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

Tests of linkage, allelic and genotypic association between schizophrenia and the gene for the D3 dopamine receptor, DRD3.

Genomic imprinting in the Icelandic/ British schizophrenia study: Preliminary results

Genome wide parametric genetic linkage analysis of bipolar and related unipolar affective disorders (manic depression) implicates chromosomes 1 and 12.

Thordur Sigmundsson

Papers

Tests of linkage, allelic and genotypic association between schizophrenia and the gene for the D3 dopamine receptor, DRD3.

Genomic imprinting in the Icelandic/ British schizophrenia study: Preliminary results

Genome wide parametric genetic linkage analysis of bipolar and related unipolar affective disorders (manic depression) implicates chromosomes 1 and 12.

Minor physical anomalies in schizophrenic patients and their relatives

157 – Catechol-O-methyltransferase polymorphism and antisaccade eye movements in schizophrenia