Genetics of complex disease

To find true genetic associations in complex diseases, such as allergic rhinitis and chronic rhinosinusitis, is a difficult task. Both are polygenetic diseases where it is believed that genetic variation in several genes make up their phenotypes. In addition, the environment of the affected individuals also play an important role, further obscuring eventual associations. Today most genetic association studies of polygenetic disease perform tests on the whole-genome level, but this has not always been the case. By 2012 a total of 56 genetic association studies had been published in allergic rhinitis and by 2013 a total of 27 studies in chronic rhinosinusitis. In but a few exceptions, all studies of the two diseases targeted candidate genes in small case and control groups. Replication attempts of significant associations from previous studies has shown some promise by pointing out more likely candidates. However, these associations do not explain the heritability of the studied diseases to any great extent. To find this missing heritability researchers have to look beyond common variants and instead focus on other potential targets. Re-sequencing studies of candidate genes could find rare variants with much higher effects sizes and studies of RNA and proteins should also prove to be helpful. New technologies and advances in molecular biology are looking promising but it is still hard to interpret all the new data. Polygenetic disorders are hard to study, low effect sizes makes novel candidate genes hard to discover. However, it is a numbers game, as more and more studies are made, more information will be available and eventually the genetic component, however big or small it is, of complex diseases will be solved

Replication study of genetic variants associated with chronic rhinosinusitis and nasal polyposis

Not all network applications can make do with the best-effort service of the original Internet design. Many new applications, Including multimedia and mission-critical ones, require a certain level of service from the network to operate properly. The difficulty of finding such preferential paths is compounded by the intrinsic inaccuracies of the network state information maintained by the nodes that have to make such decisions. We choose a stochastic framework to select paths for applications that want more cooperation from the network to operate satisfactorily. We represent the stochasticity of links by means of a new composite metric composed of an interval with a lower and upper bound and an associated probability. The interpretation and relevance of our metric is such that in the next decision time period the expected value of the resource is between the upper and the lower bound with the associated probability. Simple and straightforward methods of computing our composite metric are presented. An algorithm, called Augmented-Dijkstra, with the same complexity as the standard Dijkstra, provides an effective solution for statistical bandwidth guarantees. Simulation results evaluate and confirm the effectiveness of our approach. ©2006 IEEE.link_to_subscribed_fulltex

Comparison of variants found in 310 CRS patients and 379 EUR background population controls from the 1000Genomes project.

<p>Circles denote synonymous mutations and stars denote missense mutations. Intron 1 has been shortened by 3.5 kb to increase resolution.</p

<i>PARS2</i> gene region with exons and analyzed SNP markers.

<p>The linkage disequilibrium pattern (LD) are reported as R² and estimated using the EUR population of the 1000Genomes project.</p

Promoter and coding variants found in 310 CRS patients.

<p>Promoter and coding variants found in 310 CRS patients.</p

Chronic rhinosinusitis patients show accumulation of genetic variants in PARS2

Genetic studies of chronic rhinosinusitis (CRS) have identified a total of 53 CRS-associated SNPs that were subsequently evaluated for their reproducibility in a recent study. The rs2873551 SNP in linkage disequilibrium with PARS2 showed the strongest association signal. The present study aims to comprehensively screen for rare variants in PARS2 and evaluate for accumulation of such variants in CRS-patients. Sanger sequencing and long-range PCR were used to screen for rare variants in the putative promoter region and coding sequence of 310 CRS-patients and a total of 21 variants were detected. The mutation spectrum was then compared with data from European populations of the 1000Genomes project (EUR) and the Exome Aggregation Consortium (ExAC). The CRS population showed a significant surplus of low-frequency variants compared with ExAC data. Haplotype analysis of the region showed a significant excess of rare haplotypes in the CRS population compared to the EUR population. Two missense mutations were also genotyped in the 310 CRS patients and 372 CRS-negative controls, but no associations with the disease were found. This is the first re-sequencing study in CRS research and also the first study to show an association of rare variants with the disease