Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood (n = 6454) and lung (n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank-derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

INTRODUCTION:Bronchodilator responsiveness (BDR) is associated with progression to COPD. Genetic risk for COPD, summarized by polygenic risk scores (PRS), predicts low lung function and COPD. However, it remains unclear whether genetic predisposition to COPD is related to BDR and whether PRS and BDR together influence lung function decline in individuals at risk for the disease. METHODS:We analyzed data from COPDGene participants with a smoking history and normal spirometry at study enrollment. We cross-sectionally examined the association of a PRS with 2005-BDR-FEV1 % (change relative to pre-bronchodilator) and 2021-BDR-FEV1 % (change relative to predicted). We also examined the association of PRS, 2005-BDR-FEV1 %, and 2021-BDR-FEV1 % with progression to COPD and longitudinal FEV1 decline between enrollment and follow-up adjusted for demographics, smoking history, and FEV1 at enrollment. RESULTS:PRS did not correlate with 2005-BDR-FEV1 % in 1446 African Americans (AA) but PRS correlates with BDR in both unadjusted (rho = 0.01, P < 0.001) and adjusted analysis in 3378 non-Hispanic Whites (NHW). NHW participants with BDR had higher PRS than those without. Models including 2005-BDR-FEV1 % demonstrated better accuracy than those including PRS (Area under the curve: 0.762 vs 0.743 in NHW; 0.693 vs 0.653 in AA). BDR models also outperformed PRS models for longitudinal FEV1 decline. Mediation analysis showed that about one third of the PRS effect on FEV1 decline in NHW was explained through BDR. CONCLUSIONS:BDR is more strongly associated with progression to COPD and FEV1 decline than PRS, and part of the PRS effect is mediated through BDR.

Background: Stroke remains one of the leading causes of death and morbidity worldwide, with a disproportionately higher burden among women. Recent advancements in omics, including proteomics, present a unique opportunity to uncover sex differences in pathways implicated in stroke. Methods: Using the OLINK platform, 2,911 proteins were measured in 24,041 men and 28,251 women from the UK Biobank, including 609 men and 445 women who developed ischemic stroke (IS). Median time from blood collection to IS was 8.6 years (IQR 5.0–11.3) in men and 9.1 years (IQR 5.5–12.0) in women. Each IS case was matched to 20 age-matched controls. Sex-specific associations between proteins and IS were assessed using conditional logistic regression (CLR) adjusted for demographic, clinical, and behavioral factors. Proteins significantly associated with IS (FDR p -value < 0.05) in at least one sex were used to derive sex-specific IS scores via LASSO logistic regression (70% training, 30% testing). Sex differences in protein–IS associations were evaluated using protein–sex interaction terms in CLR models that were fit to a combined sample of men and women. Results: 148 proteins were associated with incident IS in men (29 proteins), women (92 proteins), or both (27 proteins), meeting an FDR p -value < 0.05. No protein showed a significant protein-sex interaction at FDR p -value < 0.05. However, 9 proteins showed suggestive sex interactions ( p -value < 0.05; FDR p -value < 0.12). These proteins were involved in immune regulation, posttranslational modification, cell adhesion and signaling, and synaptic function. Cerebellin-4 was inversely associated with IS in women (odds ratio (OR) = 0.84, 95% CI: 0.77–0.93) but not in men (OR = 0.99, 95% CI: 0.91–1.07). Ribonuclease T2 and Desmocollin-2 were each positively associated with IS in both sexes, with stronger effects in women, while the remaining six proteins were significantly positively associated with IS in women only. The sex-specific IS scores remained significantly associated with IS after adjusting for risk factors, with ORs per 1 SD increase of 1.42 (95% CI: 1.18–1.70) in men and 1.58 (95% CI: 1.30–1.93) in women. Conclusion: This study identifies proteomic signatures associated with incident IS risk in men and women. Proteins having sex-specific associations were primarily involved in pathways related to immune response, intercellular signaling, post-translational modification, and synaptic function and plasticity.

Chronic obstructive pulmonary disease (COPD) exhibits marked heterogeneity in lung function decline, mortality, exacerbations, and other disease-related outcomes. Omic risk scores (ORS) estimate the cumulative contribution of omics, such as the transcriptome, proteome, and metabolome, to a particular trait. This study evaluated associations between blood-based ORS and COPD-related traits in both smoking-enriched and general population cohorts. ORS were developed and tested in 3,339 participants of Genetic Epidemiology of COPD (COPDGene) with blood RNA-sequencing, proteomic, and metabolomic data. Single- and multi-omic risk scores were trained on 24 cross-sectional and five longitudinal traits using 80

Rationale:Chronic lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis (BE), may differ by sex in symptom onset, diagnostic delays, and disease burden. This study examined health care experiences and symptom burden among individuals with self-reported COPD, BE, or nontuberculous mycobacteria (NTM). Methods:This cross-sectional study analyzed data from an online survey of U.S. and international participants with self-reported COPD, BE, or NTM, recruited via COPD Foundation social media. The questionnaire, developed with input from COPD Foundation leadership, physician-researchers, and patient stakeholders, assessed health care experiences, disease burden, and symptoms. A subset of women answered menopause-related questions. Descriptive statistics were compared by sex and disease group: COPD (with/without BE or NTM) and BE (with/without NTM). T-tests assessed continuous variables; Chi-square or Fisher's exact tests analyzed categorical variables. Results:Among 632 respondents (mean age 70±9 years, 74% women), 68% reported COPD and 32% BE. Women with COPD were younger (p=0.048) and sought care sooner after symptom onset (p<0.010) than men. More women with COPD did not have their diagnosis explained by a health care provider (p=0.038) and reported diagnosis-related anxiety, depression, or fear (p=0.007). Among participants with BE, men were more likely to receive a confirmed diagnosis sooner (p=0.038) and during hospitalization (p=0.024). Disease management burden, pulmonologist visit frequency, Chronic Airways Assessment Test scores, numbers of comorbidities, and financial burden were similar across groups. Over 75% of women were postmenopausal, and one-third reported worsened pulmonary symptoms postmenopause. Conclusions:Differences in diagnostic delays and symptom burden highlight the need for further research into health care disparities to improve pulmonary care and outcomes.

Background: Pulmonary diseases have sex-specific predilections across the lifespan. The rigor of preclinical research is paramount to ensure the reproducibility and applicability of findings to clinical studies. The overarching goal was to identify current research gaps and the need for consideration of sex as a biological variable (SABV) in preclinical pulmonary research. The objective was to provide a roadmap and the best standards to incorporate and investigate the role of biological sex in preclinical models of lung diseases. Methods: A multidisciplinary working group of 17 international investigators from the American Thoracic Society Assembly on Allergy, Immunology, and Inflammation, external content experts, and researchers engaged in lung basic and translational research. They reviewed the literature, identified critical knowledge gaps, and provided recommendations. Results: The research statement provides an updated summary of the currently available evidence on the standards of SABV research in preclinical models and then offers specific research recommendations focused on the needs of researchers in the pulmonary field. The statement identifies knowledge gaps and develops guidance for experimental design and key considerations for incorporating SABV in two major topic areas: 1) in vivo; and 2) in vitro models. Furthermore, the group developed a checklist to guide researchers in including SABV in preclinical studies. Conclusions: This statement provides a roadmap for the investigation of SABV in preclinical models. This will increase the applicability of findings to both sexes, uncover sex-biased mechanisms in lung diseases, and identify novel therapeutic targets.

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10-9). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

Rationale: Chronic lung diseases, such as COPD and bronchiectasis (BE), may manifest differently by gender in symptom presentation, time to diagnosis, and overall disease burden. This study aimed to assess perceptions of individuals with self-reported COPD, BE, or non-tuberculous mycobacteria (NTM) regarding healthcare experiences and disease-related symptoms. Methods: This cross-sectional study analyzed data from US-based and international participants with self-reported COPD, BE, or NTM using an online survey. Participants were recruited through the COPD Foundation (COPDF) social media channels and completed a questionnaire developed with input from a steering committee that included COPDF leadership, physician-researchers, and patient stakeholders. The survey explored participants’ experiences with healthcare, disease burden, and self-reported symptoms. A subset of women answered additional questions regarding menopause-related symptom changes. Descriptive statistics were calculated and analyzed across self-identified genders and two disease groups: COPD (with or without BE or NTM) and BE (with or without NTM or COPD). Continuous variables were compared using ANOVA, while categorical variables were analyzed using chi-square or Fisher's exact test. Results: Of 632 respondents included in these analyses (mean age 70±9 years, 74% women), 68% reported COPD and 32% BE (both groups included individuals with or without additional diagnoses). Women with COPD were younger than men (p=0.048) and had a shorter duration between symptom onset and initial healthcare visit (< 6 months) (p<0.01). Compared to men, a higher proportion of women with COPD reported that their diagnosis was not explained by a healthcare provider (p=0.0381) and that they experienced anxiety, depression, or fear related to their diagnosis (p=0.0074). Among participants with BE, men and women were similar in age, though a higher proportion of men had shorter intervals (<6 months) between initial healthcare visit and confirmed diagnosis (p=0.0244) and received their diagnosis during hospitalization (p=0.0244). Both men and women across diagnoses reported similar levels of disease management burden, pulmonologist visit frequency, CAAT scores, numbers of comorbidities, and financial difficulties related to their lung condition. Over 75% of women identified as post-menopausal, with approximately one-third reporting worsening pulmonary symptoms associated with menopause. Conclusions: Despite similarities in disease management and comorbidity burden, women with BE and men with COPD reported longer times to initial healthcare visits and diagnostic delays, respectively. Additionally, over one-third of post-menopausal women experienced symptom exacerbation since menopause. These findings underscore the need to further explore gender-based differences and disparities in healthcare access and pulmonary care to enhance lung health outcomes across genders.

BackgroundLung adenocarcinoma shows distinct differences between males and females in incidence, prognosis, and treatment response, suggesting unique molecular mechanisms that remain underexplored. This study aims to identify sex-specific molecular signatures and therapeutic targets in lung adenocarcinoma using multi-omics approaches to inform personalized treatment strategies.MethodsWe conducted an integrative analysis of transcriptomic and proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) datasets, comparing male and female lung adenocarcinoma profiles. Transcription factor activity was assessed using TIGER on gene expression data, while kinase activity was evaluated with PTM-SEA on proteomic data. These results were combined to build a kinase-transcription factor signaling network. Potential sex-specific drugs were identified using the PRISM drug screening database.ResultsThe analysis revealed significant sex-based differences in transcription factor and kinase activity. Notably, NR3C1, AR, and AURKA exhibited sex-biased expression and activity. The constructed signaling network highlighted druggable pathways linked to cancer-related processes, with distinct profiles in males and females. PRISM screening identified glucocorticoid receptor agonists and aurora kinase inhibitors as promising sex-specific therapeutic candidates.ConclusionsOur findings underscore the importance of considering sex differences in lung adenocarcinoma molecular profiles. The integration of transcriptomic and proteomic data reveals sex-specific pathways and potential therapies, paving the way for personalized treatment approaches tailored to male and female patients.

Rationale: As the global population ages, identifying risk factors for age-related diseases is crucial for public health. Loss of Y chromosome (LOY), a somatic mutation in aging men, is linked to various age-related conditions, yet its role in chronic obstructive pulmonary disease (COPD) is underexplored. Considering COPD's complex interactions with environmental factors like smoking, this study investigates the relationship between LOY and lung function using a multi-omic approach. We hypothesize that LOY may exacerbate respiratory decline and accelerate aging in men with COPD. Methods: We evaluated associations between LOY and respiratory outcomes using cross-sectional, longitudinal, and prospective analyses in 5,097 male participants (ages 40–85) from the COPDGene Study, with a median follow-up of 5.9 years. Primary outcomes included lung function (FEV1/FVC ratio), COPD severity (GOLD grades 1–4), quantitative emphysema, and epigenetic age acceleration, assessed using the DunedinPoAm38 clock to determine biological age relative to chronological age. All models were adjusted for smoking status, smoking pack-years, height, age, age2, ancestry-informative principal components, and batch. Statistical thresholds were set at p<0.05. Additional analyses were conducted to investigate LOY-associated biological pathways, including an Epigenome-Wide Association Study (EWAS) of DNA methylation CpGs measured by the Illumina Epic Array, a Differentially Methylated Regions (DMR) analysis, and a Proteome-Wide Association Study (PWAS) of proteins measured using an aptamer (SOMAmer)-based approach. Results: Cross-sectional findings showed LOY was significantly associated with lower FEV1/FVC ratio (β=-0.122; 95%CI:-0.196,-0.047), increased emphysema (β=0.125; 95%CI:0.030,0.220) and accelerated epigenetic age (β=0.181; 95%CI:0.069,0.293). Longitudinal analysis demonstrated accelerated lung function decline in individuals with LOY (β=-0.006; 95%CI:-0.012,-0.001). Prospective analysis indicated that baseline LOY predicted lower lung function, with a reduced FEV1/FVC ratio (β=-0.159; 95%CI:-0.237,-0.083) after 5 years and accelerated epigenetic age (β=0.198; 95%CI:0.122,0.275). EWAS identified 3,680 genome-wide significant CpG sites associated with LOY, including 42 on the Y chromosome. Pathway enrichment highlighted associations with insulin signaling, and inflammation. DMR analysis identified 474 genome-wide significant methylation regions, with the strongest signal on the Y chromosome, enriched in pathways including Hippo signaling. PWAS revealed 12 proteins with FDR-significant differential expression associated with LOY, involving collagen binding and inflammation. Conclusions: This study associates LOY with decreased lung function, accelerated epigenetic age, and lung function decline over time. The multi-omic approach reveals epigenetic and proteomic signatures associated with LOY, supporting its potential as a biomarker for COPD. Findings highlight metabolic and inflammatory pathways, suggesting further investigation into LOY's relevance in respiratory health disparities and age-related diseases.

OBJECTIVE:Examine clinical and demographic variables associated with new onset depression and anxiety symptoms and assess moderation by sex in COPDGene, a cohort study of current and former smokers at risk for or with chronic obstructive pulmonary disease (COPD). METHODS:In the COPDGene study, 2653 adults had the hospital anxiety (HADS-A) and depression (HADS-D) scales available at phase 2 and 3, as well as clinical and demographic variables available at 2 and non-elevated HADS at phase 2. We defined new onset depression symptoms as HADS-D elevated at phase 3 (HADS-D ≥ 8) versus no new onset as HADS-D not elevated at either phase (HADS-D < 8). New onset anxiety symptoms were defined identically using HADS-A. We used logistic regression models among all participants and stratified by sex and assessed sex interactions for variables associated with the outcome for only one sex. RESULTS:Among males, COPD Assessment test (CAT) score was positively associated with new onset depression (β = 0.08, p = 1.9 × 10-5) and anxiety (β = 0.06, p = 1.4 × 10-3) symptoms. Among females, the modified Medical Research Council (mMRC) dyspnea was positively associated with new onset anxiety symptoms (β = 0.33, p = 1.4 × 10-3). We found sex by CAT score (β = -0.06, p = 0.02) and sex by mMRC dyspnea (β = 0.42, p = 5.1 × 10-3) interactions on new onset anxiety symptoms, and sex by CAT score interaction (β = -0.05, p = 0.04) on new onset depression symptoms. CONCLUSIONS:These findings highlight the importance of understanding factors that increase risk for depression and anxiety among smokers at risk for or with COPD and are moderated by sex.

RATIONALE Occupational exposures including Vapors, Gas, Dust or Fumes (VGDF) and additional Social Determinants of Health (SDOH) may contribute to adverse respiratory outcomes, although molecular causes are understudied. DNA methylation is influenced by multiple environmental exposures and may reveal novel insights into complex diseases. Studying the interaction between VGDF, SDOH and DNA methylation (DNAm) on lung function may reveal molecular mechanisms associated with COPD. METHODS COPDGene is a large-scale multicenter longitudinal cohort. The IlluminaEPIC array was used to assay leukocyte DNA methylation (DNAm) for 5,433 COPDGene blood samples from the five-year visit. VGDF were categorized by self-report of occupational exposures. Poverty was defined as self-reported annual income less than $15,000. Robust linear regression was performed across all samples to address the association between site-specific CpG methylation and lung function (FEV1), including the evaluation of interactions between VGDF and poverty and DNAm. All models were adjusted for age, age2, sex, height, height2, pack-years of smoking, cell proportions, genetic ancestry and the smoking-associated CpG site near AHRR (cg05575921). P-values were set at 10-3 for interactions. Gene set enrichment analysis was performed using GO and KEGG. Epigenetic age acceleration was calculated using the difference between the Horvath pan-tissue clock and chronologic age in years. RESULTS The prevalence of dusty jobs (yes, N=1405) and fumes (yes, N=1402) is 26%, with 786 subjects reporting exposures to both dust and fumes; 243 with VGDF were classified with income in the poverty range. We identified 4,101 CpGs demonstrating a significant interaction between methylation and fumes exposure, and 23,635 significant marks for the interaction term between dust exposure and DNAm in association with FEV1. There were 1,207 overlapping associations between CpGs for dust and fumes for FEV1. In a three-way comparison that included 2,201 associations for the interaction between poverty and DNAm, we identified 29 differentially methylated genes, including F2RL3, MYLK and ITPK1. Pathway enrichment included inflammatory/immune processes associated with VGDF and poverty. We observed epigenetic age acceleration of 1.8 years associated with occupational dust and 2.3 years associated with occupational fumes; epigenetic age acceleration increased to 2.7 years (95% CI: 2.0, 3.4) when VGDF exposures were associated with low income. CONCLUSIONS Lung function may be impacted by VGDF and poverty through epigenetic mechanisms. Analyses of VGDF and lung function highlight molecular associations related to both inflammation and accelerated aging, with further perturbation in the context of social disparities, thus revealing compounding effects on lung health.

Rationale:Short-term exposure to fine particulates (PM2.5) transiently increases the risk of respiratory exacerbations, but the contribution of chronic, long-term particulate exposure to respiratory exacerbations is poorly defined. Objectives:To assess long-term effects of PM2.5 exposure on risk of severe respiratory exacerbations. Methods:A longitudinal cohort of current and former smokers with and without COPD were surveyed every six months for severe exacerbation events. PM2.5 concentrations at participant addresses were estimated using satellite, reanalysis, and ground-based monitoring data sources. Measurements and Main Results:The relative risk of severe exacerbation increased by a factor of 1.516 (CI: 1.226, 1.873; p = 0.00012) for every 10 μg/m3 increase in long-term PM2.5 exposure across all participants. The effect in the non-COPD participants was greater, with a relative risk of 2.639 (CI: 1.840, 3.756; p<0.0001). Significant effect modifiers with greater effect of PM2.5, included prior exacerbations, female sex, and neighborhood characteristics and as well as smoking status, white race, disease severity, asthma diagnosis, and age at enrollment. Significant positive associations for PM2.5 on exacerbations were identified at levels below the EPA primary annual standard for PM2.5 of 9.0 μg/m3. Conclusions:Persistent exposure to fine particulates is a significant risk factor for severe respiratory exacerbations in current and former smokers, and in patients with or at risk of COPD. The effect of fine particulates on the risk of severe exacerbations appears to be greater in those current and former smokers without COPD. The EPA annual PM2.5 standard may be inadequate to prevent ongoing lung injury.

Importance:Individuals at risk for chronic obstructive pulmonary disease (COPD) but without spirometric airflow obstruction can have respiratory symptoms and structural lung disease on chest computed tomography. Current guidelines recommend COPD diagnostic schemas that do not incorporate imaging abnormalities. Objective:To determine whether a multidimensional COPD diagnostic schema that includes respiratory symptoms and computed tomographic imaging abnormalities identifies additional individuals with disease. Design, Setting, and Participants:This cohort study included 2 longitudinal cohorts: the Genetic Epidemiology of COPD (COPDGene), which enrolled 10 305 participants between November 9, 2007, and April 15, 2011, with longitudinal follow-up through August 31, 2022; and the Canadian Cohort Obstructive Lung Disease (CanCOLD), which enrolled 1561 participants between November 26, 2009, and July 15, 2015, with follow-up through December 31, 2023. Exposure:Exposure included the new multidimensional COPD diagnostic schema, defined by (1) major diagnostic category: presence of the major criterion (airflow obstruction based on postbronchodilator forced expiratory volume in the first second of expiration [FEV1]/forced vital capacity ratio <0.70) and at least 1 of 5 minor criteria (emphysema or bronchial wall thickening on computed tomography, dyspnea, poor respiratory quality of life, and chronic bronchitis); or (2) minor diagnostic category: presence of least 3 of 5 minor criteria (which must include emphysema and bronchial wall thickening for individuals with respiratory symptoms potentially due to other causes). Main Outcomes and Measures:All-cause mortality, respiratory cause-specific mortality, exacerbations, and annualized change in FEV1. Results:Among 9416 adults in COPDGene (mean [SD] age at enrollment, 59.6 [9.0] years; 5035 [53.5%] were men; 3071 [32.6%] were Black; 6345 (67.4%) were White; 4943 [52.5%] currently smoked), 811 of 5250 individuals (15.4%) without airflow obstruction were newly classified as having COPD by minor diagnostic category, and 282 of 4166 individuals (6.8%) with airflow obstruction were classified as not having COPD. Reclassified individuals with a new COPD diagnosis had greater all-cause mortality (adjusted hazard ratio, 1.98; 95% CI, 1.67-2.35; P < .001) and respiratory-specific mortality (adjusted hazard ratio, 3.58; 95% CI, 1.56-8.20; P = .003), more exacerbations (adjusted incidence rate ratio, 2.09; 95% CI, 1.79-2.44; P < .001), and more rapid FEV1 decline (adjusted β = -7.7 mL/y; 95% CI, -13.2 to -2.3; P = .006) compared with individuals classified as not having COPD. Among individuals with airflow obstruction on spirometry, those no longer classified as having COPD based on this new diagnostic schema had outcomes similar to those without airflow obstruction. Among 1341 adults in CanCOLD, individuals newly classified as having COPD experienced more exacerbations (adjusted incidence rate ratio, 2.09; 95% CI, 1.25-3.51; P < .001). Conclusions and Relevance:A new COPD diagnostic schema integrating respiratory symptoms, respiratory quality of life, spirometry, and structural lung abnormalities on computed tomographic imaging newly classified some individuals as having COPD. These individuals had an increased risk of all-cause and respiratory-related death, frequent exacerbations, and rapid lung function decline compared with individuals classified as not having COPD. Some individuals with airflow obstruction without respiratory symptoms or evidence of structural lung disease were no longer classified as having COPD.

Sex and gender have emerged as critical considerations relevant to chronic obstructive pulmonary disease (COPD). Sex differences in lung development and physiologic response to hormones and environmental exposures influence COPD susceptibility, progression, severity, morbidity, and mortality. Gender has been poorly measured in the context of COPD, and gendered exposures further impact biology. The hormonal milieu is critical to study across the life course. Differences in immunity and inflammation likely impact sex- and gender-related features of COPD. Emerging evidence from multiple types of omics data is revealing new genes and pathways to consider as relevant to sex- and gender-divergent features of COPD. Much research to date has focused on autosomes, but the growing awareness of a role for allosomes is highlighting knowledge gaps. Reproductive aging impacts lung function and requires more investigation. Network medicine holds promise as an approach to sex and gender omics to uncover drivers of COPD in men and women.

The identification of Alzheimer's disease (AD)-associated genomic variants has provided powerful insight into disease etiology. Genome-wide association studies (GWASs) of AD have successfully identified previously unidentified targets but have almost exclusively used additive genetic models. Here, we performed a family-based GWAS of a recessive inheritance model using whole-genome sequencing from families affected by AD. We found an association between AD risk and the variant rs7161410, which is located in an intron of the PRKCH gene encoding protein kinase C eta (PKCη). In addition, a rare PRKCH missense mutation, K65R, was in linkage disequilibrium with rs7161410 and was present in homozygous carriers of the rs7161410 risk allele. In vitro analysis revealed that the catalytic rate, lipid dependence, and peptide substrate binding of the purified variant were indistinguishable from those of the wild-type kinase. However, cellular studies revealed that the K65R PKCη variant had reduced cytosolic activity and, instead, enhanced localization and signaling at the Golgi. Moreover, the K65R variant had altered interaction networks in transfected cells, particularly with proteins involved in Golgi processes such as vesicle transport. In human brain tissue, the AD-associated recessive genotype of rs7161410 was associated with increased expression of PRKCH, particularly in the amygdala. This association of aberrant PKCη signaling with AD and the insight into how its function is altered may lead to previously unidentified therapeutic targets for prevention and treatment.

RATIONALE. Significant sex-differences exist in asthma across the lifespan. Asthma prevalence and severity are greater in pre-pubescent boys compared to girls but greater in women after puberty. In women, asthma may improve after menopause when sex hormones wane. To address potential mechanisms underlying these changes, we compared the airway transcriptomics signatures of post-menopausal vs. premenopausal women. METHODS. We used bulk RNA seq data from bronchial epithelial cells from three different cohorts (SARP III, GEO-GSE85567, GEO-GSE201955) to perform a comprehensive analysis of differential gene expression and regulation. Data were combined into a meta-analysis, to compare pre-menopausal (n=114 cases with asthma, 48 controls) to post-menopausal women (n=52 cases with asthma, 13 controls). Differential gene expression between pre- and postmenopausal women was analyzed separately for asthma (Figure 1A) and control groups (not shown). Significant differentially expressed genes (DEGs) were identified by contrasting effect sizes (log fold-changes) between asthma and control groups using a Z-score interaction test. Accordingly, a scatter plot (Figure 1B) was created to represent whether differential gene expression between pre- and post-menopausal conditions is modified by disease status (asthma vs. control). The scatter plot also highlights that these findings are related to asthma per. se. and not to normal aging and menopausal transition. Pathway enrichment analysis was conducted using the differential expression data, followed by differential regulation analysis of the identified pathways. Statistical significance was assessed using a false discovery rate (FDR) threshold of 5%. RESULTS. Out of 15,468 genes that passed quality control, 19 genes were differentially expressed in bronchial epithelial cells from pre- and post-menopausal women with asthma (as compared to controls) (Figure 1A). Of these, 5 genes were down-regulated (ITLN1, POSTN, FCRL3, CCL22, PCSK6), and 14 genes were up-regulated (SPP1, S100A9, A2ML1, TNFRSF10C, CSF3R, OLFM1, C1QL2, NLRP3, HAL, PI3, RNASE1, TMEM178B, TNNI3, RNF175) when comparing pre- and post-menopausal women with asthma (Figure 1A). Of these 19 DEGs, 14 were differentially expressed in pre- as compared to post-menopausal women with asthma, but not in controls (Figure 1B). Comparing pre- to post-menopausal women with asthma, biologic pathways related to the innate and adaptive immune system activation and mitochondrial function (Electron transport Chain oxidative phosphorylation and ATP production) were both differentially regulated and expressed. CONCLUSIONS. This analysis highlights several DEGs and pathways that characterize asthma pathogenesis when comparing pre- and post-menopausal women, and emphasize the role of female sex hormones on the immune system response and mitochondrial function in asthma pathogenesis.