Elsevier

Biological Psychiatry

Volume 60, Issue 6, 15 September 2006, Pages 554-562
Biological Psychiatry

Original article
A Single Nucleotide Polymorphism Fine Mapping Study of Chromosome 1q42.1 Reveals the Vulnerability Genes for Schizophrenia, GNPAT and DISC1: Association with Impairment of Sustained Attention

https://doi.org/10.1016/j.biopsych.2006.04.024Get rights and content

Background

The marker D1S251 of chromosome 1q42.1 showed significant association with schizophrenia in a Taiwanese sample. We used single nucleotide polymorphism (SNP) fine mapping to search for the vulnerability genes of schizophrenia.

Methods

We selected 120 SNPs covering 1 Mb around D1S251 from the public database. These selected SNPs were initially validated if allele frequency was >10%. Forty-seven validated SNPs were genotyped in 102 families with at least 2 siblings affected with schizophrenia.

Results

Two SNP blocks showed significant association with schizophrenia. Block 1 (five-SNP), located between intron 2 and intron 13 of the glyceronephosphate O-acyltransferase (GNPAT) gene, showed the most significant associations using single-locus TDT (z = −2.07, p = .038, df = 1) and haplotype association analyses (z = −1.99, p = .046, df = 1). Block 2 (two-SNP), located between intron 4 and intron 5 of the disrupted-in-schizophrenia 1 (DISC1) gene, also showed the most significant results in both the single-locus (z = −3.22, p = .0013, df = 1) and haplotype association analyses (z = 3.35, p = .0008, df = 1). The association of the DISC1 gene with schizophrenia was mainly in the patient group with sustained attention deficits as assessed by the Continuous Performance Test.

Conclusions

Chromosome 1q42.1 harbors GNPAT and DISC1 as candidate genes for schizophrenia, and DISC1 is associated with sustained attention deficits.

Section snippets

Subjects

Schizophrenic patients who had at least one affected sibling (the proband cases) were identified from the Department of Psychiatry, National Taiwan University Hospital, and the university-affiliated Taoyuan Psychiatric Center. This research project was approved by the Institutional Review Board of National Taiwan University Hospital. Data collection was initiated after informed consents were obtained from the identified study subjects and their families. All family members were personally

SNP Validation

An SNP was considered valid if the frequency of minor allele was larger than 10% and the genotyping missing rate was smaller than 30%. Forty-seven of 120 SNPs met the validity criteria. The 47 SNPs span across 1591 kb around the D1S251 marker (Table 1) and cover 12 known functional genes of COG2, AGT, CAPN9, FLJ14525, FLJ 22584, ARV1, TRIM67, GNPAT, DKFZP547NO43 (Clorf124), EGLN1, TRAX, and DISC1. Four genes, CAPN9, ARV1, TRIM67, and Clorf124, did not have valid SNPs for further analyses. As

Discussion

We found two haplotype blocks using SNP fine mapping study around the D1S251 marker with significant association with schizophrenia. The first block of rs487047-rs508908-rs538643-rs539699-rs578945 covers the genetic region of the GNPAT (or DHAPAT) gene, and the second block of rs2793092-rs2793091 is located within the DISC1 gene. The first block in the GNPAT gene encodes the dihydroxyacetone-phosphate acyltransferase enzyme (DHAPAT) that is located within peroxisomes and catalyzes the

References (73)

  • J.R. O’Connell et al.

    PedCheck: A program for identification of genotype incompatibilities in linkage analysis

    Am J Hum Genet

    (1998)
  • C.A. Riccio et al.

    The continuous performance test: A window on the neural substrates for attention?

    Arch Clin Neuropsychol

    (2002)
  • K.W. Sax et al.

    Symptom correlates of attentional improvement following hospitalization for a first episode of affective psychosis

    Biol Psychiatry

    (1998)
  • R.B. Schutgens et al.

    Deficiency of acyl-CoA: Dihydroxyacetone phosphate acyltransferase in patients with Zellweger (cerebro-hepato-renal) syndrome

    Biochem Biophys Res Commun

    (1984)
  • E. Sobel et al.

    Detection and integration of genotyping errors in statistical genetics

    Am J Hum Genet

    (2002)
  • J. Tost et al.

    Genotyping single nucleotide polymorphisms by MALDI mass spectrometry in clinical applications

    Clin Biochem

    (2005)
  • L.E. Wolf et al.

    Wisconsin Card Sorting deficits in the offspring of schizophrenics in the New York High-Risk Project

    Schizophr Res

    (2002)
  • G.R. Abecasis et al.

    Merlin—rapid analysis of dense genetic maps using sparse gene flow trees

    Nat Genet

    (2002)
  • G.R. Abecasis et al.

    Pedigree tests of transmission disequilibrium

    Eur J Hum Genet

    (2000)
  • N.C. Andreasen

    The Scale for the Assessment of Negative Symptoms (SANS)

    (1983)
  • N.C. Andreasen

    The Scale for the Assessment of Positive Symptoms (SAPS)

    (1984)
  • J.C. Barrett et al.

    Haploview: Analysis and visualization of LD and haplotype maps

    Bioinformatics

    (2005)
  • A.S. Bassett et al.

    Is schizophrenia linked to chromosome 1q?

    Science

    (2002)
  • K.E. Burdick et al.

    DISC1 and neurocognitive function in schizophrenia

    Neuroreport

    (2005)
  • J.H. Callicott et al.

    Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia

    Proc Natl Acad Sci U S A

    (2005)
  • T.D. Cannon et al.

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

    Arch Gen Psychiatry

    (2005)
  • Chen QY, Chen Q, Feng GY, Lindpaintner K, Wang LJ, Chen ZX, et al (in press): Case-control association study of...
  • W.J. Chen et al.

    Sustained attention deficits as markers of genetic susceptibility to schizophrenia

    Am J Med Genet (Seminars in Medical Genetics)

    (2000)
  • W.J. Chen et al.

    Performance of the Continuous Performance Test among community samples

    Schizophr Bull

    (1998)
  • W.J. Chen et al.

    Sustained attention deficit and schizotypal personality features in nonpsychotic relatives of schizophrenic patients

    Am J Psychiatry

    (1998)
  • B. Cornblatt et al.

    Attention and clinical symptoms in schizophrenia

    Psychiatr Q

    (1997)
  • B.A. Cornblatt et al.

    Impaired attention, genetics, and the pathophysiology of schizophrenia

    Schizophr Bull

    (1994)
  • N. Craddock et al.

    Genes for schizophrenia and bipolar disorder?Implications for psychiatric nosology

    Schizophr Bull

    (2006)
  • D. Curtis et al.

    Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23-q24, and suggests the presence of additional loci on 1p and 1q

    Psychiatr Genet

    (2003)
  • E.R. Elias et al.

    Developmental delay and growth failure caused by a peroxisomal disorder, dihydroxyacetonephosphate acyltransferase (DHAP-AT) deficiency

    Am J Med Genet

    (1998)
  • T.E. Goldberg et al.

    Further evidence for dementia of the prefrontal type in schizophrenia?A controlled study of teaching the Wisconsin Card Sorting Test

    Arch Gen Psychiatry

    (1987)
  • Cited by (61)

    • Schizophrenia and neurogenesis: A stem cell approach

      2017, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Among these findings: 1) changes in cytoarchecture of pyramidal neurons in dorsolateral prefrontal cortex of brains of patients with SCZ, 2) changes in glutamate binding, transcription, and subunit protein expression in the prefrontal cortex, thalamus, and hippocampus, 3) decreases in the NR1 and/or increases in the NR3A subunits of NMDA receptors in hippocampus and frontal cortical areas, 4) high expression of the excitatory aminoacid transporters, which remove glutamate from the synapse, in the thalamus, 5) changes in the NMDA receptor-affiliated intracellular proteins such as PSD95 and SAP102, both modulating glutamate-associated intracellular signaling events, in the prefrontal cortex and thalamus, and 6) alterations in the levels of amino acids N-acethylaspartate and N-acethylaspartylglutamate, this latter an endogenous ligand of the metabotropic glutamate receptor 3 subtype, and in the activity of the enzyme that cleaves these amino acids and glutamate in the CSF and post-mortem tissue from individuals with SCZ (Abi-Darham, 2009; Catts et al., 2013). It is of note that repeated administration of the NMDA receptor antagonist phencyclidine has been shown to decrease neurogenesis in the DG of the rat hippocampus (Liu et al., 2006a; Liu et al., 2006b; Liu et al., 2006c; Maeda et al., 2007), what is more with that which can be blocked by the atypical antipsychotic clozapine (Maeda et al., 2007; Beraki et al., 2008). In the same way, ketamine has been shown to interfere with the proliferation and differention of NSCs in the VZ/SVZ of neonatal rats (Huang et al., 2015).

    • Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study

      2016, Schizophrenia Research
      Citation Excerpt :

      Given the prior associations of the GRM1 and NRG1 variants with CVLT total score and the TAAR6 variant with DS-CPT d’, these associations likely reflect a portion of the shared genetic component between the primary and candidate endophenotypes (Greenwood et al., 2011). Of the 40 genes on the COGS SNP Chip with prior evidence of association with schizophrenia, 17 were associated with at least one of the candidate endophenotypes: COMT, DAOA, DGCR2, DISC1, DRD3, DTNBP1, ERBB4, GRID1, GRIK3, GRIK4, GRIN2B, GRM4, NRG1, PRODH, SLC1A2, SP4, TAAR6, and ZDHHC8, including five SNPs with prior association to schizophrenia (Fallin et al., 2005; Funke et al., 2004; Liu et al., 2006; Mukai et al., 2004; Shifman et al., 2006; Stefanis et al., 2007). The collective results across all SNPs and candidate endophenotypes were highly significant according to the bootstrap Total Significance Test analysis.

    • Avoiding mouse traps in schizophrenia genetics: Lessons and promises from current and emerging mouse models

      2012, Neuroscience
      Citation Excerpt :

      Linkage and association studies have linked common variants in the DISC1 locus with psychiatric disorders in karyotypically normal patient populations (Allen et al., 2008), but the possibility that these results are merely due to chance cannot be excluded. Several studies also provide suggestive evidence that healthy subjects and patients with SCZ carrying DISC1 variants display changes in gray matter volume in the hippocampus, prefrontal cortex, and other brain regions (Callicott et al., 2005; Cannon et al., 2005; Di Giorgio et al., 2008; Szeszko et al., 2008), as well as deficits in working, short-term, and long-term memory (Burdick et al., 2005; Cannon et al., 2005; Hennah et al., 2005), attention (Hennah et al., 2005; Liu et al., 2006) and hippocampal and prefrontal cortical activation (Callicott et al., 2005; Prata et al., 2008). It should be noted that like other associations studies, these studies of DISC1 have not produced any statistically unequivocal results, and there have been multiple studies which have found no association between DISC1 and SCZ or other mental diseases (Devon et al., 2001; Chen et al., 2007; Kim et al., 2008; Sanders et al., 2008; Hayesmoore et al., 2008; Lim et al., 2009; Zhang et al., 2005).

    View all citing articles on Scopus
    View full text