Number Of Trios Research Articles

Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

BackgroundThe contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known.MethodsCase–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches.ResultsQuerying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy.ConclusionsIn this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy.ImpactWe performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures.Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy.Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

Application of Dempster-Schafer Method in Family-Based Association Studies

In experiments designed for family-based association studies, methods such as transmission disequilibrium test require large number of trios to identify single-nucleotide polymorphisms associated with the disease. However, unavailability of a large number of trios is the Achilles' heel of many complex diseases, especially for late-onset diseases. In this paper, we propose a novel approach to this problem by means of the Dempster-Shafer method. The simulation studies show that the Dempster-Shafer method has a promising overall performance, in identifying single-nucleotide polymorphisms in the correct association class, as it has 90 percent accuracy even with 60 trios.

Serotonin 2A Receptor Gene Polymorphism in Korean Children with Attention-Deficit/Hyperactivity Disorder

ObjectiveThe purpose of this study was to investigate the association between the T102C polymorphism in the serotonin 2A receptor gene and attention-deficit/hyperactivity disorder (ADHD) in Korean patients.MethodsA total of 189 Korean children with ADHD as well as both parents of the ADHD children and 150 normal children participated in this study. DNA was extracted from blood samples from all of the subjects, and genotyping was conducted. Based on the allele and genotype information obtained, case-control analyses were performed to compare the ADHD and normal children, and Transmission disequilibrium tests (TDTs) were used for family-based association testing (number of trios=113). Finally, according to the significant finding which was showed in the case-control analyses, the results of behavioral characterastics and neuropsychological test were compared between ADHD children with and without the C allele.ResultsIn the case-control analyses, statistically significant differences were detected in the frequencies of genotypes containing the C allele (χ2=4.73, p=0.030). In the family-based association study, TDTs failed to detect linkage disequilibrium of the T102C polymorphism associated with ADHD children. In the ADHD children, both the mean reaction time and the standard deviation of the reaction time in the auditory continuous performance test were longer in the group with the C allele compared to the group without the C allele.ConclusionThe results of this study suggest that there is a significant genetic association between the T102C polymorphism in the serotonin 2A receptor gene and ADHD in Korean children.

A haplotype inference algorithm for trios based on deterministic sampling

BackgroundIn genome-wide association studies, thousands of individuals are genotyped in hundreds of thousands of single nucleotide polymorphisms (SNPs). Statistical power can be increased when haplotypes, rather than three-valued genotypes, are used in analysis, so the problem of haplotype phase inference (phasing) is particularly relevant. Several phasing algorithms have been developed for data from unrelated individuals, based on different models, some of which have been extended to father-mother-child "trio" data.ResultsWe introduce a technique for phasing trio datasets using a tree-based deterministic sampling scheme. We have compared our method with publicly available algorithms PHASE v2.1, BEAGLE v3.0.2 and 2SNP v1.7 on datasets of varying number of markers and trios. We have found that the computational complexity of PHASE makes it prohibitive for routine use; on the other hand 2SNP, though the fastest method for small datasets, was significantly inaccurate. We have shown that our method outperforms BEAGLE in terms of speed and accuracy for small to intermediate dataset sizes in terms of number of trios for all marker sizes examined. Our method is implemented in the "Tree-Based Deterministic Sampling" (TDS) package, available for download at http://www.ee.columbia.edu/~anastas/tdsConclusionsUsing a Tree-Based Deterministic sampling technique, we present an intuitive and conceptually simple phasing algorithm for trio data. The trade off between speed and accuracy achieved by our algorithm makes it a strong candidate for routine use on trio datasets.

Power consequences of linkage disequilibrium variation between populations

We quantify the degree to which LD differences exist in the human genome and investigates the consequences that variations in patterns of LD between populations can have on the power of case-control or family-trio association studies. Although only a small proportion of SNPs show significant LD differences (0.8-5%), these can introduce artificial signals of associations and reduce the power to detect true associations in case-control designs, even when meta-analytic approaches are used to account for stratification. We show that combining trios from different populations in the presence of significant LD differences can adversely affect power even though the number of trios has increased. Our results have implications on genetic studies conducted in populations with substantial population structure and show that the use of meta-analytic approaches or family-based designs to protect Type 1 error does not prevent loss of power due to differences in LD across populations.