Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Les lacs du littoral Aquitain : qualité à protéger

National audiencePrésentation du milieu et des résultats d'observations

A Statistical Association Test for the Identification of Clustered Disease Risk Variants

International audienceGenome-wide association studies have identified numerous common variants associated with a wide variety of complex diseases. However these variations only explain a small proportion of the heritability. A hypothesis is that rare variants may play an important role in disease risk. Testing association between rare variants and diseases represents a challenge due to their very low frequency in the population. Statistical methods have been developed testing the association with group of rare variants, since CAST (Cohort Allelic Sum Test) described in 2007 by Morgenthaler and Thilly. Few of these tests (Fier et al., 2012; Ionita-Laza et al., 2012; Lin, 2014; Schaid et al., 2013) take into account spatial genetic information. However, it is has been shown that disease variants may cluster in important functional domains of genes. For instance, pathogenic mutations are localized in the gene FLNA, causing congenital malformations (Robertson et al., 2003). Ionita-Laza et al. also identified in 2012, clusters of rare disease variants in the gene LRP2, associated with autism spectrum disorders.We developed a statistical test, DoEstRare, whose aim is detecting clusters of disease rare variants while preserving sufficient power when there is no cluster but still enrichment of rare alleles (overall the sequence). The DoEstRare statistics consists in comparing the mutation distributions, estimated by kernel method, between cases and controls.We compared the power and the type I error of our method to several published association tests for rare variants. Power and type I error computations are based on simulations conducted under two main genetic scenarios: absence or presence of one cluster of causal variants, varying also the proportion of causal variants. We are also now simulating with the software COSI according to the model developed in Schaffner et al. (2005) in order to mimic the demographical history of the European population. We observed the change in power according to the introduction of different statistical components. This test is thus adapted to non-cluster situations with the use of a burden component. A weighting scheme is also adopted in order to better discriminate between causal and neutral variants. We show consistent increase in power in both scenarios (for X % up to39.7% increase at best compared to SKAT-O). While this may be specific of the simulations carried out here, we think that DoEstRare represents a convenient and powerful alternative to test rare allele variants effects when there is no prior hypothesis of the real distribution of causative alleles

Statistical tests for Rare Variants Data Rare Variants in Human Genetic Diseases: Comparison of Association Statistical Tests

International audienceMany genome wide-association studies (GWAS) have been performed to assess genetic factors involved in complex diseases. However, most of the associated common variants explain only a small proportion of the complex diseases genetic architecture. This empirical observation and the fast development of whole-genome sequencing led the research community to reconsider the importance of rare variants for identifying association with complex disease. From a statistical point of view, research about rare variants imposes to take in account the problem of their rare occurrence and their individually small contributions to the disease susceptibility. This is the reason why a large part of the existing statistical methods implemented for analyzing common variants do not work for rare variants, leading to the development of many specific new tests. Most of the methods allowing to detect the association between rare variants and diseases consist on collapsing or pooling multiple rare variants together in a single or some “supervariant(s)”. Collective frequencies will then be reasonably high to test the computed collapsed genotype variable. Currently a lot of statistical methods exist for rare variants, including among others pooled association tests (Cohort Allelic Sums Test (CAST), Combined Multivariate and Collapsing (CMC), Weighted Sum Statistic (WSS), Replication-Based Test (RBT), Variable Threshold approach (VT)), methods based on model selection (C-alpha test, …) and methods based on kernel (KBAC, SKAT).Our study will focus on the comparison and the evaluation of these existing statistical methods. The main objective of this study is to learn about methods, analyzing advantages and limitations, and to draw up a warning guide of use of rare variants tests. To investigate their performance, we will both work on simulated data, reflecting various possible real scenarios (independent or correlated rare mutations; different effects of both rare and common variants, …) but also on real sequencing data consisting on 200 patients with a diagnosis of Brugada Syndrome (BrS) and 1000 available exome data of the cohort from the project UK10K, as controls. Comparison will be made on robustness and statistical power of each test in the simulation set-ups but also in the practical set-up.We will propose an analytical framework in order to find the best way to combine rare variant tests and detect true positive association

0210 : Effect of SCN5A mutations and SCN10A, SCN5A and HEY2 frequent variants on ECG of Brugada patients during ajmaline test

International audienceIntroduction Inactivating mutations in the SCN5A and frequent variants in SCN10A, SCN5A and HEY2 genes have been both associated with Brugada syndrome. The myocardial transmural electrical gradient that could explain the ‘Brugada’ ECG pattern, is considered as increased by inactivation of the sodium channel. Na channel blocker drug can likewise increase or unmask this pattern. To better assess phenotype correlation with those SCN5A mutation and frequent variants, we compare ECG parameters during Na channel blocker test according to the genetical status. Methods ECG parameters (P, PR, QRS, QT peak and QT end intervals; J wave amplitude in V1, V2, V3) were double measured in 73 unrelated Brugada patients with a positive Na blocker challenge. Data were measured at baseline and at the end of the test. Each patient was screened for SCN5A mutation and SCN10A, SCN5A and HEY2 frequent variants by direct sequencing and genotyped using Axiom Genome-Wide CEU 1 arrays (Affymetrix). Results The 10 patients carrying known SCN5A mutations (14%) didn’t show any clinical differences at baseline with those without SCN5A mutation. Baseline ECGs revealed a lengthening of PR (181 ±27 vs 156 ±30 p=0.017) and QRS interval (101 ±15 vs 89 ±14 p=0.020). No other parameter was significantly different. Once ECG parameters fulfilled diagnostic criteria for Brugada pattern, ECG parameters were not significantly different in the 2 groups. A similar effect on ECG was found in patients without SCN5A mutations but carrying more than 4 frequent variants. SCN10A polymorphism (rs10428132) was associated with a progressive effect on PR (p=0.044) and QRS (p=0.030) duration according to the risk allele number. According to the genetic status, no clinical difference was found after a mean follow up of 6 years. Conclusion Frequent variants associated with Brugada syndrome could present the same effect on ECG than SCN5A mutations. Lengthening of PR and QRS interval observed at baseline in those patients disappears during NA blocker test suggesting a non cumulative and a saturable effect of SCN5A in brugada syndrome’s pathophysiology

Generation of human induced pluripotent stem cell lines from four unrelated healthy control donors carrying European genetic background

International audienceFour human induced pluripotent stem cell (hiPSC) lines have been generated from healthy control European donors, and validated. This resource represents a useful tool for stem cell-based research, as references for developmental studies and disease modeling linked to any type of human tissue and organ, in an ethnical-, sex- and age-matched context. They providea reliable in-vitro model for single cell- and tissue-based investigations, and are also a valuable tool for genome editing-based studies

Le Bassin Adour-Garonne : Chap 5.3

International audienceCette monographie du Bassin hydrographique Adour-Garonne comprend une introduction sur le contexte géographique, hydrographique et sociétal du bassin in cluant de courtes signalétiques des grosses villes et de leur relation à l'hydrosystème. Le 1er chapitre décrit les principales caractéristiques des cours d'eau du bassin (longueur, aire et caractéristiques du bassin versant). Ensuite sont successivement abordés des aspects historiques de l'occupation de ces bassins ; une description biogéographique, la géologie, le climat et les usages du sol ; la géomorphologie, l'hydrologie et l'hydrochimie-biogéochimie ; la biodiversité aquatique et riparienne, avec une signalétique sur chaque grand maillon biologique concerné : végétation riparienne, Phytobenthos et phytoplancton, macrophytes aquaatiques, macro-invertébrés, poissons et oiseaux. Enfin, un chapitre fait l'état d'éléments de gestion du Bassin, sur des aspects et enjeux économiques d'une part, sur la politique de protection des zones naturelles et enfin sur lles spécificités de mise en application de la Directive Européenne sur l'Eau sur l'hydrosystème Adour-Garonne

Le Bassin Adour-Garonne : Chap 5.3

International audienceCette monographie du Bassin hydrographique Adour-Garonne comprend une introduction sur le contexte géographique, hydrographique et sociétal du bassin in cluant de courtes signalétiques des grosses villes et de leur relation à l'hydrosystème. Le 1er chapitre décrit les principales caractéristiques des cours d'eau du bassin (longueur, aire et caractéristiques du bassin versant). Ensuite sont successivement abordés des aspects historiques de l'occupation de ces bassins ; une description biogéographique, la géologie, le climat et les usages du sol ; la géomorphologie, l'hydrologie et l'hydrochimie-biogéochimie ; la biodiversité aquatique et riparienne, avec une signalétique sur chaque grand maillon biologique concerné : végétation riparienne, Phytobenthos et phytoplancton, macrophytes aquaatiques, macro-invertébrés, poissons et oiseaux. Enfin, un chapitre fait l'état d'éléments de gestion du Bassin, sur des aspects et enjeux économiques d'une part, sur la politique de protection des zones naturelles et enfin sur lles spécificités de mise en application de la Directive Européenne sur l'Eau sur l'hydrosystème Adour-Garonne

Fine-scale human genetic structure in Western France

International audienceThe difficulties arising from association analysis with rare variants underline the importance of suitable reference population cohorts, which integrate detailed spatial information. We analyzed a sample of 1684 individuals from Western France, who were genotyped at genome-wide level, from two cohorts D.E.S.I.R and CavsGen. We found that fine-scale population structure occurs at the scale of Western France, with distinct admixture proportions for individuals originating from the Brittany Region and the Vendée Department. Genetic differentiation increases with distance at a high rate in these two parts of Northwestern France and linkage disequilibrium is higher in Brittany suggesting a lower effective population size. When looking for genomic regions informative about Breton origin, we found two prominent associated regions that include the lactase region and the HLA complex. For both the lactase and the HLA regions, there is a low differentiation between Bretons and Irish, and this is also found at the genome-wide level. At a more refined scale, and within the Pays de la Loire Region, we also found evidence of fine-scale population structure, although principal component analysis showed that individuals from different departments cannot be confidently discriminated. Because of the evidence for fine-scale genetic structure in Western France, we anticipate that rare and geographically localized variants will be identified in future full-sequence analyses