A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.

Although countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. By mining the medical records of over 110 million patients, we examine the extent to which Mendelian variation contributes to complex disease risk. We detect thousands of associations between Mendelian and complex diseases, revealing a nondegenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this "Mendelian code." Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute nonadditively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases.

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; ßz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; ß = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

VEGF Polymorphisms (VEGF-936 C/T, VEGF-634 G/C and VEGF-2578 C/A) and Cardiovascular Implications in Long COVID Patients.

The COVID-19 pandemic has raised awareness of the virus's long-term non-pulmonary consequences. This study examined the relationship between genetic polymorphisms of VEGF and cardiac dysfunction and subclinical atherosclerosis in patients recovering from COVID-19. This study included 67 patients previously diagnosed with COVID-19. VEGF-936C/T, VEGF-634G/C, and VEGF-2578C/A statuses were determined. Conventional echocardiography and arterial parameters assessments were performed at inclusion and at six months after the first assessment. For VEGF-936C/T, dominant and over-dominant models showed a significant increase in ejection fraction at six months after COVID (p = 0.044 and 0.048) and was also a predictive independent factor for the augmentation index (ß = 3.07; p = 0.024). The dominant model showed a rise in RV-RA gradient (3.702 mmHg) (p = 0.028 95% CI: 0.040-7.363), with the over-dominant model indicating a greater difference (4.254 mmHg) (p = 0.025 95% CI: 0.624-7.884). The findings for VEGF-634G/C were not statistically significant, except for a difference in TAPSE during initial evaluation, using the codominant model. For VEGF-2578C/A, a difference in ventricular filling pressure (E/E'ratio) was best described under the recessive model. Our research suggests that the VEG-936C/T genotype may impact the baseline level and subsequent changes in cardiac function and subclinical atherosclerosis. These findings offer valuable insights into the complex correlation between genetic polymorphisms and cardiovascular disfunction in long COVID patients.

The Impact of Long COVID on the Quality of Life.

Background and Objectives: The term long COVID refers to patients with a history of confirmed COVID-19 infection, who present symptoms that last for at least 2 months and cannot be explained by another diagnosis. Objectives: The present study aims to determine the most common symptoms of the long COVID syndrome and their impact on the quality of life. Materials and Methods: A prospective observational study was conducted on patients diagnosed with mild and moderate COVID-19 (based on a positive SARS-CoV-2 molecular diagnostic or rapid antigen test and severity form definition) at the Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania. Clinical examinations with detailed questions about symptoms were performed at the time of the diagnosis of COVID-19 and the six-month follow-up. Two years after COVID-19 infection, patients were invited to complete an online quality-of-life questionnaire regarding long COVID symptoms. Results: A total of 103 patients (35.92% males) with a mean age of 41.56 ± 11.77 were included in this study. Of the total number of patients, 65.04% presented mild forms of COVID-19. Data regarding the vaccination status showed that 83.5% were vaccinated against SARS-CoV-2. The most common symptoms at diagnosis were cough (80.6%), fatigue (80.4%), odynophagia (76.7%), and headaches (67.6%), with female patients being statistically more likely to experience it (p = 0.014). Patients with moderate forms of the disease had higher levels of both systolic (p = 0.008) and diastolic (p = 0.037) blood pressure at diagnosis, but no statistical difference was observed in the 6-month follow-up. The most common symptoms at 2 years (in 29 respondent subjects) were represented by asthenia (51.7%), headache (34.5%), memory disorders (27.6%), abdominal meteorism (27.6%), and arthralgia (27.6%). In terms of cardiovascular symptoms, fluctuating blood pressure values (20.7%), palpitations (17.2%), and increased heart rate values (17.2%) were recorded. Conclusions: If at the time of diagnosis, the most frequent manifestations of the disease were respiratory, together with headache and fatigue, at re-evaluation, asthenia, decreased effort tolerance, and neuropsychiatric symptoms prevailed. Regarding the cardiovascular changes as part of the long COVID clinical picture, some patients developed prehypertension, palpitations, and tachycardia.

Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis.

BACKGROUND: Viruses may drive immune mechanisms responsible for chronic rhinosinusitis with nasal polyposis (CRSwNP), but little is known about the underlying molecular mechanisms. OBJECTIVES: To identify epigenetic and transcriptional responses to a common upper respiratory pathogen, rhinovirus (RV), that are specific to patients with CRSwNP using a primary sinonasal epithelial cell culture model. METHODS: Airway epithelial cells were collected at surgery from patients with CRSwNP (cases) and from controls without sinus disease, cultured, and then exposed to RV or vehicle for 48 h. Differential gene expression and DNA methylation (DNAm) between cases and controls in response to RV were determined using linear mixed models. Weighted gene co-expression analysis (WGCNA) was used to identify (a) co-regulated gene expression and DNAm signatures, and (b) genes, pathways, and regulatory mechanisms specific to CRSwNP. RESULTS: We identified 5585 differential transcriptional and 261 DNAm responses (FDR <0.10) to RV between CRSwNP cases and controls. These differential responses formed three co-expression/co-methylation modules that were related to CRSwNP and three that were related to RV (Bonferroni corrected p < .01). Most (95%) of the differentially methylated CpGs (DMCs) were in modules related to CRSwNP, whereas the differentially expressed genes (DEGs) were more equally distributed between the CRSwNP- and RV-related modules. Genes in the CRSwNP-related modules were enriched in known CRS and/or viral response immune pathways. CONCLUSION: RV activates specific epigenetic programs and correlated transcriptional networks in the sinonasal epithelium of individuals with CRSwNP. These novel observations suggest epigenetic signatures specific to patients with CRSwNP modulate response to viral pathogens at the mucosal environmental interface. Determining how viral response pathways are involved in epithelial inflammation in CRSwNP could lead to therapeutic targets for this burdensome airway disorder.

Optimal Timing of Cardioverter-Defibrillator Implantation in Patients with Left Ventricular Dysfunction after Acute Myocardial Infarction.

Background: Prevention of sudden cardiac death (SCD) early after acute myocardial infarction (AMI) is still a challenge, without clear recommendations in spite of the high incidence of life-threatening ventricular arrhythmias, as implantable cardiac defibrillator (ICD) placement is not indicated in the first 40 days after an AMI; this timing is aleatory and it is owed to fact that the two pivotal studies for evaluation of ICDs in primary prevention, MADIT and MADIT II, excluded the patients within three, respectively four weeks after AMI. Methods: We conducted a retrospective, single-center study that included 77 patients with AMI. All patients were monitored by continuous ECG in the first week after the event. Transthoracic echocardiography was performed at discharge and 40 days after the event. Patients with ejection fraction of 35% or less as assessed by 2D echocardiography 40 days after the MI, which received an ICD for the primary prevention of SCD, were included in the study. The subjects were followed for a median of 38 months, by means of device interrogation and echocardiography. Results: We divided our patients into two groups: in the first group, with left ventricular ejection fraction (LVEF) under 30% after MI, all patients remained in the reduced ejection fraction heart failure category, with an increase from an initial mean of 18.93 ± 4.99% to a mean of 22.18 ± 4.53% after a period of 40 days; we obtained a positive and statistically significant correlation (p < 0.001 and r - 0.547), and all patients presented indication of ICD implant 40 day after MI. In the second group with LVEF between 30% and 35% after MI, the mean LVEF increased from an initial mean of 31.73 ± 1.33% to a mean of 32.33 ± 1.49% after a period of 40 days. A statistically significant correlation (p - 0.02 and r - 0.78) was obtained, although 3 patients presented a LVEF over 35% at 40 days post-MI. Most of the ICD therapies (14.54%) appeared in patients with LVEF < 30% and these patients also presented a higher percentage of NSVT at initial ECG monitoring (54% vs. 50%) and NSVT at ICD interrogation (80% vs. 66.7%); statistical significance was not reached - p > 0.05. The majority of the ICD therapies (11.9% from 13.4%) appeared in patients with NSVT at initial ECG monitoring; also, these presented an increased number of NSVT at ICD interrogation (77.6% vs. 6%) when compared to patients without VT detection at the initial ECG monitoring. Still, statistical significance was not reached - p > 0.15. Conclusions: The patients could benefit from ICD implant earlier than stated in the actual guidelines, since there are insufficient data in the literature for the waiting time of 40 days. Correlated with the increased risk of SCD in the first months post myocardial infarction, the present study proves the benefit of early ICD implantation considering that all our patients with a low ejection fraction immediately after infarction remained in the same category and the great majority (96.1%) required the implantation of an ICD after 40 days. Thus, we could avoid exposing our patients at risk of SCD for an unnecessary prolonged period, and choose early ICD implantation.

Chromosome 17q12-21 Variants Are Associated with Multiple Wheezing Phenotypes in Childhood.

Rationale: Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated with asthma, are also associated with childhood wheezing phenotypes remains poorly explored.Objectives: To determine whether wheezing phenotypes, defined by latent class analysis (LCA), are associated with nine 17q12-21 SNPs and if so, whether these relationships differ by race/ancestry.Methods: Data from seven U.S. birth cohorts (n = 3,786) from the CREW (Children's Respiratory Research and Environment Workgroup) were harmonized to represent whether subjects wheezed in each year of life from birth until age 11 years. LCA was then performed to identify wheeze phenotypes. Genetic associations between SNPs and wheeze phenotypes were assessed separately in European American (EA) (n = 1,308) and, for the first time, in African American (AA) (n = 620) children.Measurements and Main Results: The LCA best supported four latent classes of wheeze: infrequent, transient, late-onset, and persistent. Odds of belonging to any of the three wheezing classes (vs. infrequent) increased with the risk alleles for multiple SNPs in EA children. Only one SNP, rs2305480, showed increased odds of belonging to any wheezing class in both AA and EA children.Conclusions: These results indicate that 17q12-21 is a "wheezing locus," and this association may reflect an early life susceptibility to respiratory viruses common to all wheezing children. Which children will have their symptoms remit or reoccur during childhood may be independent of the influence of rs2305480.

Integrating predicted transcriptome from multiple tissues improves association detection.

Integration of genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) studies is needed to improve our understanding of the biological mechanisms underlying GWAS hits, and our ability to identify therapeutic targets. Gene-level association methods such as PrediXcan can prioritize candidate targets. However, limited eQTL sample sizes and absence of relevant developmental and disease context restrict our ability to detect associations. Here we propose an efficient statistical method (MultiXcan) that leverages the substantial sharing of eQTLs across tissues and contexts to improve our ability to identify potential target genes. MultiXcan integrates evidence across multiple panels using multivariate regression, which naturally takes into account the correlation structure. We apply our method to simulated and real traits from the UK Biobank and show that, in realistic settings, we can detect a larger set of significantly associated genes than using each panel separately. To improve applicability, we developed a summary result-based extension called S-MultiXcan, which we show yields highly concordant results with the individual level version when LD is well matched. Our multivariate model-based approach allowed us to use the individual level results as a gold standard to calibrate and develop a robust implementation of the summary-based extension. Results from our analysis as well as software and necessary resources to apply our method are publicly available.

Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: A Systematic Review.

Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of advanced malignancies, like melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and Hodgkin lymphoma. ICIs act upon T lymphocytes and antigen-presenting cells, targeting programmed cell death protein 1 (PD1), programmed cell death protein ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), breaking the immune tolerance of the T cells against malignant cells and enhancing the body's own immune response. A variety of cardiac-adverse effects are associated with ICI-based treatment, including pericarditis, arrhythmias, cardiomyopathy, and acute coronary syndrome, with myocarditis being the most studied due to its often-unexpected onset and severity. Overall, Myocarditis is rare but presents an immune-related adverse event (irAE) that has a high fatality rate. Considering the rising number of oncological patients treated with ICIs and the severity of their potential adverse effects, a good understanding and continuous investigation of cardiac irAEs is of the utmost importance. This systematic review aimed to revise recent publications (between 2016-2022) on ICI-induced cardiac toxicities and highlight the therapeutical approach and evolution in the selected cases.

Epigenetic landscape links upper airway microbiota in infancy with allergic rhinitis at 6 years of age.

BACKGROUND: The upper airways present a barrier to inhaled allergens and microbes, which alter immune responses and subsequent risk for diseases, such as allergic rhinitis (AR). OBJECTIVE: We tested the hypothesis that early-life microbial exposures leave a lasting signature in DNA methylation that ultimately influences the development of AR in children. METHODS: We studied upper airway microbiota at 1 week, 1 month, and 3 months of life, and measured DNA methylation and gene expression profiles in upper airway mucosal cells and assessed AR at age 6 years in children in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort. RESULTS: We identified 956 AR-associated differentially methylated CpGs in upper airway mucosal cells at age 6 years, 792 of which formed 3 modules of correlated differentially methylated CpGs. The eigenvector of 1 module was correlated with the expression of genes enriched for lysosome and bacterial invasion of epithelial cell pathways. Early-life microbial diversity was lower at 1 week (richness P = .0079) in children with AR at age 6 years, and reduced diversity at 1 week was also correlated with the same module's eigenvector (ρ = -0.25; P = 3.3 × 10-5). We show that the effect of microbiota richness at 1 week on risk for AR at age 6 years was mediated in part by the epigenetic signature of this module. CONCLUSIONS: Our results suggest that upper airway microbial composition in infancy contributes to the development of AR during childhood, and this trajectory is mediated, at least in part, through altered DNA methylation patterns in upper airway mucosal cells.

Association of HLA-DRB1∗09:01 with tIgE levels among African-ancestry individuals with asthma.

BACKGROUND: Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970s, and yet, the precise role of HLA alleles in asthma is not fully understood. Numerous genome-wide association studies were recently conducted on asthma, but were always limited to simple genetic markers (single nucleotide polymorphisms) and not complex HLA gene polymorphisms (alleles/haplotypes), therefore not capturing the biological relevance of this complex locus for asthma pathogenesis. OBJECTIVE: To run the first HLA-centric association study with asthma and specific asthma-related phenotypes in a large cohort of African-ancestry individuals. METHODS: We collected high-density genomics data for the Consortium on Asthma among African-ancestry Populations in the Americas (N = 4993) participants. Using computer-intensive machine-learning attribute bagging methods to infer HLA alleles, and Easy-HLA to infer HLA 5-gene haplotypes, we conducted a high-throughput HLA-centric association study of asthma susceptibility and total serum IgE (tIgE) levels in subjects with and without asthma. RESULTS: Among the 1607 individuals with asthma, 972 had available tIgE levels, with a mean tIgE level of 198.7 IU/mL. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1∗09:01 was associated with increased tIgE levels (P = 8.5 × 10-4; weighted effect size, 0.51 [0.15-0.87]). CONCLUSIONS: We identified for the first time an HLA allele associated with tIgE levels in African-ancestry individuals with asthma. Our report emphasizes that by leveraging powerful computational machine-learning methods, specific/extreme phenotypes, and population diversity, we can explore HLA gene polymorphisms in depth and reveal the full extent of complex disease associations.

Antimicrobial Activity of MgB2 Powders Produced via Reactive Liquid Infiltration Method.

We report for the first time on the antimicrobial activity of MgB2 powders produced via the Reactive Liquid Infiltration (RLI) process. Samples with MgB2 wt.% ranging from 2% to 99% were obtained and characterized, observing different levels of grain aggregation and of impurity phases. Their antimicrobial activity was tested against Staphylococcus aureus ATCC BAA 1026, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Candida albicans ATCC 10231. A general correlation is observed between the antibacterial activity and the MgB2 wt.%, but the sample microstructure also appears to be very important. RLI-MgB2 powders show better performances compared to commercial powders against microbial strains in the planktonic form, and their activity against biofilms is also very similar.

Sintered and 3D-Printed Bulks of MgB2-Based Materials with Antimicrobial Properties.

Pristine high-density bulk disks of MgB2 with added hexagonal BN (10 wt.%) were prepared using spark plasma sintering. The BN-added samples are machinable by chipping them into desired geometries. Complex shapes of different sizes can also be obtained by the 3D printing of polylactic acid filaments embedded with MgB2 powder particles (10 wt.%). Our present work aims to assess antimicrobial activity quantified as viable cells (CFU/mL) vs. time of sintered and 3D-printed materials. In vitro antimicrobial tests were performed against the bacterial strains Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923, Enterococcus faecium DSM 13590, and Enterococcus faecalis ATCC 29212; and the yeast strain Candida parapsilosis ATCC 22019. The antimicrobial effects were found to depend on the tested samples and microbes, with E. faecium being the most resistant and E. coli the most susceptible.

Multifractality through Non-Markovian Stochastic Processes in the Scale Relativity Theory. Acute Arterial Occlusions as Scale Transitions.

By assimilating biological systems, both structural and functional, into multifractal objects, their behavior can be described in the framework of the scale relativity theory, in any of its forms (standard form in Nottale's sense and/or the form of the multifractal theory of motion). By operating in the context of the multifractal theory of motion, based on multifractalization through non-Markovian stochastic processes, the main results of Nottale's theory can be generalized (specific momentum conservation laws, both at differentiable and non-differentiable resolution scales, specific momentum conservation law associated with the differentiable-non-differentiable scale transition, etc.). In such a context, all results are explicated through analyzing biological processes, such as acute arterial occlusions as scale transitions. Thus, we show through a biophysical multifractal model that the blocking of the lumen of a healthy artery can happen as a result of the "stopping effect" associated with the differentiable-non-differentiable scale transition. We consider that blood entities move on continuous but non-differentiable (multifractal) curves. We determine the biophysical parameters that characterize the blood flow as a Bingham-type rheological fluid through a normal arterial structure assimilated with a horizontal "pipe" with circular symmetry. Our model has been validated based on experimental clinical data.

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos.

BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. OBJECTIVE: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. METHODS: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

Association Tests for Rare Variants.

Over the past few years, interest in the identification of rare variants that influence human phenotype has led to the development of many statistical methods for testing for association between sets of rare variants and binary or quantitative traits. Here, I review some of the most important ideas that underlie these methods and the most relevant issues when choosing a method for analysis. In addition to the tests for association, I review crucial issues in performing a rare variant study, from experimental design to interpretation and validation. I also discuss the many challenges of these studies, some of their limitations, and future research directions.

Imputing Gene Expression in Uncollected Tissues Within and Beyond GTEx.

Gene expression and its regulation can vary substantially across tissue types. In order to generate knowledge about gene expression in human tissues, the Genotype-Tissue Expression (GTEx) program has collected transcriptome data in a wide variety of tissue types from post-mortem donors. However, many tissue types are difficult to access and are not collected in every GTEx individual. Furthermore, in non-GTEx studies, the accessibility of certain tissue types greatly limits the feasibility and scale of studies of multi-tissue expression. In this work, we developed multi-tissue imputation methods to impute gene expression in uncollected or inaccessible tissues. Via simulation studies, we showed that the proposed methods outperform existing imputation methods in multi-tissue expression imputation and that incorporating imputed expression data can improve power to detect phenotype-expression correlations. By analyzing data from nine selected tissue types in the GTEx pilot project, we demonstrated that harnessing expression quantitative trait loci (eQTLs) and tissue-tissue expression-level correlations can aid imputation of transcriptome data from uncollected GTEx tissues. More importantly, we showed that by using GTEx data as a reference, one can impute expression levels in inaccessible tissues in non-GTEx expression studies.

Survey of the Heritability and Sparse Architecture of Gene Expression Traits across Human Tissues.

Understanding the genetic architecture of gene expression traits is key to elucidating the underlying mechanisms of complex traits. Here, for the first time, we perform a systematic survey of the heritability and the distribution of effect sizes across all representative tissues in the human body. We find that local h2 can be relatively well characterized with 59% of expressed genes showing significant h2 (FDR < 0.1) in the DGN whole blood cohort. However, current sample sizes (n ≤ 922) do not allow us to compute distal h2. Bayesian Sparse Linear Mixed Model (BSLMM) analysis provides strong evidence that the genetic contribution to local expression traits is dominated by a handful of genetic variants rather than by the collective contribution of a large number of variants each of modest size. In other words, the local architecture of gene expression traits is sparse rather than polygenic across all 40 tissues (from DGN and GTEx) examined. This result is confirmed by the sparsity of optimal performing gene expression predictors via elastic net modeling. To further explore the tissue context specificity, we decompose the expression traits into cross-tissue and tissue-specific components using a novel Orthogonal Tissue Decomposition (OTD) approach. Through a series of simulations we show that the cross-tissue and tissue-specific components are identifiable via OTD. Heritability and sparsity estimates of these derived expression phenotypes show similar characteristics to the original traits. Consistent properties relative to prior GTEx multi-tissue analysis results suggest that these traits reflect the expected biology. Finally, we apply this knowledge to develop prediction models of gene expression traits for all tissues. The prediction models, heritability, and prediction performance R2 for original and decomposed expression phenotypes are made publicly available (https://github.com/hakyimlab/PrediXcan).

A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle.

Chromosome 17q12-21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12-21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus.

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control.

RATIONALE: Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches. OBJECTIVES: To identify molecular pathways and interrelated genes whose differential expression was associated with asthma control. METHODS: We performed gene set enrichment analyses of asthma control in 1,170 adults with asthma, each with gene expression data derived from either whole blood (WB) or unstimulated CD4+ T lymphocytes (CD4), and a self-reported asthma control score representing either the preceding 6 months (chronic) or 7 days (acute). Our study comprised a discovery WB cohort (n = 245, chronic) and three independent, nonoverlapping replication cohorts: a second WB set (n = 448, acute) and two CD4 sets (n = 300, chronic; n = 77, acute). MEASUREMENTS AND MAIN RESULTS: In the WB discovery cohort, we found significant overrepresentation of genes associated with asthma control in 1,106 gene sets from the Molecular Signatures Database (false discovery rate, <5%). Of these, 583 (53%) replicated in at least one replication cohort (false discovery rate, <25%). Suboptimal control was associated with signatures of eosinophilic and granulocytic inflammatory signals, whereas optimal control signatures were enriched for immature lymphocytic patterns. These signatures included two related biologic processes related to activation by TREM-1 (triggering receptor expressed on myeloid cells 1) and lipopolysaccharide. CONCLUSIONS: Together, these results demonstrate the existence of specific, reproducible transcriptomic components in blood that vary with degree of asthma control and implicate a novel biologic target (TREM-1).