The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.

The International HapMap Project

Genetic factors strongly affect susceptibility to common diseases and also influence disease-related quantitative traits. Identifying the relevant genes has been difficult, in part because each causal gene only makes a small contribution to overall heritability. Genetic association studies offer a potentially powerful approach for mapping causal genes with modest effects, but are limited because only a small number of genes can be studied at a time. Genome-wide association studies will soon become possible, and could open new frontiers in our understanding and treatment of disease. However, the execution and analysis of such studies will require great care.

Genome-wide association studies for common diseases and complex traits

Context There are many published twin studies of schizophrenia. Although these studies have been reviewed previously, to our knowledge, no review has provided quantitative summary estimates of the impact of genes and environment on liability to schizophrenia that also accounted for the different ascertainment strategies used. Objective To calculate meta-analytic estimates of heritability in liability and shared and individual-specific environmental effects from the pooled twin data. Data Sources We used a structured literature search to identify all published twin studies of schizophrenia, including MEDLINE, dissertation, and books-in-print searches. Study Selection Of the 14 identified studies, 12 met the minimal inclusion criteria of systematic ascertainment. Data Synthesis By using a multigroup twin model, we found evidence for substantial additive genetic effects—the point estimate of heritability in liability to schizophrenia was 81% (95% confidence interval, 73%-90%). Notably, there was consistent evidence across these studies for common or shared environmental influences on liability to schizophrenia—joint estimate, 11% (95% confidence interval, 3%-19%). Conclusions Despite evidence of heterogeneity across studies, these meta-analytic results from 12 published twin studies of schizophrenia are consistent with a view of schizophrenia as a complex trait that results from genetic and environmental etiological influences. These results are broadly informative in that they provide no information about the specific identity of these etiological influences, but they do provide a component of a unifying empirical basis supporting the rationality of searches for underlying genetic and common environmental etiological factors.

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Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies.

This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications.

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia

The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.

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Neuregulin 1 and Susceptibility to Schizophrenia

Changes in the Hamilton Depression Rating Scale and the P(300) auditory event-related potential were assessed in 10 patients with depression before and after a treatment course of five daily sessions of 10 Hz repetitive transcranial magnetic stimulation (rTMS) over the left prefrontal cortex. The patients were initially randomly allocated either to an active or a placebo rTMS treatment. All patients received both types of treatment separated by an interval of 4 weeks. The median Hamilton score decreased by 7 points following active rTMS and by 1 point after sham (p=0.075). Active rTMS was associated with a significant increase in the P(300) amplitude compared with sham (p=0.02). There was no correlation between changes in P(300) measurements and the Hamilton scores after active treatment. We conclude that five daily sessions of left prefrontal rTMS treatment is not of sufficient duration to make a significant improvement in depressive symptoms.

The effects of repetitive transcranial magnetic stimulation on depressive symptoms and the P(300) event-related potential.

BACKGROUND Information regarding the determinants of successful vocational rehabilitation (VR) is scarce OBJECTIVE Investigate whether sex, duration, quality of life and financial circumstances influence the success of VR METHODS The study group consisted of 519 participants (293 women, 56%), who finished VR in the period 2000-2014 The group was divided into the following subgroups: dropouts, unsuccessful and successful VR Data were collected by questionnaire RESULTS Income had the most impact on whether the outcome was successful Having supplemental income when entering the VR program increased the likelihood of a successful conclusion, odds ratio (OR) 560 (95% CI; 243-1359) (p < 0001), being on sick leave OR 502 (95% CI 193-1379) (p < 0001) or rehabilitation pension OR 193 (95% CI 107-352) (p < 003) The participants in the successful sub-group were older (p < 006) and stayed in rehabilitation longer (p < 0001), compared to those who were unsuccessful However, the effect on OR was limited: 103 (95% CI 101-106) and 104 (95% CI 102-107), respectively CONCLUSIONS For this sample, supplemental income appears to be the most important factor for a successful rehabilitation outcome Checking financial status at the beginning of the rehabilitation process could minimize financial strain and increase the likelihood of success

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Determinants of outcome of vocational rehabilitation.

Demand for Vocational Rehabilitation in Iceland has been steadily rising in recent years where the presence of young patients has increased proportionally the most. It is essential that public spending is efficient without compromising the treatment quality. It is worth exploring if a solution for increasing the efficiency in this healthcare section is to use Artificial Intelligence (AI). An innovative project on developing, testing, and implementing specialised AI software in its services is being performed in Janus Rehabilitation. The software, named Volvan in Icelandic, can identify latent areas of possible interest in patient's circumstances which might affect the outcome of their treatment, and assist specialists in providing timely and appropriate interventions. The accuracy, precision, and recall of its predictions have been verified in two recent publications. Volvan seems to be a promising tool for individualised rehabilitation, where patients are dealing with difficult and complex problems. Janus Rehabilitation is in the process of launching Volvan as an unbiased member of the interdisciplinary teams of specialists. The aim of this report is to introduce Volvan and the associated research.

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Omar Hjaltason

Papers

Neuregulin 1 and Susceptibility to Schizophrenia

The effects of repetitive transcranial magnetic stimulation on depressive symptoms and the P(300) event-related potential.

Determinants of outcome of vocational rehabilitation.

[Novel Innovation: Can Artificial Intelligence make Rehabilitation more Efficient?]