Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 x 10(-13)) and African ancestries (rs2066702; P = 2.2 x 10(-9)). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.Peer reviewe

Mining the human phenome using allelic scores that index biological intermediates

J. Kaprio ja M-L. Lokki työryhmien jäseniä.It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.Peer reviewe

Deficient inhibition in alcohol-dependence: let's consider the role of the motor system!

Impaired inhibitory control contributes to the development, maintenance, and relapse of alcohol-dependence, but the neural correlates of this deficit are still unclear. Because inhibitory control has been labeled as an executive function, most studies have focused on prefrontal areas, overlooking the contribution of more "primary" structures, such as the motor system. Yet, appropriate neural inhibition of the motor output pathway has emerged as a central aspect of healthy behavior. Here, we tested the hypothesis that this motor inhibition is altered in alcohol-dependence. Neural inhibitory measures of motor activity were obtained in 20 detoxified alcohol-dependent (AD) patients and 20 matched healthy subjects, using a standard transcranial magnetic stimulation procedure whereby motor-evoked potentials (MEPs) are elicited in a choice reaction time task. Moreover, behavioral inhibition and trait impulsivity were evaluated in all participants. Finally, the relapse status of patients was assessed 1 year after the experiment. As expected, AD patients displayed poorer behavioral inhibition and higher trait impulsivity than controls. More importantly, the MEP data revealed a considerable shortage of neural motor inhibition in AD patients. Interestingly, this neural defect was strongest in the patients who ended up relapsing during the year following the experiment. Our data suggest a strong motor component in the neural correlates of altered inhibitory control in AD patients. They also highlight an intriguing relationship with relapse and the perspective of a new biomarker to follow strategies aiming at reducing relapse in AD patients