Search

Although a genetic component is known to have an important role in the etiology of developmental dyslexia (DD), we are far from understanding the molecular etiopathogenetic pathways. Reduced measures of neurobiological functioning related to reading (dis)ability, i.e. endophenotypes (EPs), are promising targets for gene finding and the elucidation of the underlying mechanisms. In a sample of 100 nuclear families with DD (229 offspring) and 83 unrelated typical readers, we tested whether a set of well‐established, cognitive phenotypes related to DD [i.e. rapid auditory processing (RAP), rapid automatized naming (RAN), multisensory nonspatial attention and visual motion processing] fulfilled the criteria of the EP construct. Visual motion and RAP satisfied all testable criteria (i.e. they are heritable, associate with the disorder, co‐segregate with the disorder within a family and represent reproducible measures) and are therefore solid EPs of DD. Multisensory nonspatial attention satisfied three of four criteria (i.e. it associates with the disorder, co‐segregates with the disorder within a family and represents a reproducible measure) and is therefore a potential EP for DD. Rapid automatized naming is heritable but does not meet other criteria of the EP construct. We provide the first evidence of a methodologically and statistically sound approach for identifying EPs for DD to be exploited as a solid alternative basis to clinical phenotypes in neuroscience. [ABSTRACT FROM AUTHOR]

Attention problems affect a substantial number of children and adolescents and are predictive of academic underachievement and lower global adaptive functioning. Considerable variability has been observed with regard to the individual development of attention problems over time. In particular, the period of adolescence is characterized by substantial maturation of executive functioning including attentional processing, with the influence of genetic and environmental factors on individual trajectories not yet well understood. In the present investigation, we evaluated whether the monoamine oxidase A functional promoter polymorphism, MAOA-LPR, plays a role in determining continuity of parent-rated attention problems during adolescence. At the same time, a potential effect of severe life events (SLEs) was taken into account. A multi-group path analysis was used in a sample of 234 adolescents (149 males, 85 females) who took part in an epidemiological cohort study at the ages of 11 and 15 years. Attention problems during early adolescence were found to be a strong predictor of attention problems in middle adolescence. However, in carriers of the MAOA-LPR low-activity variant (MAOA-L) stability was found to be significantly higher than in carriers of the high-activity variant (MAOA-H). Additionally, only in MAOA-L carriers did SLEs during adolescence significantly impact on attention problems at the age of 15 years, implying a possible gene x environment interaction. To conclude, we found evidence that attention problems during adolescence in carriers of the MAOA-L allele are particularly stable and malleable to life stressors. The present results underline the usefulness of applying a more dynamic GxE perspective. [ABSTRACT FROM AUTHOR]

Even if substantial heritability has been reported and candidate genes have been identified extensively, all known marker associations explain only a small proportion of the phenotypic variance of developmental dyslexia (DD) and related quantitative phenotypes. Gene-by-gene interaction (also known as 'epistasis'-G × G) triggers a non-additive effect of genes at different loci and should be taken into account in explaining part of the missing heritability of this complex trait. We assessed potential G × G interactions among five DD candidate genes, i.e., DYX1C1, DCDC2, KIAA0319, ROBO1, and GRIN2B, upon DD-related neuropsychological phenotypes in 493 nuclear families with DD, by implementing two complementary regression-based approaches: (1) a general linear model equation whereby the trait is predicted by the main effect of the number of rare alleles of the two genes and by the effect of the interaction between them, and (2) a family-based association test to detect G × G interactions between two unlinked markers by splitting up the association effect into a between- and a within-family genetic orthogonal components. After applying 500,000 permutations and correcting for multiple testing, both methods show that G × G effects between markers within the DYX1C1, KIAA0319/TTRAP, and GRIN2B genes lower the memory letters composite z-score of on average 0.55 standard deviation. We provided initial evidence that the effects of familial transmission of synergistic interactions between genetic risk variants can be exploited in the study of the etiology of DD, explain part of its missing heritability, and assist in designing customized charts of individualized neurocognitive impairments in complex disorders, such as DD. [ABSTRACT FROM AUTHOR]

A population genetics approach is used to identify the most likely introduction site and introduction pathway for the North American forest pathogen Heterobasidion irregulare using 101 isolates from six sites in Italy and 34 isolates from five sites in North America. Diversity indices based on sequences from ten loci indicate the highest diversity in Italy is found in Castelfusano/Castelporziano and that diversity progressively decreases with increasing distance from that site. AMOVA, Bayesian clustering and principal coordinates analyses based on 12 SSR loci indicate high levels of gene flow among sites, high frequency of admixing, and fail to identify groups of genotypes exclusive to single locations. Cumulatively, these analyses suggest the current infestation is the result of multiple genotypes expanding their range from a single site. Based on two sequenced loci, a single source site in North America could provide enough variability to explain the variability observed in Italy. These results support the notion that H. irregulare was introduced originally in Castelporziano: because Castelporziano has been sealed off from the rest of the world for centuries except for a camp set up by the US military in 1944, we conclude the fungus may have been transported in infected wood used by the military. Finally, spatial autocorrelation analyses using SSR data indicate a significant under-dispersion of alleles up to 0.5-10 km, while a significant overdispersion of alleles was detected at distances over 80 km: these ranges can be used to make predictions on the likely dispersal potential of the invasive pathogen. [ABSTRACT FROM AUTHOR]

While the genetic and environmental contributions to developmental dyslexia ( DD) have been studied extensively, the effects of identified genetic risk susceptibility and of specified environmental hazardous factors have usually been investigated separately. We assessed potential gene-by-environment ( GxE) interactions on DD-related reading, spelling and memory phenotypes. The presence of GxE effects were investigated for the DYX1C1, DCDC2, KIAA0319 and ROBO1 genes, and for seven specified environmental moderators in 165 nuclear families in which at least one member had DD, by implementing a general test for GxE interaction in sib-pair-based association analysis of quantitative traits. Our results support a diathesis-stress model for both reading and memory composites: GxE effects were found between some specified environmental moderators (i.e. maternal smoke during pregnancy, birth weight and socio-economic status) and the DYX1C1- 1259C/G marker. We have provided initial evidence that the joint analysis of identified genetic risk susceptibility and measured putative risk factors can be exploited in the study of the etiology of DD and reading-related neuropsychological phenotypes, and may assist in identifying/preventing the occurrence of DD. [ABSTRACT FROM AUTHOR]

A total of 669 isolates of Phytophthora ramorum, the pathogen responsible for Sudden Oak Death, were collected from 34 Californian forests and from the ornamental plant-trade. Seven microsatellite markers revealed 82 multilocus genotypes (MGs) of which only three were abundant (>10%). Iteratively collapsing based upon minimum ΦST, yielded five meta-samples and five singleton populations. Populations in the same meta-sample were geographically contiguous, with one exception, possibly explained by the trade of infected plants from the same source into different locations. Multidimensional scaling corroborated this clustering and identified nursery populations as genetically most distant from the most recent outbreaks. A minimum-spanning network illustrated the evolutionary relationships among MGs, with common genotypes at the centre and singletons at the extremities; consistent with colonization by a few common genotypes followed by local evolution. Coalescent migration analyses used the original data set and a data set in which local genotypes were collapsed into common ancestral genotypes. Both analyses suggested that meta-samples 1 (Santa Cruz County) and 3 (Sonoma and Marin Counties), act as sources for most of the other forests. The untransformed data set best explains the first phases of the invasion, when the role of novel genotypes may have been minimal, whereas the second analysis best explains migration patterns in later phases of the invasion, when prevalence of novel genotypes was likely to have become more significant. Using this combined approach, we discuss possible migration routes based on our analyses, and compare them to historical and field observations from several case studies. [ABSTRACT FROM AUTHOR]

The genetic structure of the clonally reproducing Sudden Oak Death (SOD) pathogen in California was investigated using seven variable microsatellites. A total of 35 multilocus genotypes were identified among 292 samples representative of populations from 14 forest sites and of the nursery trade.amova indicated significant genetic variability both within (44.34%) and among populations (55.66%). Spatial autocorrelation analyses indicated that Moran's index of similarity reached a minimum of 0.1 at 350 m, increased to 0.4 at 1500 m and then decreased to zero at 10 km. These results suggest a bimodal pattern of spread, with medium range dispersal (1500–10 000 m) putatively attributed to the presence of strong winds. Lack of genetic structure was identified for three groups of populations. One group notably included the nurseries’ population and two forest populations, both linked to early reports of the pathogen. A neighbour-joining analysis based on pairwise ΦST values indicated that the clade inclusive of the nurseries’ populations is basal to all California populations. A network analysis identified three common genotypes as the likely founders of the California infestation and proposes a stepwise model for local evolution of novel genotypes. This was supported by the identification in the same locations of novel genotypes and of their 1- or 2-step parents. We hypothesize that the few undifferentiated population groups indicate historical human spread of the pathogen, while the general presence of genetically structured populations indicates that new infestations are currently generated by rare medium or long-range natural movement of the pathogen, followed by local generation of new genotypes. [ABSTRACT FROM AUTHOR]

Helicobacter pyloriinfection leads to a broad spectrum of disease manifestations such as gastritis, ulcer disease, and even gastric carcinoma. The genetically determined immune response and subsequent inflammation influence the degree of mucosal damage. Adhesion molecules of the CD11 cluster play an important role in adherence of neutrophils to endothelial cells in inflammation. We conducted a haplotype-based analysis of the CD11 cluster in a sample of 315 patients withH. pyloriinfection and investigated associations with gastric erosions and ulcer disease. Twelve single nucleotide polymorphisms (SNPs) covering the genesCD11a,CD11b, andCD11cwere genotyped by Taqman technology. Linkage disequilibrium (LD) was assessed within the CD11 cluster and haplotype case-control analysis was conducted. Sliding window haplotype analysis identified a haplotype consisting of the markers CD11c exon 15 and intron 31 associated with gastric ulcer disease. Patients carrying the haplotype GA bear a 2.4-fold increased risk. No significant associations of single markers with disease outcome were found. High-density LD mapping and mutation detection of CD11c in larger samples will be necessary to confirm our findings and identify the causative variant. Thus, we conclude that genetic variants in the CD11 cluster may play a role in the development of gastric ulcer in chronicH. pyloriinfection presumably by influencing leukocyte adhesion. The biological effect of genetic variants of CD11c in gastric inflammation needs further clarification. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection results in chronic hepatitis in more than 80% of infected patients while 10–20% of patients recover spontaneously. Host genetic factors may influence the ability to clear the virus after infection. Six single nucleotide polymorphisms and a 32 bp deletion in the genes coding for CCR3, CCR2 and CCR5 (which are all located in a cluster on chromosome 3) were investigated in 465 consecutively recruited patients infected with HCV and 370 matched controls. Genetic variants were tested for association with spontaneous viral elimination and, in the chronically infected patients, stage of fibrosis and response to antiviral therapy. The G190A polymorphism (variant allele Ile64) in the first transmembrane domain of CCR2 was under-represented in the 29 patients who had cleared the hepatitis C virus spontaneously ( P = 0·018). None of the other variants in the CCR gene cluster showed association with the natural course of the infection, stage of fibrosis or response to therapy. [ABSTRACT FROM AUTHOR]

Infliximab (anti-TNF-α monoclonal antibody)induces remission in 30-40% of Crohn's disease patients. Treatment response is a stable trait. Two cohorts from independent, prospective clinical trials of infliximab in Crohn's disease were studied. Hypotheses were generated in an exploratory cohort (n = 90) and then tested in a confirmatory cohort (n = 444), using a statistical design, which is stable against type 1 and type 2 errors. In the exploratory cohort, the mutant 196Arg allele of TNFR-II (exon 6 polymorphism) and a novel silent polymorphism in exon 2 of TNFR-II were associated with lack of response to infliximab (83.3% in homozygote mutant 196 Arg patients vs 36.9% in heterozygotes and wild4type homozygotes (P = 0.036) and 85.7% in homozygote mutant exon 2 patients vs 36.1% (P = 0.01), respectively). None of the homozygote mutant individuals (0/6) achieved clinical remission, whereas the remission rate was 35.7% (30/84) in wild4type homozygotes and heterozygotes. In the large second cohort, the observed genotype-phenotype associations were not replicated. Other polymorphisms (TNF-α promoter -238, -308, -376, -857, -1031, TNF-R-I -609, +36 (exon 1), TNF-R-II 1663, 1690 (3'-UTR)) were not associated with treatment response in both cohorts (P > 0.5). None of the polymorphisms was associated with refractory Crohn's disease itself when compared to healthy controls. In a two-cohort study, a series of polymorphisms in the TNF, the TNF-R-I and in the TNF-R-II genes could be thoroughly excluded as pharmacogenetic markers for a treatment response to infliximab and as etiologic factors for Crohn's disease, respectively. The discrepancy between the two cohorts observed for the TNF-R-II exon 6 and exon 2 polymorphism may point to a weak effect on... [ABSTRACT FROM AUTHOR]