Association of DISC1/TRAX Haplotypes With Schizophrenia, Reduced Prefrontal Gray Matter, and Impaired Short- and Long-term Memory

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Abstract
Schizophrenia is a complexly inherited disorder involving multiple genes of small effect influencing numerous central nervous system trait deficits.1 Two genes in the chromosome 1q42 region—disrupted-in-schizophrenia 1 (DISC1) and translin-associated factor X (TRAX)—represent particularly good candidate loci based on positional and functional considerations. Although the evidence for linkage of this region to schizophrenia has been negligible in some studies,2 the translocation break point that cosegregates with schizophrenia in a Scottish pedigree3,4 and the peak linkage signal in the 1q42 region within the Finnish population5-7 are intragenic to DISC1, with several other linkage and association findings also pointing to this region.8-15 The DISC1 gene is expressed in neurons and glia and is translated to a protein that has an impact on neurodevelopmental and neurochemical processes thought to be involved in the pathophysiology of schizophrenia, including neuritic outgrowth, neuronal migration, synaptogenesis, and glutamatergic transmission.16-19 Recently, 2 haplotypes incorporating different blocks of single-nucleotide polymorphic (SNP) markers in the DISC1 gene were found to be associated with schizophrenia (one undertransmitted and the other overtransmitted to affected cases) in a study of multiplex families from Finland.6 How these genetic variations influence central nervous system trait components associated with schizophrenia remains to be determined, although it is notable that carriers of the (1;11)(q42;q14.3) translocation show deficits in the amplitude of the P300 electrophysiological response.12 Another locus affected by the balanced translocation in the Scottish pedigree DISC2 is not known to form a protein but is thought to act through its RNA as a regulator of DISC1.3