Transcriptome-wide association studies (TWASs) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans-expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian genome-wide TWAS (BGW-TWAS) method that leverages both cis-and trans-eQTL information for a TWAS. Our BGW-TWAS method is based on Bayesian variable selection regression, which not only accounts for cis-and trans-eQTL of the target gene but also enables efficient computation by using summary statistics from standard eQTL analyses. Our simulation studies illustrated that BGW-TWASs achieved higher power compared to existing TWAS methods that do not assess trans-eQTL information. We further applied BWG-TWAS to individual-level GWAS data (N ¼ $3.3K), which identified significant associations between the genetically regulated gene expression (GReX) of ZC3H12B and Alzheimer dementia (AD) (p value ¼ 5.42 3 10 À13 ), neurofibrillary tangle density (p value ¼ 1.89 3 10 À6 ), and global measure of AD pathology (p value ¼ 9.59 3 10 À7 ). These associations for ZC3H12B were completely driven by trans-eQTL. Additionally, the GReX of KCTD12 was found to be significantly associated with b-amyloid (p value ¼ 3.44 3 10 À8 ) which was driven by both cis-and trans-eQTL. Four of the top driven trans-eQTL of ZC3H12B are located within APOC1, a known major risk gene of AD and blood lipids. Additionally, by applying BGW-TWAS with summary-level GWAS data of AD (N ¼ $54K), we identified 13 significant genes including known GWAS risk genes HLA-DRB1 and APOC1, as well as ZC3H12B.

Smoking tobacco contributes to 11.5% of deaths worldwide and, in some countries, more hospitalizations than alcohol and drugs combined. Globally in 2015, 25% of men and 5% of women smoked. In the United States, a higher proportion of people in prison smoke than do community-dwelling individuals. To determine smoking prevalence in prisons worldwide, we systematically reviewed the literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines; we also examined whether prisons banned smoking or treated smokers. We searched databases for articles published between 2012 and 2016 and located 85 relevant articles with data representing 73.5% of all incarcerated persons from 50 countries. In 35 of 36 nations (97%) with published prevalence data, smoking for the incarcerated exceeded community rates 1.04- to 62.6-fold. Taking a conservative estimate of a 2-fold increase, we estimated that, globally, 14.5 million male and 26,000 female smokers pass through prisons annually. Prison authorities’ responses include permitting, prohibiting, or treating tobacco use. Bans may temporarily improve health and reduce in-prison health care costs but have negligible effect after prison release. Evidence-based interventions for smoking cessation effective outside prisons are effective inside; effects persist after release. Because smoking prevalence is heightened in prisons, offering evidence-based interventions to nearly 15 million smokers passing through yearly would improve global health.

Background People living with human immunodeficiency virus (HIV) infection have higher risk for chronic kidney disease (CKD), defined by a reduced estimated glomerular filtration rate (eGFR). Previous studies have implicated epigenetic changes related to CKD; however, the mechanism of HIV-related CKD has not been thoroughly investigated. Methods We conducted an epigenome-wide association study of eGFR among 567 HIV-positive and 117 HIV-negative male participants in the Veterans Aging Cohort Study to identify epigenetic signatures of kidney function. Results By surveying more than 400 000 cytosine guanine dinucleotide (CpG) sites measured from peripheral blood mononuclear cells, we identified 15 sites that were significantly associated with eGFR (false discovery rate Q value < 0.05) among HIV-positive participants. The most significant CpG sites, located at MAD1L1, TSNARE1/BAI1, and LTV1, were all negatively associated with eGFR (cg06329547, P = 5.25 × 10–9; cg23281907, P = 1.37 × 10–8; cg18368637, P = 5.17 × 10–8). We also replicated previously reported eGFR-associated CpG sites including cg17944885 (P = 2.5 × 10–5) located between ZNF788 and ZNF20 on chromosome 19 in the pooled population. Conclusions In this study we uncovered novel epigenetic associations with kidney function among people living with HIV and suggest potential epigenetic mechanisms linked with HIV-related CKD risk.

Background: Epigenomic (e.g., DNA methylation [DNAm]) changes have been hypothesized as intermediate step linking environmental exposures with allergic disease.Associations between individual DNAm at CpGs and allergic diseases have been reported, but their joint predictive capability is unknown.Methods: Data were obtained from 240 children of the German LISA cohort. DNAm was measured in blood clots at 6 (N = 234) and 10 years (N = 227) using the Illumina EPIC chip. Presence of aeroallergen sensitization was measured in blood at 6, 10, and 15 years. We calculated six methylation risk scores (MRS) for allergy-related phenotypes, like total and specific IgE, asthma, or any allergies, based on available publications and assessed their performances both cross-sectionally (biomarker) and prospectively (predictor of the disease). Dose-response associations between aeroallergen sensitization and MRS were evaluated.Results: All six allergy-related MRS were highly correlated (r > .86), and seven CpGs were included in more than one MRS. Cross-sectionally, we observed an 81% increased risk for aeroallergen sensitization at 6 years with an increased MRS by one standard deviation (best-performing MRS, 95% confidence interval = [43%; 227%]).Significant associations were also seen cross-sectionally at 10 years and prospectively, though the effect of the latter was attenuated when restricted to participants not sensitized at baseline. A clear dose-response relationship with levels of aeroallergen sensitization could be established cross-sectionally, but not prospectively. Conclusion:We found good classification and prediction capabilities of calculated allergy-related MRS cross-sectionally, underlining the relevance of alteredThis is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Itch, initiated by the activation of sensory neurons, is associated frequently with dermatological diseases. MrgprA3 þ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulation of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here, we performed RNA sequencing of genetically labeled MrgprA3 þ neurons under both naïve and allergic contact dermatitis conditions. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3 þ neurons, suggesting that MrgprA3 þ neurons are a direct neuronal target for histamine and Mrgpr agonists. In addition, PTPN6 and PCDH12 were identified as highly selective markers of MrgprA3 þ neurons. We also discovered that MrgprA3 þ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potential targets for combating itch.

Prenatal tobacco exposure (PTE) and prenatal alcohol exposure (PAE) have been associated with an increased risk of delayed neurodevelopment in children as well as differential newborn DNA methylation (DNAm). However, the biological mechanisms connecting PTE and PAE, DNAm, and neurodevelopment are largely unknown. Here we aim to determine whether differential DNAm mediates the association between PTE and PAE and neurodevelopment at 6 (N=113) and 24 months (N=187) in children from the South African Drakenstein Child Health Study. PTE and PAE were assessed antenatally using urine cotinine measurements and the ASSIST questionnaire, respectively. Cord blood DNAm was measured using the EPIC and 450K BeadChips. Neurodevelopment (cognitive, language, motor, adaptive behavior, socioemotional) was measured using the Bayley Scales of Infant and Toddler Development, Third Edition. We constructed methylation risk scores (MRS) for PTE and PAE and conducted causal mediation analysis (CMA) with these MRS as mediators. Next, we conducted a high-dimensional mediation analysis to identify individual CpG sites as potential mediators, followed by a CMA to estimate the average causal mediation effects (ACME) and total effect (TE). PTE and PAE were associated with neurodevelopment at 6 but not at 24 months. PTE MRS reached a prediction accuracy (R2) of 0.23 but did not significantly mediate the association between PTE and neurodevelopment. PAE MRS was not predictive of PAE (R2=0.006). For PTE, 31 CpG sites and 8 CpG sites were identified as significant mediators (ACME and TE P<0.05) for the cognitive and motor domains at 6 months, respectively. For PAE, 16 CpG sites and 1 CpG site were significant mediators for the motor and adaptive behavior domains at 6 months, respectively. Several genes including MAD1L1, CAMTA1, and ALDH1A2 have been implicated in neurodevelopmental delay, suggesting that differential DNAm may partly explain the biological mechanisms underlying the relationship between PTE and PAE and child neurodevelopment.

Genome-wide association studies (GWAS) of circulating metabolites have revealed the role of genetic regulation on the human metabolome. Most previous investigations focused on European ancestry, and few studies have been conducted among populations of African descent living in Africa, where the infectious disease burden is high (e.g., human immunodeficiency virus (HIV)). It is important to understand the genetic associations of the metabolome in diverse at-risk populations including people with HIV (PWH) living in Africa. After a thorough literature review, the reported significant gene–metabolite associations were tested among 490 PWH in South Africa. Linear regression was used to test associations between the candidate metabolites and genetic variants. GWAS of 154 plasma metabolites were performed to identify novel genetic associations. Among the 29 gene–metabolite associations identified in the literature, we replicated 10 in South Africans with HIV. The UGT1A cluster was associated with plasma levels of biliverdin and bilirubin; SLC16A9 and CPS1 were associated with carnitine and creatine, respectively. We also identified 22 genetic associations with metabolites using a genome-wide significance threshold (p-value < 5 × 10−8). In a GWAS of plasma metabolites in South African PWH, we replicated reported genetic associations across ancestries, and identified novel genetic associations using a metabolomics approach.