Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

The relationship between adiposity-associated inflammation and coronary artery and abdominal aortic calcium differs by strata of central adiposity: The Multi-Ethnic Study of Atherosclerosis (MESA)

Adipokines regulate metabolic processes linked to coronary artery (CAC) and abdominal aorta calcification (AAC). Because adipokine and other adiposity-associated inflammatory marker (AAIM) secretions differ between visceral and subcutaneous adipose tissue, we hypothesized that central adiposity modifies associations between AAIMs and CAC and AAC. We evaluated 1878 MESA participants with complete measures of AAIMs, anthropometry, CAC, and AAC. Associations of AAIMs with CAC and AAC prevalence and severity were analyzed per standard deviation of predictors (SD) using log binomial and linear regression models. The waist-to-hip ratio (WHR) was dichotomized at median WHR values based on sex/ethnicity. CAC and AAC prevalence were defined as any calcium (Agatston score >0). Severity was defined as ln (Agatston score). Analyses examined interactions with WHR and were adjusted for traditional cardiovascular disease risk factors. Each SD higher interleukin-6 (IL-6), fibrinogen and CRP was associated with 5% higher CAC prevalence; and each SD higher IL-6 and fibrinogen was associated with 4% higher AAC prevalence. Associations of IL-6 and fibrinogen with CAC severity, but not CAC prevalence, were significantly different among WHR strata. Median-and-above WHR: each SD higher IL-6 was associated with 24.8% higher CAC severity. Below-median WHR: no association (p interaction=0.012). Median-and-above WHR: each SD higher fibrinogen was associated with 19.6% higher CAC severity. Below-median WHR: no association (p interaction=0.034). Adiponectin, leptin, resistin, and tumor necrosis factor-alpha were not associated with CAC or AAC prevalence or severity. These results support findings that adiposity-associated inflammation is associated with arterial calcification, and further add that central adiposity may modify this association

Pharmacogenetic testing in the Veterans Health Administration (VHA): policy recommendations from the VHA Clinical Pharmacogenetics Subcommittee

PurposeThe Veterans Health Administration (VHA) Clinical Pharmacogenetics Subcommittee is charged with making recommendations about whether specific pharmacogenetic tests should be used in healthcare at VHA facilities. We describe a process to inform VHA pharmacogenetic testing policy.MethodsAfter developing consensus definitions of clinical validity and utility, the Subcommittee identified salient drug-gene pairs with potential clinical application in VHA. Members met monthly to discuss each drug-gene pair, the evidence of clinical utility for the associated pharmacogenetic test, and any VHA-specific testing considerations. The Subcommittee classified each test as strongly recommended, recommended, or not routinely recommended before drug initiation.ResultsOf 30 drug-gene pair tests reviewed, the Subcommittee classified 4 (13%) as strongly recommended, including HLA-B*15:02 for carbamazepine-associated Stevens-Johnston syndrome and G6PD for rasburicase-associated hemolytic anemia; 12 (40%) as recommended, including CYP2D6 for codeine toxicity; and 14 (47%) as not routinely recommended, such as CYP2C19 for clopidogrel dosing.ConclusionOnly half of drug-gene pairs with high clinical validity received Subcommittee support for policy promoting their widespread use across VHA. The Subcommittee generally found insufficient evidence of clinical utility or available, effective alternative strategies for the remainders. Continual evidence review and rigorous outcomes research will help promote the translation of pharmacogenetic discovery to healthcare

Genome-wide physical activity interactions in adiposity:a meta-analysis of 200,452 adults

Abstract Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery

Lessons learned from the eMERGE Network: balancing genomics in discovery and practice

The Electronic Medical Records and Genomics (eMERGE) Network, established in 2007, is a consortium of academic and integrated health systems conducting discovery and implementation research in translational genomics. Here, we outline the history of the network, highlight major impacts and lessons learned, and present the tools and resources developed for large-scale genomic analyses and translation into a clinical setting. The network developed methods to extract phenotypes from the electronic medical record to perform genome-wide and phenome-wide association studies. Recruited cohorts were clinically sequenced off a custom panel for targeted sequencing of variants and monogenic disease risks and returned to participants to investigate the impact of return of genomic results. After generating a 105,000 participant-imputed genome-wide association study (GWAS) dataset for discovery, the network enrolled and sequenced 24,998 participants. Integration of these results into the medical record and the effects of results on participants provided key lessons to the field. These learned lessons inform genetic research in diverse populations and provide insights into the clinical impact of return and implementation of genomic medicine using the electronic medical record. The lessons produced by the eMERGE Network can be utilized by other consortia as translational genomic medicine research evolves

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Abstract Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids