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Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.

BackgroundDNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Further identification of specific CpG sites and the pollutants that are associated with methylation of these CpG sites in immune cells could impact our understanding of asthma pathophysiology. In this study, we sought to identify some CpG sites in specific genes that could be associated with asthma regulation (Foxp3 and IL10) and to identify the different AAPs for which exposure prior to the blood draw is linked to methylation levels at these sites. We recruited subjects from Fresno, California, an area known for high levels of AAPs. Blood samples and responses to questionnaires were obtained (n = 188), and in a subset of subjects (n = 33), repeat samples were collected 2 years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365 days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures.ResultsAsthma was significantly associated with higher differentially methylated regions (DMRs) of the Foxp3 promoter region (p = 0.030) and the IL10 intronic region (p = 0.026). Additionally, at the 90-day time period (90 days prior to the blood draw), Foxp3 methylation was positively associated with NO2, CO, and PM2.5 exposures (p = 0.001, p = 0.001, and p = 0.012, respectively). In the subset of subjects retested 2 years later (n = 33), a positive association between AAP exposure and methylation was sustained. There was also a negative correlation between the average Foxp3 methylation of the promoter region and activated Treg levels (p = 0.039) and a positive correlation between the average IL10 methylation of region 3 of intron 4 and IL10 cytokine expression (p = 0.030).ConclusionsShort-term and long-term exposures to high levels of CO, NO2, and PM2.5 were associated with alterations in differentially methylated regions of Foxp3. IL10 methylation showed a similar trend. For any given individual, these changes tend to be sustained over time. In addition, asthma was associated with higher differentially methylated regions of Foxp3 and IL10.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper., Author(s): Adam E. Locke [sup.1] [sup.2] [sup.3] , Karyn Meltz Steinberg [sup.2] [sup.4] , Charleston W. K. Chiang [sup.5] [sup.6] [sup.7] , Susan K. Service [sup.5] , Aki S. Havulinna [...]

Background: DNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Further identification of specific CpG sites and the pollutants that are associated with methylation of these CpG sites in immune cells could impact our understanding of asthma pathophysiology. In this study, we sought to identify some CpG sites in specific genes that could be associated with asthma regulation (Foxp3 and IL10) and to identify the different AAPs for which exposure prior to the blood draw is linked to methylation levels at these sites. We recruited subjects from Fresno, California, an area known for high levels of AAPs. Blood samples and responses to questionnaires were obtained (n = 188), and in a subset of subjects (n = 33), repeat samples were collected 2 years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365 days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures. Results: Asthma was significantly associated with higher differentially methylated regions (DMRs) of the Foxp3 promoter region (p = 0.030) and the IL10 intronic region (p = 0.026). Additionally, at the 90-day time period (90 days prior to the blood draw), Foxp3 methylation was positively associated with NO2, CO, and PM2.5 exposures (p = 0.001, p = 0.001, and p = 0.012, respectively). In the subset of subjects retested 2 years later (n = 33), a positive association between AAP exposure and methylation was sustained. There was also a negative correlation between the average Foxp3 methylation of the promoter region and activated Treg levels (p = 0.039) and a positive correlation between the average IL10 methylation of region 3 of intron 4 and IL10 cytokine expression (p = 0.030). Conclusions: Short-term and long-term exposures to high levels of CO, NO2, and PM2.5 were associated with alterations in differentially methylated regions of Foxp3. IL10 methylation showed a similar trend. For any given individual, these changes tend to be sustained over time. In addition, asthma was associated with higher differentially methylated regions of Foxp3 and IL10. [ABSTRACT FROM AUTHOR]

We consider resequencing studies of associated loci and the problem of prioritizing sequence variants for functional follow-up. Working within the multivariate linear regression framework helps us to account for the joint effects of multiple genes; and adopting a Bayesian approach leads to posterior probabilities that coherently incorporate all information about the variants' function. We describe two novel prior distributions that facilitate learning the role of each variable site by borrowing evidence across phenotypes and across mutations in the same gene. We illustrate their potential advantages with simulations and reanalyzing a data set of sequencing variants. [ABSTRACT FROM AUTHOR]

Objective: South Asians (SAs) may possess a unique predisposition to insulin resistance (IR). We explored this possibility by investigating the relationship between 'gold standard' measures of adiposity, fitness, selected proteomic biomarkers, and insulin sensitivity among a cohort of SAs and Europeans (EURs)., Methods: A total of 46 SAs and 41 EURs completed 'conventional' (lifestyle questionnaires, standard physical exam) as well as 'gold standard' (dual energy X-ray absorptiometry scan, cardiopulmonary exercise test, and insulin suppression test) assessments of adiposity, fitness, and insulin sensitivity. In a subset of 28 SAs and 36 EURs, we also measured the blood-levels of eleven IR-related proteins. We conducted Spearman correlation to identify correlates of steady-state plasma glucose (SSPG) derived from the insulin suppression test, followed by multivariable linear regression analyses of SSPG, adjusting for age, sex and ancestral group., Results: Sixteen of 30 measures significantly associated with SSPG, including one conventional and eight gold standard measures of adiposity, one conventional and one gold standard measure of fitness, and five proteins. Multivariable regressions revealed that gold standard measures and plasma proteins attenuated ancestral group differences in IR, suggesting their potential utility in assessing IR, especially among SAs., Conclusion: Ancestral group differences in IR may be explained by accurate measures of adiposity and fitness, with specific proteins possibly serving as useful surrogates for these measures, particularly for SAs., Competing Interests: Conflict of Interest: Authors have no conflicts of interest.

Background: DNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Further identification of specific CpG sites and the pollutants that are associated with methylation of these CpG sites in immune cells could impact our understanding of asthma pathophysiology. In this study, we sought to identify some CpG sites in specific genes that could be associated with asthma regulation ( Foxp3 and IL10 ) and to identify the different AAPs for which exposure prior to the blood draw is linked to methylation levels at these sites. We recruited subjects from Fresno, California, an area known for high levels of AAPs. Blood samples and responses to questionnaires were obtained ( n  = 188), and in a subset of subjects ( n  = 33), repeat samples were collected 2 years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365 days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures., Results: Asthma was significantly associated with higher differentially methylated regions (DMRs) of the Foxp3 promoter region ( p  = 0.030) and the IL10 intronic region ( p  = 0.026). Additionally, at the 90-day time period (90 days prior to the blood draw), Foxp3 methylation was positively associated with NO 2 , CO, and PM 2.5 exposures ( p  = 0.001, p  = 0.001, and p  = 0.012, respectively). In the subset of subjects retested 2 years later ( n  = 33), a positive association between AAP exposure and methylation was sustained. There was also a negative correlation between the average Foxp3 methylation of the promoter region and activated Treg levels ( p  = 0.039) and a positive correlation between the average IL10 methylation of region 3 of intron 4 and IL10 cytokine expression ( p  = 0.030)., Conclusions: Short-term and long-term exposures to high levels of CO, NO 2 , and PM 2.5 were associated with alterations in differentially methylated regions of Foxp3 . IL10 methylation showed a similar trend. For any given individual, these changes tend to be sustained over time. In addition, asthma was associated with higher differentially methylated regions of Foxp3 and IL10 ., Competing Interests: All methods and procedures were approved by the Stanford University Institutional Review Board for the Protection of Human Subjects. Written informed consent was received from parents of subjects prior to inclusion in the study.Not applicableThe authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.