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The functional interpretation of genome-wide association studies (GWAS) is challenging due to the cell-type-dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTLs) for 659 microdissected human kidney samples and identified cell-type-eQTLs by mapping interactions between cell type abundances and genotypes. By partitioning heritability using stratified linkage disequilibrium score regression to integrate GWAS with single-cell RNA sequencing and single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing data, we prioritized proximal tubules for kidney function and endothelial cells and distal tubule segments for blood pressure pathogenesis. Bayesian colocalization analysis nominated more than 200 genes for kidney function and hypertension. Our study clarifies the mechanism of commonly used antihypertensive and renal-protective drugs and identifies drug repurposing opportunities for kidney disease. Cell-type-specific eQTL maps in the human kidney generated from the analysis of over 600 microdissected kidney samples, together with single-cell RNA sequencing and single-nucleus ATAC-seq, prioritize cell types influencing kidney function, hypertension and other traits.

India rolled out COVID-19 vaccinations for adults in January 2021 and children aged 12-18 in early 2022. A 2021 survey indicated that 63% of Indian parents were willing to vaccinate their children against COVID-19, with few studies examining vaccine hesitancy and acceptability. The the Behavioral and Social Drivers of Vaccination (BeSD) framework helps demonstrate which factors may affect vaccination uptake. Our study examined parents' intentions-to-vaccinate their children below 18 years of age against COVID-19 in Mysore, India and their decision-making process using the BeSD framework. From November 2021 to May 2022, 506 parents/guardians of children below 18 years of age living in Mysore district, India were consented and interviewed by phone or face-to-face. We assessed their own COVID-19 vaccination status, vaccine confidence (Vaccine Confidence Index), intention-to-vaccinate their child against COVID-19, and other factors affecting vaccination such as demographic variables. Multivariable ordinal logistic regression was conducted to examine the association of influencing factors based on the literature and BeSD framework using Stata version 16.1. Intention-to-vaccinate was presented as odds ratios (OR) with associated 95% confidence intervals (95%CI). The majority (91.3%) of the 506 participants fully trusted COVID-19 vaccines for their children. The same number (91.3%) had been fully vaccinated themselves, and 78.3% reported being (very) likely to vaccinate their children against COVID-19. Vaccine-hesitant and vaccine-confident groups were not significantly different socio-demographically. As parental age increased, parents had higher odds to express intention-to-vaccinate their child (OR: 1.04, 95%CI: 1.01-1.08). Parents from urban Mysore had lower odds to vaccinate their child compared to those from rural areas (OR: 0.53, 95%CI: 0.35-0.82). Most parents expressed vaccine confidence and intention-to-vaccinate their child against COVID-19. Exploring decision-making processes among parents is a crucial strategy to ensure effective implementation of vaccination programs.

Keloids are raised scars that grow beyond original wound boundaries, resulting in pain and disfigurement. Reasons for keloid development are not well-understood, and current treatment options are limited. Keloids are more likely to occur in darker-skinned individuals of African and Asian descent than in Europeans. We performed a genome-wide association study (GWAS) examining keloid risk across and within continental ancestry groups, incorporating 7837 cases and 1,593,009 controls. We detected 26 loci in the multi-ancestry analysis, 12 of which replicated in an independent dataset. Heritability estimates were 6%, 21%, and 34% for the European, East Asian, and African ancestry analyses, respectively. Genetically predicted gene expression and colocalization analyses identified 27 gene-tissue pairs, nine in skin and fibroblasts. Pathway analyses implicated integrin signaling and upstream regulators involved in cancer, fibrosis, and sex hormone signaling. This investigation nearly quintuples the number of keloid-associated risk loci, illuminating biological processes in keloid pathology. Keloids are fibroproliferative scars with higher prevalence in individuals of African and Asian ancestry. Here, the authors perform a multi-ancestry GWAS identifying 26 loci and pathways linked to fibrosis, integrin signalling, and hormone regulation.

Pharmacologic clinical trials for heart failure with preserved ejection fraction have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction. Whether differences in the genetic underpinnings of these major heart failure subtypes may provide insights into the disparate outcomes of clinical trials remains unknown. We utilize a large, uniformly phenotyped, single cohort of heart failure sub-classified into heart failure with reduced and with preserved ejection fractions based on current clinical definitions, to conduct detailed genetic analyses of the two heart failure sub-types. We find different genetic architectures and distinct genetic association profiles between heart failure with reduced and with preserved ejection fraction suggesting differences in underlying pathobiology. The modest genetic discovery for heart failure with preserved ejection fraction (one locus) compared to heart failure with reduced ejection fraction (13 loci) despite comparable sample sizes indicates that clinically defined heart failure with preserved ejection fraction likely represents the amalgamation of several, distinct pathobiological entities. Development of consensus sub-phenotyping of heart failure with preserved ejection fraction is paramount to better dissect the underlying genetic signals and contributors to this highly prevalent condition. While the genetic basis of heart failure has been explored by genetic studies, the differences between subtypes are not well understood. Here, the authors performed genetic analyses on the two major subtypes of heart failure in a large biobank with genetic and health record data, finding unique genetic architecture for each subtype.

Discovering novel uses for existing drugs, through drug repurposing, can reduce the time, costs, and risk of failure associated with new drug development. However, prioritizing drug repurposing candidates for downstream studies remains challenging. Here, we present a high-throughput approach to identify and validate drug repurposing candidates. This approach integrates human gene expression, drug perturbation, and clinical data from publicly available resources. We apply this approach to find drug repurposing candidates for two diseases, hyperlipidemia and hypertension. We screen >21,000 compounds and replicate ten approved drugs. We also identify 25 (seven for hyperlipidemia, eighteen for hypertension) drugs approved for other indications with therapeutic effects on clinically relevant biomarkers. For five of these drugs, the therapeutic effects are replicated in the All of Us Research Program database. We anticipate our approach will enable researchers to integrate multiple publicly available datasets to identify high priority drug repurposing opportunities for human diseases. Prioritizing drug repurposing candidates for downstream studies remains challenging. Here, the authors present a high-throughput approach to identify and validate drug repurposing candidates, integrating human gene expression, drug perturbation, and clinical data from publicly available resources.

Investigation of in utero , tissue-specific molecular pathways contributing to prenatal programming of childhood-onset asthma is needed to develop effective, targeted prevention strategies. We aimed to examine the relationship between predicted gene expression in placenta and childhood-onset asthma and to compare relationships between childhood- and adult-onset asthma. Asthma genome-wide association study published summary statistics were obtained from the UK Biobank and published placental gene expression quantitative trait loci were obtained from the Rhode Island Child Health Study. We used S-PrediXcan to evaluate and compare associations between placental predicted gene expression and childhood- and adult-onset asthma and to determine whether signals were placenta-specific. Among 8,038 tested placental predicted expression-asthma associations, we identified 56 (0.7%) genes only significantly associated with childhood-onset asthma, 12 (0.1%) genes only significantly associated with adult-onset asthma, and 18 (0.2%) shared genes. Predicted expression of several genes ( ACTL9 , AMN , C9orf38 , C11orf30 , CTSE , EFCAB13 , EIF4E1B , FN1 , GLS2 , IL6 , IVL , LZIC , MAN2A2 , MEGT1 , RACGAP1 , SMAD6 , SPATA5 , TMEM25 , VTI1B , WDR19 ) was not significantly associated with childhood- or adult-onset asthma in any non-placental tissue, suggesting that the associations may be placenta-specific. This study identified alterations in predicted expression of placental genes associated with transcriptional pathways critical to the development of asthma. We identified unique and shared pathways, particularly related to immune regulation, associated with childhood- and adult-onset. This expands our understanding of the fetal origins of asthma, highlights the placenta as an informative tissue in understanding asthma pathogenesis, and identifies target genes to prioritize for future functional studies.

We evaluated whether black race is associated with higher incidence of End Stage Renal Disease (ESRD) among a cohort of blacks and whites of similar, generally low socioeconomic status, and whether risk factor patterns differ among blacks and whites and explain the poorly understood racial disparity in ESRD. Incident diagnoses of ESRD among 79,943 black and white participants in the Southern Community Cohort Study (SCCS) were ascertained by linkage with the United States Renal Data System (USRDS) from 2002 through 2009. Person-years of follow up were calculated from date of entry into the SCCS until date of ESRD diagnosis, date of death, or September 1, 2009, whichever occurred first. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for incident ESRD among black and white participants in relation to baseline characteristics. After 329,003 person-years of follow-up, 687 incident cases of ESRD were identified in the cohort. The age-adjusted ESRD incidence rate was 273 (per 100,000) among blacks, 3.5-fold higher than the rate of 78 among whites. Risk factors for ESRD included male sex (HR = 1.6; 95% CI 1.4-1.9), low income (HR = 1.5; 95% CI 1.2-1.8 for income below vs. above $15,000), smoking (HR = 1.2; 95% CI 1.02-1.4) and histories of diabetes (HRs increasing to 9.4 (95% CI 7.4-11.9) among those with ≥20 years diabetes duration) and hypertension (HR = 2.9; 95% CI 2.3-3.7). Patterns and magnitudes of association were virtually identical among blacks and whites. After adjustment for these risk factors, blacks continued to have a higher risk for ESRD (HR = 2.4; 95% CI = 1.9-3.0) relative to whites. The black-white disparity in risk of ESRD was attenuated but not eliminated after control for known risk factors in a closely socioeconomically matched cohort. Further research characterizing biomedical factors, including CKD progression, in ESRD occurrence in these two racial groups is needed.

Background Abdominal aortic aneurysm (AAA) is a leading cause of death in the USA. We evaluated the incidence and predictors of AAA in a prospectively followed cohort. Methods We calculated age-adjusted AAA incidence rates (IR) among 18 782 participants aged ≥65 years in the Southern Community Cohort Study who received Medicare coverage from 1999–2012, and assessed predictors of AAA using multivariable Cox proportional hazards models, overall and stratified by sex, adjusting for demographic, lifestyle, socioeconomic, medical and other factors. HRs and 95% CIs were calculated for AAA in relation to factors ascertained at enrolment. Results Over a median follow-up of 4.94 years, 281 cases were identified. Annual IR was 153/100 000, 401, 354 and 174 among blacks, whites, men and women, respectively. AAA risk was lower among women (HR 0.48, 95% CI 0.36 to 0.65) and blacks (HR 0.51, 95% CI 0.37 to 0.69). Smoking was the strongest risk factor (former: HR 1.91, 95% CI 1.27 to 2.87; current: HR 5.55, 95% CI 3.67 to 8.40), and pronounced in women (former: HR 3.4, 95% CI 1.83 to 6.31; current: HR 9.17, 95% CI 4.95 to 17). A history of hypertension (HR 1.44, 95% CI 1.04 to 2.01) and myocardial infarction or coronary artery bypass surgery (HR 1.9, 95% CI 1.37 to 2.63) was negatively associated, whereas a body mass index ≥25 kg/m2 (HR 0.72; 95% CI 0.53 to 0.98) was protective. College education (HR 0.6, 95% CI 0.37 to 0.97) and black race (HR 0.44, 95% CI 0.28 to 0.67) were protective among men. Conclusions Smoking is a major risk factor for incident AAA, with a strong and similar association between men and women. Further studies are needed to evaluate benefits of ultrasound screening for AAA among women smokers.

Uterine leiomyomata or fibroids are highly heritable, common, and benign tumors of the uterus with poorly understood etiology. Previous GWAS have reported 72 associated genes but included limited numbers of non-European individuals. Here, we identify 11 novel genes associated with fibroids across multi-ancestry and ancestry-stratified GWAS analyses. We replicate a known fibroid GWAS gene in African ancestry individuals and estimate the SNP-based heritability of fibroids in African ancestry populations as 15.9%. Using genetically predicted gene expression and colocalization analyses, we identify 46 novel genes associated with fibroids. These genes are significantly enriched in cancer, cell death and survival, reproductive system disease, and cellular growth and proliferation networks. We also find that increased predicted expression of HEATR3 in uterine tissue is associated with fibroids across ancestry strata. Overall, we report genetic variants associated with fibroids coupled with functional and gene pathway enrichment analyses. Here, the authors present multi-ancestry genome-wide meta-analyses of uterine fibroids, identifying 11 new gene associations, and demonstrating that heritability is higher in African ancestries.

Fibroproliferative diseases are common complex traits featuring scarring and overgrowth of connective tissue which vary widely in presentation because they affect many organ systems. Most fibroproliferative diseases are more prevalent in African-derived populations than in European populations, leading to pronounced health disparities. It is hypothesized that the increased prevalence of these diseases in African-derived populations is due to selection for pro-fibrotic alleles that are protective against helminth infections. We constructed a genetic risk score (GRS) of fibroproliferative disease risk-increasing alleles using 147 linkage disequilibrium-pruned variants identified through genome-wide association studies of seven fibroproliferative diseases with large African-European prevalence disparities. A comparison of the fibroproliferative disease GRS between 1000 Genomes Phase 3 populations detected a higher mean GRS in AFR (mean = 148 risk alleles) than EUR (mean = 136 risk alleles; T-test p-value = 1.75x10-123). To test whether differences in GRS burden are systematic and may be due to selection, we employed the quantitative trait loci (QTL) sign test. The QTL sign test result indicates that population differences in risk-increasing allele burdens at these fibroproliferative disease variants are systematic and support a model featuring selective pressure (p-value = 0.011). These observations were replicated in an independent sample and were more statistically significant (T-test p-value = 7.26x10-237, sign test p-value = 0.015). This evidence supports the role of selective pressure acting to increase frequency of fibroproliferative alleles in populations of African relative to European ancestry populations.