in children and youth with severe exacerbations was performed in 1283 exacerbators and 2027 controls without asthma of Latino ancestry. Independent suggestive variants (P ≤ 5 × 10 ) were selected for replication in 448 African Americans exacerbators and 595 controls. Case-only analyses were performed comparing the exacerbators with additional 898 Latinos and 524 African Americans asthma patients without exacerbations, while adjusting by treatment category as a proxy of asthma severity. We analyzed the functionality of associated variants with in silico methods and by correlating genotypes with methylation levels in whole blood in a subset of 473 Latinos.

Results: We identified two genome-wide significant associations for susceptibility to asthma with severe exacerbations, including a novel locus located at chromosome 2p21 (rs4952375, odds ratio = 1.39, P = 3.8 × 10 ), which was also associated with asthma exacerbations in a case-only analysis (odds ratio = 1.25, P = 1.95 × 10 ). This polymorphism is an expression quantitative trait locus of the long intergenic non-protein coding RNA 1913 (LINC01913) in lung tissues (P = 1.3 × 10 ) and influences methylation levels of the protein kinase domain-containing cytoplasmic (PKDCC) gene in whole-blood cells (P = 9.8 × 10 ).

Conclusion: We identified a novel susceptibility locus for severe asthma exacerbations in Hispanic/Latino and African American youths with functional effects in gene expression and methylation status of neighboring genes.
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http://dx.doi.org/10.1111/pai.13337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886969PMC
January 2021

On the cross-population generalizability of gene expression prediction models.

PLoS Genet 2020 08 14;16(8):e1008927. Epub 2020 Aug 14.

Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.

The genetic control of gene expression is a core component of human physiology. For the past several years, transcriptome-wide association studies have leveraged large datasets of linked genotype and RNA sequencing information to create a powerful gene-based test of association that has been used in dozens of studies. While numerous discoveries have been made, the populations in the training data are overwhelmingly of European descent, and little is known about the generalizability of these models to other populations. Here, we test for cross-population generalizability of gene expression prediction models using a dataset of African American individuals with RNA-Seq data in whole blood. We find that the default models trained in large datasets such as GTEx and DGN fare poorly in African Americans, with a notable reduction in prediction accuracy when compared to European Americans. We replicate these limitations in cross-population generalizability using the five populations in the GEUVADIS dataset. Via realistic simulations of both populations and gene expression, we show that accurate cross-population generalizability of transcriptome prediction only arises when eQTL architecture is substantially shared across populations. In contrast, models with non-identical eQTLs showed patterns similar to real-world data. Therefore, generating RNA-Seq data in diverse populations is a critical step towards multi-ethnic utility of gene expression prediction.
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http://dx.doi.org/10.1371/journal.pgen.1008927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449671PMC
August 2020

Whole-Genome Sequencing Identifies Novel Functional Loci Associated with Lung Function in Puerto Rican Youth.

Am J Respir Crit Care Med 2020 10;202(7):962-972

Department of Bioengineering and Therapeutic Sciences and.

Puerto Ricans have the highest childhood asthma prevalence in the United States (23.6%); however, the etiology is uncertain. In this study, we sought to uncover the genetic architecture of lung function in Puerto Rican youth with and without asthma who were recruited from the island ( = 836). We used admixture-mapping and whole-genome sequencing data to discover genomic regions associated with lung function. Functional roles of the prioritized candidate SNPs were examined with chromatin immunoprecipitation sequencing, RNA sequencing, and expression quantitative trait loci data. We discovered a genomic region at 1q32 that was significantly associated with a 0.12-L decrease in the lung volume of exhaled air (95% confidence interval, -0.17 to -0.07;  = 6.62 × 10) with each allele of African ancestry. Within this region, two SNPs were expression quantitative trait loci of in nasal airway epithelial cells and in esophagus mucosa. The minor alleles of these SNPs were associated with significantly decreased lung function and decreased gene expression. Another admixture-mapping peak was observed on chromosome 5q35.1, indicating that each Native American ancestry allele was associated with a 0.15-L increase in lung function (95% confidence interval, 0.08-0.21;  = 5.03 × 10). The region-based association tests identified four suggestive windows that harbored candidate rare variants associated with lung function. We identified common and rare genetic variants that may play a critical role in lung function among Puerto Rican youth. We independently validated an inflammatory pathway that could potentially be used to develop more targeted treatments and interventions for patients with asthma.
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http://dx.doi.org/10.1164/rccm.202002-0351OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528787PMC
October 2020

Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand and Gene-By-Air-Pollution Interaction.

Genetics 2020 07 23;215(3):869-886. Epub 2020 Apr 23.

Department of Medicine, University of California, San Francisco, California 94143.

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.
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http://dx.doi.org/10.1534/genetics.120.303231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337089PMC
July 2020

Expression of SMARCD1 interacts with age in association with asthma control on inhaled corticosteroid therapy.

Respir Res 2020 Jan 28;21(1):31. Epub 2020 Jan 28.

PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, 401 Park Drive, Suite 401, Boston, MA, 02215-5301, USA.

Background: Global gene expression levels are known to be highly dependent upon gross demographic features including age, yet identification of age-related genomic indicators has yet to be comprehensively undertaken in a disease and treatment-specific context.

Methods: We used gene expression data from CD4+ lymphocytes in the Asthma BioRepository for Integrative Genomic Exploration (Asthma BRIDGE), an open-access collection of subjects participating in genetic studies of asthma with available gene expression data. Replication population participants were Puerto Rico islanders recruited as part of the ongoing Genes environments & Admixture in Latino Americans (GALA II), who provided nasal brushings for transcript sequencing. The main outcome measure was chronic asthma control as derived by questionnaires. Genomic associations were performed using regression of chronic asthma control score on gene expression with age in years as a covariate, including a multiplicative interaction term for gene expression times age.

Results: The SMARCD1 gene (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1) interacted with age to influence chronic asthma control on inhaled corticosteroids, with a doubling of expression leading to an increase of 1.3 units of chronic asthma control per year (95% CI [0.86, 1.74], p = 6 × 10), suggesting worsening asthma control with increasing age. This result replicated in GALA II (p = 3.8 × 10). Cellular assays confirmed the role of SMARCD1 in glucocorticoid response in airway epithelial cells.

Conclusion: Focusing on age-dependent factors may help identify novel indicators of asthma medication response. Age appears to modulate the effect of SMARCD1 on asthma control with inhaled corticosteroids.
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http://dx.doi.org/10.1186/s12931-020-1295-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988322PMC
January 2020

Identification of CFTR variants in Latino patients with cystic fibrosis from the Dominican Republic and Puerto Rico.

Pediatr Pulmonol 2020 02 30;55(2):533-540. Epub 2019 Oct 30.

Department of Pediatrics, Centro de Neumología Pediátrica, San Juan, Puerto Rico.

Background: In cystic fibrosis (CF), the spectrum and frequency of CFTR variants differ by geography and race/ethnicity. CFTR variants in White patients are well-described compared with Latino patients. No studies of CFTR variants have been done in patients with CF in the Dominican Republic or Puerto Rico.

Methods: CFTR was sequenced in 61 Dominican Republican patients and 21 Puerto Rican patients with CF and greater than ​​​​60 mmol/L sweat chloride. The spectrum of CFTR variants was identified and the proportion of patients with 0, 1, or 2 CFTR variants identified was determined. The functional effects of identified CFTR variants were investigated using clinical annotation databases and computational prediction tools.

Results: Our study found 10% of Dominican patients had two CFTR variants identified compared with 81% of Puerto Rican patients. No CFTR variants were identified in 69% of Dominican patients and 10% of Puerto Rican patients. In Dominican patients, there were 19 identified CFTR variants, accounting for 25 out of 122 disease alleles (20%). In Puerto Rican patients, there were 16 identified CFTR variants, accounting for 36 out of 42 disease alleles (86%) in Puerto Rican patients. Thirty CFTR variants were identified overall. The most frequent variants for Dominican patients were p.Phe508del and p.Ala559Thr and for Puerto Rican patients were p.Phe508del, p.Arg1066Cys, p.Arg334Trp, and p.I507del.

Conclusions: In this first description of the CFTR variants in patients with CF from the Dominican Republic and Puerto Rico, there was a low detection rate of two CFTR variants after full sequencing with the majority of patients from the Dominican Republic without identified variants.
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http://dx.doi.org/10.1002/ppul.24549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571374PMC
February 2020

Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis.

Mol Genet Genomic Med 2019 12 16;7(12):e1007. Epub 2019 Oct 16.

Cardiovascular Research Institute, University of California, San Francisco, CA, USA.

Background: Homozygous Familial Hypercholesterolemia (HoFH) is an inherited recessive condition associated with extremely high levels of low-density lipoprotein (LDL) cholesterol in affected individuals. It is usually caused by homozygous or compound heterozygous functional mutations in the LDL receptor (LDLR). A number of mutations causing FH have been reported in literature and such genetic heterogeneity presents great challenges for disease diagnosis.

Objective: We aim to determine the likely genetic defects responsible for three cases of pediatric HoFH in two kindreds.

Methods: We applied whole exome sequencing (WES) on the two probands to determine the likely functional variants among candidate FH genes. We additionally applied 10x Genomics (10xG) Linked-Reads whole genome sequencing (WGS) on one of the kindreds to identify potentially deleterious structural variants (SVs) underlying HoFH. A PCR-based screening assay was also established to detect the LDLR structural variant in a cohort of 641 patients with elevated LDL.

Results: In the Caucasian kindred, the FH homozygosity can be attributed to two compound heterozygous LDLR damaging variants, an exon 12 p.G592E missense mutation and a novel 3kb exon 1 deletion. By analyzing the 10xG phased data, we ascertained that this deletion allele was most likely to have originated from a Russian ancestor. In the Mexican kindred, the strikingly elevated LDL cholesterol level can be attributed to a homozygous frameshift LDLR variant p.E113fs.

Conclusions: While the application of WES can provide a cost-effective way of identifying the genetic causes of FH, it often lacks sensitivity for detecting structural variants. Our finding of the LDLR exon 1 deletion highlights the broader utility of Linked-Read WGS in detecting SVs in the clinical setting, especially when HoFH patients remain undiagnosed after WES.
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http://dx.doi.org/10.1002/mgg3.1007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900368PMC
December 2019

Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma.

Chest 2019 12 23;156(6):1068-1079. Epub 2019 Sep 23.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.

Background: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma.

Methods: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician's diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes.

Results: A genome-wide significant association was identified between baseline FEV/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10 in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV (P = 3.3 × 10), postbronchodilator (PB) FEV (7.3 × 10), and PB FEV/FVC ratio (P = 2.7 × 10). The identified baseline FEV/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR.

Conclusions: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.
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http://dx.doi.org/10.1016/j.chest.2019.08.2202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904857PMC
December 2019

Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity.

Am J Hum Genet 2019 10 19;105(4):747-762. Epub 2019 Sep 19.

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA; Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute, University of California San Francisco, San Francisco, CA 94158, USA; Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada; Genome Quebec Innovation Center, McGill University, Montreal, QC H3A 0G1, Canada. Electronic address:

Runs of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations.
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http://dx.doi.org/10.1016/j.ajhg.2019.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817522PMC
October 2019

Genome of the Komodo dragon reveals adaptations in the cardiovascular and chemosensory systems of monitor lizards.

Nat Ecol Evol 2019 08 29;3(8):1241-1252. Epub 2019 Jul 29.

Gladstone Institutes, San Francisco, CA, USA.

Monitor lizards are unique among ectothermic reptiles in that they have high aerobic capacity and distinctive cardiovascular physiology resembling that of endothermic mammals. Here, we sequence the genome of the Komodo dragon Varanus komodoensis, the largest extant monitor lizard, and generate a high-resolution de novo chromosome-assigned genome assembly for V. komodoensis using a hybrid approach of long-range sequencing and single-molecule optical mapping. Comparing the genome of V. komodoensis with those of related species, we find evidence of positive selection in pathways related to energy metabolism, cardiovascular homoeostasis, and haemostasis. We also show species-specific expansions of a chemoreceptor gene family related to pheromone and kairomone sensing in V. komodoensis and other lizard lineages. Together, these evolutionary signatures of adaptation reveal the genetic underpinnings of the unique Komodo dragon sensory and cardiovascular systems, and suggest that selective pressure altered haemostasis genes to help Komodo dragons evade the anticoagulant effects of their own saliva. The Komodo dragon genome is an important resource for understanding the biology of monitor lizards and reptiles worldwide.
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http://dx.doi.org/10.1038/s41559-019-0945-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668926PMC
August 2019

Ambient air pollution, asthma drug response, and telomere length in African American youth.

J Allergy Clin Immunol 2019 09 24;144(3):839-845.e10. Epub 2019 Jun 24.

Department of Medicine, University of California, San Francisco, Calif; Environmental Health Sciences Division, School of Public Health, University of California, Berkeley, Calif. Electronic address:

Background: Telomere length (TL) can serve as a potential biomarker for conditions associated with chronic oxidative stress and inflammation, such as asthma. Air pollution can induce oxidative stress. Understanding the relationship between TL, asthma, and air pollution is important for identifying risk factors contributing to unhealthy aging in children.

Objectives: We sought to investigate associations between exposures to ambient air pollutants and TL in African American children and adolescents and to examine whether African ancestry, asthma status, and steroid medication use alter the association.

Methods: Linear regression was used to examine associations between absolute telomere length (aTL) and estimated annual average residential ozone (O) and fine particulate matter with a diameter of 2.5 μm or less (PM) exposures in a cross-sectional analysis of 1072 children in an existing asthma case-control study. African ancestry, asthma status, and use of steroid medications were examined as effect modifiers.

Results: Participants' aTLs were measured by using quantitative PCR. A 1-ppb and 1 μg/m increase in annual average exposure to O and PM were associated with a decrease in aTL of 37.1 kilo-base pair (kb; 95% CI, -66.7 to -7.4 kb) and 57.1 kb (95% CI, -118.1 to 3.9 kb), respectively. African ancestry and asthma were not effect modifiers; however, exposure to steroid medications modified the relationships between TL and pollutants. Past-year exposure to O and PM was associated with shorter TLs in patients without steroid use.

Conclusion: Exposure to air pollution was associated with shorter TLs in nonasthmatic children and adolescents. This was not the case for asthmatic children as a group, but those receiving steroid medication had less shortening than those not using steroids. Reduced exposure to air pollution in childhood might help to preserve TL.
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http://dx.doi.org/10.1016/j.jaci.2019.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938647PMC
September 2019

A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma.

Pharmacogenomics J 2019 06 12;19(3):249-259. Epub 2018 Sep 12.

National Laboratory of Genomics for Biodiversity (LANGEBIO), CINVESTAV, Irapuato, Guanajuato, Mexico.

Short-acting β-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the United States. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African-American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single-nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1830 Latinos (total = 2779). Finally, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p = 7.69 × 10). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958 and rs7081864, p ≤ 5 × 10). Our results failed to replicate in three additional populations of 416 Latinos and 1615 African Americans. Our findings indicate that both population-specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.
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http://dx.doi.org/10.1038/s41397-018-0042-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414286PMC
June 2019

Genetic Determinants of Telomere Length in African American Youth.

Sci Rep 2018 09 5;8(1):13265. Epub 2018 Sep 5.

Department of Medicine, University of California, San Francisco, CA, USA.

Telomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining genetic associations with TL in diverse pediatric populations such as African Americans.
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http://dx.doi.org/10.1038/s41598-018-31238-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125592PMC
September 2018

Secondhand smoke exposure and asthma outcomes among African-American and Latino children with asthma.

Thorax 2018 11 13;73(11):1041-1048. Epub 2018 Jun 13.

Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

Background: Secondhand smoke (SHS) exposures have been linked to asthma-related outcomes but quantitative dose-responses using biomarkers of exposure have not been widely reported.

Objectives: Assess dose-response relationships between plasma cotinine-determined SHS exposure and asthma outcomes in minority children, a vulnerable population exposed to higher levels of SHS and under-represented in the literature.

Methods: We performed analyses in 1172 Latino and African-American children with asthma from the mainland USA and Puerto Rico. We used logistic regression to assess relationships of cotinine levels ≥0.05 ng/mL with asthma exacerbations (defined as asthma-related hospitalisations, emergency room visits or oral steroid prescription) in the previous year and asthma control. The shape of dose-response relationships was assessed using a continuous exposure variable in generalised additive logistic models with penalised splines.

Results: The OR for experiencing asthma exacerbations in the previous year for cotinine levels ≥0.05 ng/mL, compared with <0.05 ng/mL, was 1.40 (95% CI 1.03 to 1.89), while the OR for poor asthma control was 1.53 (95% CI 1.12 to 2.13). Analyses for dose-response relationships indicated increasing odds of asthma outcomes related with increasing exposure, even at cotinine levels associated with light SHS exposures.

Conclusions: Exposure to SHS was associated with higher odds of asthma exacerbations and having poorly controlled asthma with an increasing dose-response even at low levels of exposure. Our results support the conclusion that there are no safe levels of SHS exposures.
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http://dx.doi.org/10.1136/thoraxjnl-2017-211383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225993PMC
November 2018

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

Am J Respir Crit Care Med 2018 06;197(12):1552-1564

5 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1164/rccm.201712-2529OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006403PMC
June 2018

OMSV enables accurate and comprehensive identification of large structural variations from nanochannel-based single-molecule optical maps.

Genome Biol 2017 Dec 1;18(1):230. Epub 2017 Dec 1.

Department of Computer Science and Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.

We present a new method, OMSV, for accurately and comprehensively identifying structural variations (SVs) from optical maps. OMSV detects both homozygous and heterozygous SVs, SVs of various types and sizes, and SVs with or without creating or destroying restriction sites. We show that OMSV has high sensitivity and specificity, with clear performance gains over the latest method. Applying OMSV to a human cell line, we identified hundreds of SVs >2 kbp, with 68 % of them missed by sequencing-based callers. Independent experimental validation confirmed the high accuracy of these SVs. The OMSV software is available at http://yiplab.cse.cuhk.edu.hk/omsv/ .
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http://dx.doi.org/10.1186/s13059-017-1356-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709945PMC
December 2017

Identification of a novel locus associated with skin colour in African-admixed populations.

Sci Rep 2017 03 16;7:44548. Epub 2017 Mar 16.

Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.

Skin pigmentation is a complex trait that varies largely among populations. Most genome-wide association studies of this trait have been performed in Europeans and Asians. We aimed to uncover genes influencing skin colour in African-admixed individuals. We performed a genome-wide association study of melanin levels in 285 Hispanic/Latino individuals from Puerto Rico, analyzing 14 million genetic variants. A total of 82 variants with p-value ≤1 × 10 were followed up in 373 African Americans. Fourteen single nucleotide polymorphisms were replicated, of which nine were associated with skin colour at genome-wide significance in a meta-analysis across the two studies. These results validated the association of two previously known skin pigmentation genes, SLC24A5 (minimum p = 2.62 × 10, rs1426654) and SLC45A2 (minimum p = 9.71 × 10, rs16891982), and revealed the intergenic region of BEND7 and PRPF18 as a novel locus associated with this trait (minimum p = 4.58 × 10, rs6602666). The most significant variant within this region is common among African-descent populations but not among Europeans or Native Americans. Our findings support the advantages of analyzing African-admixed populations to discover new genes influencing skin pigmentation.
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http://dx.doi.org/10.1038/srep44548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353593PMC
March 2017

High-throughput single-molecule mapping links subtelomeric variants and long-range haplotypes with specific telomeres.

Nucleic Acids Res 2017 May;45(9):e73

Drexel University, School of Biomedical Engineering, Philadelphia, PA, 19104 USA.

Accurate maps and DNA sequences for human subtelomere regions, along with detailed knowledge of subtelomere variation and long-range telomere-terminal haplotypes in individuals, are critical for understanding telomere function and its roles in human biology. Here, we use a highly automated whole genome mapping technology in nano-channel arrays to analyze large terminal human chromosome segments extending from chromosome-specific subtelomere sequences through subtelomeric repeat regions to terminal (TTAGGG)n repeat tracts. We establish detailed maps for subtelomere gap regions in the human reference sequence, detect many new large subtelomeric variants and demonstrate the feasibility of long-range haplotyping through segmentally duplicated subtelomere regions. These features make the method a uniquely valuable new tool for improving the quality of genome assemblies in complex DNA regions. Based on single molecule mapping of telomere-terminal DNA fragments, we provide proof of principle for a novel method to estimate telomere lengths linked to distinguishable telomeric haplotypes; this single-telomere genotyping method may ultimately enable delineation of human cis elements involved in telomere length regulation.
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http://dx.doi.org/10.1093/nar/gkx017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605236PMC
May 2017

In the Wrong Place with the Wrong SNP: The Association Between Stressful Neighborhoods and Cardiac Arrest Within Beta-2-adrenergic Receptor Variants.

Epidemiology 2016 09;27(5):656-62

From the aDepartment of Epidemiology, Columbia University, New York, NY; bCardiovascular Health Research Unit, University of Washington, Seattle, WA; cSeattle Children's Research Institute, Seattle, WA; dIDEAS Center, VA Salt Lake City Health Care System, Salt Lake City, UT; eNew York Academy of Medicine, New York, NY; fDepartment of Biostatistics, University of Washington, Seattle, WA; gCardiovascular Research Institute, University of California, San Francisco, CA; and hGarvan Institute of Medical Research, Sydney, Australia.

Background: Sudden cardiac arrest has been linked independently both to stressful neighborhood conditions and to polymorphisms in the ADRB2 gene. The ADRB2 gene mediates sympathetic activation in response to stress. Therefore, if neighborhood conditions cause cardiac arrest through the stress pathway, the ADRB2 variant may modify the association between neighborhood conditions, such as socioeconomic deprivation and incidence of cardiac arrest.

Methods: The Cardiac Arrest Blood Study Repository is a population-based repository of specimens and other data from adult cardiac arrest patients residing in King County, Washington. Cases (n = 1,539) were 25- to 100-year-old individuals of European descent who experienced out-of-hospital cardiac arrest from 1988 to 2004. Interactions between neighborhood conditions and the ADRB2 genotype on cardiac arrest risk were assessed in a case-only study design. Gene-environment independence was assessed in blood samples obtained from King County residents initially contacted by random-digit dialing.

Results: Fewer than 4% of study subjects resided in socioeconomically deprived neighborhoods. Nonetheless, the case-only analysis indicated the presence of supramultiplicative interaction of socioeconomic deprivation and the homozygous Gln27Glu variant (case-only odds ratio: 1.8 [95% confidence interval: 1.0, 2.9]). Interactions between population density and the homozygous Gln27Glu variant were weaker (case-only odds ratio: 1.2 [95% confidence interval: 0.97, 1.5]).

Conclusions: Findings support a supramultiplicative interaction between the Gln27Glu ADRB2 variant and socioeconomic deprivation among individuals of European descent. This result is consistent with the hypothesis that the elevation in cardiac arrest risk associated with socioeconomic deprivation operates through the stress pathway.
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http://dx.doi.org/10.1097/EDE.0000000000000503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505271PMC
September 2016

Brief Report: Whole-Exome Sequencing for Identification of Potential Causal Variants for Diffuse Cutaneous Systemic Sclerosis.

Arthritis Rheumatol 2016 09;68(9):2257-62

University of California, San Francisco.

Objective: Scleroderma is a genetically complex autoimmune disease with substantial phenotypic heterogeneity. Previous genome-wide association studies have identified common genetic variants associated with disease risk, but these studies are not designed to capture rare or potential causal variants. Our goal was to identify rare as well as common genetic variants in patients with diffuse cutaneous systemic sclerosis (dcSSc) through whole-exome sequencing (WES) in order to identify potential causal variants.

Methods: We generated WES data for 32 dcSSc patients with or without interstitial lung disease (ILD) and for 17 healthy "in-house" controls. Variants were annotated and filtered by quality, minor allele frequency, and deleterious effects on gene function. We applied a gene burden test to identify novel dcSSc and dcSSc-associated ILD candidate genes that were enriched with deleterious variants in cases compared to in-house controls as well as controls from the 1000 Genomes Project (n = 130).

Results: We identified 70 genes that were enriched with deleterious variants in dcSSc patients. Two of them (BANK1 and TERT) were in pathways previously implicated in SSc or ILD pathogenesis or known susceptibility loci. Newly identified genes (COL4A3, COL4A4, COL5A2, COL13A1, and COL22A1) were significantly enriched in the extracellular matrix-related pathway, which is relevant to the fibrotic features of dcSSc, and in the DNA repair pathway (XRCC4).

Conclusion: This study demonstrates the value of WES for the identification of novel gene variants and pathways that may contribute to scleroderma risk and/or severity. The candidate genes we discovered are potential targets for in-depth functional studies.
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http://dx.doi.org/10.1002/art.39721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568050PMC
September 2016

Genome-Wide Structural Variation Detection by Genome Mapping on Nanochannel Arrays.

Genetics 2016 Jan 28;202(1):351-62. Epub 2015 Oct 28.

Cardiovascular Research Institute, University of California, San Francisco Institute for Human Genetics, University of California, San Francisco

Comprehensive whole-genome structural variation detection is challenging with current approaches. With diploid cells as DNA source and the presence of numerous repetitive elements, short-read DNA sequencing cannot be used to detect structural variation efficiently. In this report, we show that genome mapping with long, fluorescently labeled DNA molecules imaged on nanochannel arrays can be used for whole-genome structural variation detection without sequencing. While whole-genome haplotyping is not achieved, local phasing (across >150-kb regions) is routine, as molecules from the parental chromosomes are examined separately. In one experiment, we generated genome maps from a trio from the 1000 Genomes Project, compared the maps against that derived from the reference human genome, and identified structural variations that are >5 kb in size. We find that these individuals have many more structural variants than those published, including some with the potential of disrupting gene function or regulation.
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http://dx.doi.org/10.1534/genetics.115.183483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701098PMC
January 2016
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