Child and adolescent psychiatric genetics

The current status of child and adolescent psychiatric genetics appears promising in light of the initiation of genome-wide association studies (GWAS) for diverse polygenic disorders and the molecular elucidation of monogenic Rett syndrome, for which recent functional studies provide hope for pharmacological treatment strategies. Within the last 50 years, tremendous progress has been made in linking genetic variation to behavioral phenotypes and psychiatric disorders. We summarize the major findings of the Human Genome Project and dwell on largely unsuccessful candidate gene and linkage studies. GWAS for the first time offer the possibility to detect single nucleotide polymorphisms and copy number variants without a priori hypotheses as to their molecular etiology. At the same time it is becoming increasingly clear that very large sample sizes are required in order to enable genome wide significant findings, thus necessitating further large-scaled ascertainment schemes for the successful elucidation of the molecular genetics of childhood and adolescent psychiatric disorders. We conclude by reflecting on different scenarios for future research into the molecular basis of early onset psychiatric disorders. This review represents the introductory article of this special issue of the European Child and Adolescent Psychiatry.

Genetics of male nuptial colour divergence between sympatric sister species of a Lake Victoria cichlid fish

The hypothesis of sympatric speciation by sexual selection has been contentious. Several recent theoretical models of sympatric speciation by disruptive sexual selection were tailored to apply to African cichlids. Most of this work concludes that the genetic architecture of female preference and male trait is a key determinant of the likelihood of disruptive sexual selection to result in speciation. We investigated the genetic architecture controlling male nuptial colouration in a sympatric sibling species pair of cichlid fish from Lake Victoria, which differ conspicuously in male colouration and female mating preferences for these. We estimated that the difference between the species in male nuptial red colouration is controlled by a minimum number of two to four genes with significant epistasis and dominance effects. Yellow colouration appears to be controlled by one gene with complete dominance. The two colours appear to be epistatically linked. Knowledge on how male colouration segregates in hybrid generations and on the number of genes controlling differences between species can help us assess whether assumptions made in simulation models of sympatric speciation by sexual selection are realistic. In the particular case of the two sister species that we studied a small number of genes causing major differences in male colouration may have facilitated the divergence in male colouration associated with speciation.

ABCtoolbox: a versatile toolkit for approximate Bayesian computations

Background The estimation of demographic parameters from genetic data often requires the computation of likelihoods. However, the likelihood function is computationally intractable for many realistic evolutionary models, and the use of Bayesian inference has therefore been limited to very simple models. The situation changed recently with the advent of Approximate Bayesian Computation (ABC) algorithms allowing one to obtain parameter posterior distributions based on simulations not requiring likelihood computations. Results Here we present ABCtoolbox, a series of open source programs to perform Approximate Bayesian Computations (ABC). It implements various ABC algorithms including rejection sampling, MCMC without likelihood, a Particle-based sampler and ABC-GLM. ABCtoolbox is bundled with, but not limited to, a program that allows parameter inference in a population genetics context and the simultaneous use of different types of markers with different ploidy levels. In addition, ABCtoolbox can also interact with most simulation and summary statistics computation programs. The usability of the ABCtoolbox is demonstrated by inferring the evolutionary history of two evolutionary lineages of Microtus arvalis. Using nuclear microsatellites and mitochondrial sequence data in the same estimation procedure enabled us to infer sex-specific population sizes and migration rates and to find that males show smaller population sizes but much higher levels of migration than females. Conclusion ABCtoolbox allows a user to perform all the necessary steps of a full ABC analysis, from parameter sampling from prior distributions, data simulations, computation of summary statistics, estimation of posterior distributions, model choice, validation of the estimation procedure, and visualization of the results.

High specificity of line-immunoassay based algorithms for recent HIV-1 infection independent of viral subtype and stage of disease

Background Serologic testing algorithms for recent HIV seroconversion (STARHS) provide important information for HIV surveillance. We have shown that a patient's antibody reaction in a confirmatory line immunoassay (INNO-LIATM HIV I/II Score, Innogenetics) provides information on the duration of infection. Here, we sought to further investigate the diagnostic specificity of various Inno-Lia algorithms and to identify factors affecting it. Methods Plasma samples of 714 selected patients of the Swiss HIV Cohort Study infected for longer than 12 months and representing all viral clades and stages of chronic HIV-1 infection were tested blindly by Inno-Lia and classified as either incident (up to 12 m) or older infection by 24 different algorithms. Of the total, 524 patients received HAART, 308 had HIV-1 RNA below 50 copies/mL, and 620 were infected by a HIV-1 non-B clade. Using logistic regression analysis we evaluated factors that might affect the specificity of these algorithms. Results HIV-1 RNA <50 copies/mL was associated with significantly lower reactivity to all five HIV-1 antigens of the Inno-Lia and impaired specificity of most algorithms. Among 412 patients either untreated or with HIV-1 RNA ≥50 copies/mL despite HAART, the median specificity of the algorithms was 96.5% (range 92.0-100%). The only factor that significantly promoted false-incident results in this group was age, with false-incident results increasing by a few percent per additional year. HIV-1 clade, HIV-1 RNA, CD4 percentage, sex, disease stage, and testing modalities exhibited no significance. Results were similar among 190 untreated patients. Conclusions The specificity of most Inno-Lia algorithms was high and not affected by HIV-1 variability, advanced disease and other factors promoting false-recent results in other STARHS. Specificity should be good in any group of untreated HIV-1 patients.

Genetics of GHRH, GHRH-receptor, GH and GH-receptor: its impact on pharmacogenetics

When a child is not following the normal, predicted growth curve, an evaluation for underlying illnesses and central nervous system abnormalities is required and, appropriate consideration should be given to genetic defects causing GH deficiency (GHD). Because Insulin-like-Growth Factor-I (IGF-I) plays a pivotal role, GHD could also be considered as a form of IGF-I deficiency (IGFD). Although IGFD can develop at any level of the GHRH-GH-IGF axis, a differentiation should be made between GHD (absent to low GH in circulation) and IGFD (normal to high GH in circulation). The main focus of this review is on the GH-gene, the various gene alterations and their possible impact on the pituitary gland. However, although transcription factors regulating the pituitary gland development may cause multiple pituitary hormone deficiency they may present initially as GHD. These defects are discussed in various different chapters within this book, whereas, the impact of alterations of the GHRH-, GHRH-receptor- --as well as the GH-receptor (GHR) gene--will be discussed here.

Community Genetics Reveal Elevated Levels of Sympatric Gene Flow among Morphologically Similar but Not among Morphologically Dissimilar Species of Lake Victoria Cichlid Fish

We examined genetic structure among five species of Lake Victoria haplochromine cichlids in four island communities, using a full factorial sampling design that compared genetic differentiation between pairs of species and populations of varying morphological similarity and geographical proximity. We found that allopatric conspecific populations were on average significantly more strongly differentiated than sympatric heterospecific populations of morphologically similar species. Allopatric heterospecific populations of morphologically dissimilar species were most differentiated. Our work demonstrates that phenotypic divergence can be maintained and perhaps even evolve in sympatry despite considerable gene flow between species. Conversely, phenotypic resemblance among conspecific populations can be maintained despite geographical isolation. Additionally we show that anthropogenically increased hybridization does not affect all sympatric species evenly but predominantly affects morphologically similar and closely related species. This has important implications for the evolution of reproductive isolation between species These findings are also consistent with the hypothesis of speciation reversal due to weakening of divergent selection and reproductive isolation as a consequence of habitat homogenization and offers an evolutionary mechanistic explanation for the observation that species poor assemblages in turbid areas of the lake are characterized by just one or two species in each of a few morphologically distinct genera.

Bacillus anthracis: Molecular taxonomy, population genetics, phylogeny and patho-evolution

Bacillus anthracis, the etiological agent of anthrax, manifests a particular bimodal lifestyle. This bacterial species alternates between short replication phases of 20-40 generations that strictly require infection of the host, normally causing death, interrupted by relatively long, mostly dormant phases as spores in the environment. Hence, the B. anthracis genome is highly homogeneous. This feature and the fact that strains from nearly all parts of the world have been analysed for canonical single nucleotide polymorphisms (canSNPs) and variable number tandem repeats (VNTRs) has allowed the development of molecular epidemiological and molecular clock models to estimate the age of major diversifications in the evolution of B. anthracis and to trace the global spread of this pathogen, which was mostly promoted by movement of domestic cattle with settlers and by international trade of contaminated animal products. From a taxonomic and phylogenetic point of view, B. anthracis is a member of the Bacillus cereus group. The differentiation of B. anthracis from B. cereus sensu strict, solely based on chromosomal markers, is difficult. However, differences in pathogenicity clearly differentiate B. anthracis from B. cereus and are marked by the strict presence of virulence genes located on the two virulence plasmids pXO1 and pXO2, which both are required by the bacterium to cause anthrax. Conversely, anthrax-like symptoms can also be caused by organisms with chromosomal features that are more closely related to B. cereus, but which carry these virulence genes on two plasmids that largely resemble the B. anthracis virulence plasmids. (C) 2011 Elsevier B.V. All rights reserved.

Effects of housing, perches, genetics, and 25-hydroxycholecalciferol on keel bone deformities in laying hens

Several studies have shown a high prevalence of keel bone deformities in commercial laying hens. The aim of this project was to assess the effects of perch material, a vitamin D feed additive (25-hydroxyvitamin D(3); HyD, DSM Nutritional Products, Basel, Switzerland), and genetics on keel bone pathology. The study consisted of 2 experiments. In the first experiment, 4,000 Lohmann Selected Leghorn hens were raised in aviary systems until 18 wk of age. Two factors were investigated: perch material (plastic or rubber-coated metal) and feed (with and without HyD). Afterward, the hens were moved to a layer house with 8 pens with 2 aviary systems. Daily feed consumption, egg production, mortality, and feather condition were evaluated. Every 6 wk, the keel bones of 10 randomly selected birds per pen were palpated and scored. In the second experiment, 2,000 Lohmann Brown (LB) hens and 2,000 Lohmann Brown parent stock (LBPS) hens were raised in a manner identical to the first experiment. During the laying period, the hens were kept in 24 identical floor pens but equipped with different perch material (plastic or rubber-coated metal). The same variables were investigated as in the first experiment. No keel bone deformities were found during the rearing period in either experiment. During the laying period, deformities gradually appeared and reached a prevalence of 35% in the first experiment and 43.8% in the second experiment at the age of 65 and 62 wk, respectively. In the first experiment, neither HyD nor the aviary system had any significant effect on the prevalence of keel bone deformities. In the second experiment, LBPS had significantly fewer moderate and severe deformities than LB, and rubber-coated metal perches were associated with a higher prevalence of keel bone deformities compared with plastic perches. The LBPS laid more but smaller eggs than the LB. Again, HyD did not affect the prevalence of keel bone deformities. However, the significant effect of breed affiliation strongly indicates a sizeable genetic component that may provide a basis for targeted selection.

Diagnostic performance of line-immunoassay based algorithms for incident HIV-1 infection

Background Serologic testing algorithms for recent HIV seroconversion (STARHS) provide important information for HIV surveillance. We have previously demonstrated that a patient's antibody reaction pattern in a confirmatory line immunoassay (INNO-LIA™ HIV I/II Score) provides information on the duration of infection, which is unaffected by clinical, immunological and viral variables. In this report we have set out to determine the diagnostic performance of Inno-Lia algorithms for identifying incident infections in patients with known duration of infection and evaluated the algorithms in annual cohorts of HIV notifications. Methods Diagnostic sensitivity was determined in 527 treatment-naive patients infected for up to 12 months. Specificity was determined in 740 patients infected for longer than 12 months. Plasma was tested by Inno-Lia and classified as either incident (< = 12 m) or older infection by 26 different algorithms. Incident infection rates (IIR) were calculated based on diagnostic sensitivity and specificity of each algorithm and the rule that the total of incident results is the sum of true-incident and false-incident results, which can be calculated by means of the pre-determined sensitivity and specificity. Results The 10 best algorithms had a mean raw sensitivity of 59.4% and a mean specificity of 95.1%. Adjustment for overrepresentation of patients in the first quarter year of infection further reduced the sensitivity. In the preferred model, the mean adjusted sensitivity was 37.4%. Application of the 10 best algorithms to four annual cohorts of HIV-1 notifications totalling 2'595 patients yielded a mean IIR of 0.35 in 2005/6 (baseline) and of 0.45, 0.42 and 0.35 in 2008, 2009 and 2010, respectively. The increase between baseline and 2008 and the ensuing decreases were highly significant. Other adjustment models yielded different absolute IIR, although the relative changes between the cohorts were identical for all models. Conclusions The method can be used for comparing IIR in annual cohorts of HIV notifications. The use of several different algorithms in combination, each with its own sensitivity and specificity to detect incident infection, is advisable as this reduces the impact of individual imperfections stemming primarily from relatively low sensitivities and sampling bias.