Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory

Context: Chromosome 1q42 is among several genomic regions showing replicated evidence of linkage with schizophrenia, but the specific susceptibility mechanisms underlying this relationship remain to be identified. Objective: To examine a series of haplotype blocks of single-nucleotide polymorphic markers from a segment of 1q42 spanning the disrupted-in-schizophrenia 1 (DISC1) and translin-associated factor X (TRAX) genes for association with schizophrenia and several endophenotypic traits thought to be involved in disease pathogenesis. Design: Population-based twin cohort study. Setting: Finland. Participants: Two hundred thirty-six subjects, consisting of 7 twin pairs concordant for schizophrenia (6 monozygotic [MZ] and I dizygotic [DZ]), 52 pairs discordant for schizophrenia (20 MZ and 32 DZ), and 59 demographically balanced normal pairs (28 MZ and 31 DZ), were drawn from a twin cohort consisting of all of the same-sex twins born in Finland from 1940 through 1957. Main Outcome Measures: Psychiatric diagnosis, performance on neurocognitive tests of short- and long-term memory, and gray matter volume measurements taken from high-resolution magnetic resonance images. Results: A common haplotype incorporating 3 single-nucleotide polymorphic markers near the translocation break point of DISC1 (odds ratio, 2.6 [P=.02]) and a rare haplotype incorporating 4 markers from the DISC1 and TRAX genes (odds ratio, 13.0 [P=.001]) were significantly overrepresented among individuals with schizophrenia. These haplotypes were also associated with several quantitative endophenotypic traits previously observed to covary with schizophrenia and genetic liability to schizophrenia, including impairments in short- and long-term memory functioning and reduced gray matter density in the prefrontal cortex, as demonstrated using a population-based brain atlas method, with a trend toward association with reduced hippocampal volume. Conclusions: Specific alleles of the DISC1 and TRAX genes on 1q42 appear to contribute to genetic risk for schizophrenia through disruptive effects on the structure and function of the prefrontal cortex, medial temporal lobe, and other brain regions. These effects are consistent with their production of proteins that play roles in neuritic outgrowth, neuronal migration, synaptogenesis, and glutamatergic neurotransmission.