Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Cross-sectional analysis of the association between personal exposure to household air pollution and blood pressure in adult women: Evidence from the multi-country Household Air Pollution Intervention Network (HAPIN) trial.

Elevated blood pressure (BP) is a leading risk factor for the global burden of disease. Household air pollution (HAP), resulting from the burning of biomass fuels, may be an important cause of elevated BP in resource-poor communities. We examined the exposure-response relationship of personal exposures to HAP -fine particulate matter (PM2.5), carbon monoxide (CO), and black carbon (BC) - with BP measures in women aged 40-79 years across four resource-poor settings in Guatemala, Peru, India and Rwanda. BP was obtained within a day of 24-h personal exposure measurements at baseline, when participants were using biomass for cooking. We used generalized additive models to characterize the shape of the association between BP and HAP, accounting for the interaction of personal exposures and age and adjusting for a priori identified confounders. A total of 418 women (mean age 52.2 ± 7.9 years) were included in this analysis. The interquartile range of exposures to PM2.5 was 42.9-139.5 µg/m3, BC was 6.4-16.1 µg/m3, and CO was 0.5-2.9 ppm. Both SBP and PP were positively associated with PM2.5 exposure in older aged women, achieving statistical significance around 60 years of age. The exact threshold varied by BP measure and PM2.5 exposures being compared. For example, SBP of women aged 65 years was on average 10.8 mm Hg (95% CI 1.0-20.6) higher at 232 µg/m3 of PM2.5 exposure (90th percentile) when compared to that of women of the same age with personal exposures of 10 µg/m3. PP in women aged 65 years was higher for exposures ≥90 µg/m3, with mean differences of 6.1 mm Hg (95% CI 1.8-10.5) and 9.2 mm Hg (95% CI 3.3-15.1) at 139 (75th percentile) and 232 µg/m3 (90th percentile) respectively, when compared to that of women of the same age with PM2.5 exposures of 10 µg/m3. Our findings suggest that reducing HAP exposures may help to reduce BP, particularly among older women.

Influence of Smoking Status and Intensity on Discovery of Blood Pressure Loci Through Gene-Smoking Interactions.

BACKGROUND: Genetic variation accounts for approximately 30% of blood pressure (BP) variability but most of that variability has not been attributed to specific variants. Interactions between genes and BP-associated factors may explain some "missing heritability." Cigarette smoking increases BP after short-term exposure and decreases BP with longer exposure. Gene-smoking interactions have discovered novel BP loci, but the contribution of smoking status and intensity to gene discovery is unknown. METHODS: We analyzed gene-smoking intensity interactions for association with systolic BP (SBP) in three subgroups from the Framingham Heart Study: current smokers only (N = 1,057), current and former smokers ("ever smokers," N = 3,374), and all subjects (N = 6,710). We used three smoking intensity variables defined at cutoffs of 10, 15, and 20 cigarettes per day (CPD). We evaluated the 1 degree-of-freedom (df) interaction and 2df joint test using generalized estimating equations. RESULTS: Analysis of current smokers using a CPD cutoff of 10 produced two loci associated with SBP. The rs9399633 minor allele was associated with increased SBP (5 mmHg) in heavy smokers (CPD > 10) but decreased SBP (7 mmHg) in light smokers (CPD ≤ 10). The rs11717948 minor allele was associated with decreased SBP (8 mmHg) in light smokers but decreased SBP (2 mmHg) in heavy smokers. Across all nine analyses, 19 additional loci reached P < 1 × 10(-6). DISCUSSION: Analysis of current smokers may have the highest power to detect gene-smoking interactions, despite the reduced sample size. Associations of loci near SASH1 and KLHL6/KLHL24 with SBP may be modulated by tobacco smoking.