Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

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Finding the missing heritability of complex diseases

Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain.

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

/pdf/biological-insights-from-108-schizophrenia-associated-3rfvth8dm9.pdf

Biological insights from 108 schizophrenia-associated genetic loci

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

Objective : Previous research has consistently implicated genetic factors in the pathogenesis of schizophrenia. It has been hypothesized that an abnormality in glutamatergic function is of etiologic importance in schizophrenia, and therefore the glutamate receptor family of genes are potential susceptibility loci for schizophrenia. To test this hypothesis the authors sought to detect linkage between the GluR6 glutamate receptor gene and schizophrenia. Method : Twenty-three English and Icelandic families containing multiple cases of schizophrenia were genotyped with a microsatellite trinucleotide repeat polymorphism localized at the GluR6 glutamate receptor locus. Lod scores, model-free linkage analysis, and extended relative pair analysis were used to test for linkage. Results : No statistically significant evidence of linkage between GluR6 and schizophrenia was found. Conclusions : The results do not support the hypothesis that GluR6 allelic variants provide a major gene contribution to the etiology of schizophrenia in a large proportion of these pedigrees.

Lack of evidence for close linkage of the glutamate GluR6 receptor gene with schizophrenia

Neuregulin-1 (NRG-1) is a putative susceptibility gene for schizophrenia but the neurocognitive processes that may involve NRG-1 in schizophrenia are unknown. Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes, which may be associated with brain dysfunctions underlying the pathophysiology of schizophrenia. The aim of this study was to investigate the associations of NRG-1 genotypes with AS and SPEM in schizophrenia patients and healthy controls. Patients (N = 113) and controls (N = 106) were genotyped for two NRG-1 single nucleotide polymorphisms (SNPs); SNP8NRG222662, a surrogate marker for the originally described Icelandic NRG-1 risk haplotype, and SNP8NRG243177, which has recently been associated with individual differences in brain function. Subjects underwent infrared oculographic assessment of AS and SPEM. The study replicates previous findings of impaired AS and SPEM performance in schizophrenia patients (all P < 0.005; all d = 0.5-1.5). SNP8NRG243177 risk allele carriers had marginally increased variability of AS spatial error (P = 0.050, d = 0.3), but there were no significant genotype effects on other eye movement variables and no significant diagnosis-by-genotype interactions. Generally, risk allele carriers (G allele for SNP8NRG222662 and T allele for SNP8NRG243177) had numerically worse performance than non-carriers on most AS and SPEM variables. The results do not suggest that NRG-1 genotype significantly affects AS and SPEM task performance. However, the power of the sample to identify small effects is limited and the possibility of a type II error must be kept in mind. Larger samples may be needed to reliably investigate such gene effects on oculomotor endophenotypes.

Neuregulin-1 genotypes and eye movements in schizophrenia

Exclusion of linkage of schizophrenia of the gene for the glutamate GluR5 receptor

Structural abnormalities in frontal, temporal and limbic regions and interconnecting white matter tracts in schizophrenia

Neuropsychological models propose qualitatively distinct planning impairments in the psychomotor poverty and disorganization syndromes in schizophrenia. It was proposed that poor plan initiation in psychomotor poverty would lead to longer initial planning times, while poor plan execution in disorganization would lead to greater inefficiency. Participants with psychomotor poverty (n = 30) and disorganization (n = 29) symptoms were contrasted with healthy controls (n = 28) to elucidate distinct planning impairments. Planning was compared in the Tower of London task versus real life analogue performance in the form of a board-game style diary planning task. The specificity of planning impairments was investigated by controlling for current IQ. The disorganization group demonstrated inefficient planning across both tasks, with poor performance on the Tower of London but not on the real life analogue task remaining after intelligence levels were taken into account. Initial planning times did not differ between groups. Previous associations between poor planning and symptoms may have been driven by poor planning with disorganization symptoms and associated lower order impairments in executive function or the semantic system. Targeting these impairments in people with disorganization symptoms may lead to a greater chance of success in promoting generalization to the real world. (JINS, 2011, 17, 474–484)

Thordur Sigmundsson

Papers

Lack of evidence for close linkage of the glutamate GluR6 receptor gene with schizophrenia

Neuregulin-1 genotypes and eye movements in schizophrenia

Exclusion of linkage of schizophrenia of the gene for the glutamate GluR5 receptor

Structural abnormalities in frontal, temporal and limbic regions and interconnecting white matter tracts in schizophrenia

Tower of London versus real life analogue planning in schizophrenia with disorganization and psychomotor poverty symptoms.