Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia

Volpi, Simona; Heaton, Callie; Mack, Kendra; Hamilton, Jennifer; Lannan, Rebecca; Wolfgang, Curt D.; Licamele, Louis; Polymeropoulos, Mihael H.; Lavedan, Christian

doi:10.1038/mp.2008.52

Cited by 97 publications

(64 citation statements)

References 34 publications

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“…46 NRG3_rs4933824 localizes in the gene encoding the cardiac growth factor neuregulin 3, important during cardiac development and morphogenesis and previously associated to a prolonged QT. 12,28 The reason why we did not observe any homozygous individual for the risk allele in NRG3_rs4933824 and ANK2_rs3733617 may be ascribed to their low minor allele frequency (o5%). MDR1_rs1045642 lays in the MDR1-ABCB1 gene, belonging to the superfamily of ATP-binding cassette transporters and recently described as a marker of resident cardiac stem/progenitor cell subpopulations, thus governing cardiac remodeling and regeneration.…”

Section: Discussionmentioning

confidence: 95%

“…10 SNPs selection and analysis. Candidate single nucleotide polymorphisms (SNPs) were selected among those previously described as modulating ECG intervals [11][12][13][14][15][16][17] or predisposition to arrhythmic events. [18][19][20][21][22][23][24][25][26][27][28][29][30][31] In particular, most variants were located in genes encoding cardiac voltage-dependent channels (KCNQ1, KCNH2, SCN5A, KCNJ11, KCNE1, KCNE2, KCNJ2), structural proteins (ANK2, GJA5, PALLD), sympathetic system modulators (ADRB1, ADRB2, ADRB3), blood pressure regulators (NOS1AP, PAI-1), modulators of ionic flows (PLN, CERKL, SLCO3A1), transcription factors (BRUNOL4, LITAF), regulators of cell morphology (NRG3) and other genes known to be associated to ECG intervals modulation (MDR1, CASQ2, NDRG4, NUBPL, RNF207; Supplementary Table S2).…”

Section: Genetic Analysismentioning

confidence: 99%

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Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification

Sommariva¹,

Pappone

Boneschi³

et al. 2013

Eur J Hum Genet

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Brugada syndrome is an inherited arrhythmogenic disorder leading to sudden death predominantly in the 3-4 decade. To date the only reliable treatment is the implantation of a cardioverter defibrillator; however, better criteria for risk stratification are needed, especially for asymptomatic subjects. Brugada syndrome genetic bases have been only partially understood, accounting for o30% of patients, and have been poorly correlated with prognosis, preventing inclusion of genetic data in current guidelines. We designed an observational study to identify genetic markers for risk stratification of Brugada patients by exploratory statistical analysis. The presence of genetic variants, identified by SCN5A gene analysis and genotyping of 73 candidate polymorphisms, was correlated with the occurrence of major arrhythmic events in a cohort of 92 Brugada patients by allelic association and survival analysis. In all, 18 mutations were identified in the SCN5A gene, including 5 novel, and statistical analysis indicated that mutation carriers had a significantly increased risk of major arrhythmic events (P ¼ 0.024). In addition, we established association of five polymorphisms with major arrhythmic events occurrence and consequently elaborated a pilot risk stratification algorithm by calculating a weighted genetic risk score, including the associated polymorphisms and the presence of SCN5A mutation as function of their odds ratio. This study correlates for the first time the presence of genetic variants with increased arrhythmic risk in Brugada patients, representing a first step towards the design of a new risk stratification model.

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Section: Discussionmentioning

confidence: 95%

Section: Genetic Analysismentioning

confidence: 99%

Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification

Sommariva¹,

Pappone

Boneschi³

et al. 2013

Eur J Hum Genet

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“…Recently, genome-wide association (GWA) methods were applied to analyze the genetic substrates of several psychiatric disorders and related traits, including schizophrenia, [143][144][145][146] bipolar disorder, [147][148][149][150] major depression, 151,152 neuroticism, 153,154 and antipsychotic treatment response. 155,156 Notably, these psychiatric GWA studies have detected new risk markers that were not earlier identified in candidate gene association studies, whereas none of the previously described markers were replicated or confirmed by whole genome screening. 157 To date, no GWA study has been performed in an adequately powered sample of patients with PD.…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

Advances in molecular genetics of panic disorder

2010

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The molecular genetic research on panic disorder (PD) has grown tremendously in the past decade. Although the data from twin and family studies suggest an involvement of genetic factors in the familial transmission of PD with the heritability estimate near 40%, the genetic substrate underlying panicogenesis is not yet understood. The linkage studies so far have suggested that chromosomal regions 13q, 14q, 22q, 4q31-q34, and probably 9q31 are associated with the transmission of PD phenotypes. To date, more than 350 candidate genes have been examined in association studies of PD, but most of these results remain inconsistent, negative, or not clearly replicated. Only Val158Met polymorphism of the catechol-O-methyltransferase gene has been implicated in susceptibility to PD by several studies in independent samples and confirmed in a recent meta-analysis. However, the specific role of this genetic variation in PD requires additional analysis considering its genderand ethnicity-dependent effect and putative impact on cognitive functions. The recent advantages in bioinformatics and genotyping technologies, including genome-wide association and gene expression methods, provide the means for far more comprehensive discovery in PD. The progress in clinical and neurobiological concepts of PD may further guide genetic research through the current controversies to more definitive findings.

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“…So far, only two GWASs have been conducted in drug clinical trials; each of these studies provides relevant insights for future research. A study of electrocardiographic abnormalities during iloperidone treatment of schizophrenia [46] illustrated the feasibility of performing GWASs in a phase III clinical trial evaluating the efficacy, safety and tolerability of a novel drug. A report on statinrelated myopathy demonstrated the efficiency of performing a nested case-control GWAS within a clinical trial.…”

Section: Gwass In Pharmacogenomics: Challengesmentioning

confidence: 99%

State-of-the-Art Technologies to Interrogate Genetic/Genomic Components of Drug Response

Banerjee¹,

2013

Curr Genet Med Rep

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Over the last decade, the study of genomes has rapidly advanced to the point that genomic research now serves as the basis for many medical decisions and public health initiatives. Genetic variation is likely to contribute substantially to the variation in drug response observed across human populations. Genomic tools such as sequence variation and, more specifically, personal genome sequencing incorporating genome-wide association studies and nextgeneration sequences enable the precise prediction and treatment of disease. At present, DNA-based risk assessment for common complex diseases, application of molecular signatures and dose selection of therapeutic drugs are the important issues in personalized medicine. In order to make personalized medicine effective, these genomic techniques must be standardized and integrated into health systems and clinical workflow for prediction of disease incidence, genetic and environmental information to optimize the medical care and outcomes for each patient. Technology continues to lead the field of personalized medicine since the interpretation of the human genome is progressing as the cost and duration of genomic sequencing continue to decrease sharply. This review aimed at understanding the technologies that reveal how the changes that occur within the genome can alter their functions and the genomic variations that constitute individual susceptibility to diseases and responses to therapy.

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Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia

Cited by 97 publications

References 34 publications

Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification

Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification

Advances in molecular genetics of panic disorder

State-of-the-Art Technologies to Interrogate Genetic/Genomic Components of Drug Response

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