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The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10-8) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10-8) and multi-trait analysis (P = 2.9 × 10-9) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

BackgroundIncreased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.Methods and resultsWe conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e-9) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e-8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e-8). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.ConclusionsAmong Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

Neurophysiological measurements of the response to pre-pulse and startle stimuli have been suggested to represent an important endophenotype for both substance dependence and other select psychiatric disorders. We have previously shown, in young adult Mexican Americans (MA), that presentation of a short delay acoustic pre-pulse, prior to the startle stimuli can elicit a late negative component at about 400 msec (N4S), in the event-related potential (ERP), recorded from frontal cortical areas. In the present study, we investigated whether genetic factors associated with this endophenotype could be identified. The study included 420 (age 18-30 years) MA men (n = 170), and women (n = 250). DNA was genotyped using an Affymetrix Axiom Exome1A chip. An association analysis revealed that the CCKAR and CCKBR (cholecystokinin A and B receptor) genes each had a nearby variant that showed suggestive significance with the amplitude of the N4S component to pre-pulse stimuli. The neurotransmitter cholecystokinin (CCK), along with its receptors, CCKAR and CCKBR, have been previously associated with psychiatric disorders, suggesting that variants near these genes may play a role in the pre-pulse/startle response in this cohort.

BackgroundMexican Americans, particularly those born in the United States, are at greater risk for alcohol associated morbidity and mortality. The present study sought to investigate whether specific genetic variants may be associated with alcohol use disorder phenotypes in a select population of Mexican American young adults.MethodsThe study evaluated a cohort of 427 (age 18 - 30 years) Mexican American men (n = 171) and women (n = 256). Information on alcohol dependence was obtained through interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). For all subjects, DNA was extracted from blood samples, followed by genotyping using an Affymetrix Axiom Exome1A chip.ResultsA protective variant (rs991316) located downstream from the ADH7 (alcohol dehydrogenase 7) gene showed suggestive significance in association with alcohol dependence symptom counts derived from DSM-III-R and DSM-IV criteria, as well as to clustered alcohol dependence symptoms. Additional linkage analysis suggested that nearby variants in linkage disequilibrium with rs991316 were not responsible for the observed association with the alcohol dependence phenotypes in this study.ConclusionsADH7 has been shown to have a protective role against alcohol dependence in previous studies involving other ethnicities, but has not been reported for Mexican Americans. These results suggest that variants near ADH7 may play a role in protection from alcohol dependence in this Mexican American cohort.

ObjectivesBody mass index (BMI) is a well-known measure of obesity with a multitude of genetic and non-genetic determinants. Identifying the underlying factors associated with BMI is difficult because of its multifactorial etiology that varies as a function of geoethnic background and socioeconomic setting. Thus, we pursued a study exploring the influence of the degree of Native American admixture on BMI (as well as weight and height individually) in a community sample of Native Americans (n = 846) while accommodating a variety of socioeconomic and cultural factors.MethodsParticipants' degree of Native American (NA) ancestry was estimated using a genome-wide panel of markers. The participants also completed an extensive survey of cultural and social identity measures: the Indian Culture Scale (ICS) and the Orthogonal Cultural Identification Scale (OCIS). Multiple linear regression was used to examine the relation between these measures and BMI.ResultsOur results suggest that BMI is correlated positively with the proportion of NA ancestry. Age was also significantly associated with BMI, while gender and socioeconomic measures (education and income) were not. For the two cultural identity measures, the ICS showed a positive correlation with BMI, while OCIS was not associated with BMI.ConclusionsTaken together, these results suggest that genetic and cultural environmental factors, rather than socioeconomic factors, account for a substantial proportion of variation in BMI in this population. Further, significant correlations between degree of NA ancestry and BMI suggest that admixture mapping may be appropriate to identify loci associated with BMI in this population.

This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene x environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the quality of the DNA samples collected from participants for genome-wide scanning and candidate gene analysis; (d) examine several research questions concerning the role of genetic and environmental factors in the onset and maintenance of tobacco use; and (e) ensure adherence to local and federal guidelines for ethical and legal investigations of genotypic associations with tobacco-related phenotypes in families. This investigation is unique among ongoing studies of the genetics of tobacco dependence in the extent to which equal importance has been assigned to both phenotypic and genotypic measurements.