Association of the DTNBP1 genotype with cognition and personality traits in healthy subjects

Background Schizophrenia is a complex disorder with a high heritability. Family members have an increased risk not only for schizophrenia per se but also for schizophrenia spectrum disorders. Impairment of neuropsychological functions found in schizophrenia patients are also frequently observed in their relatives. The dystrobrevin-binding protein 1 (DTNBP1) gene located at chromosome 6p22.3 is one of the most often replicated vulnerability genes for schizophrenia. In addition, this gene has been shown to modulate general cognitive abilities both in healthy subjects and in patients with schizophrenia. Method In a sample of 521 healthy subjects we investigated an association between the DTNBP1 genotype [single nucleotide polymorphism (SNP) rs1018381], personality traits [using the NEO Five-Factor Inventory (NEO-FFI) and the Schizotypal Personality Questionnaire – Brief Version (SPQ-B)] and cognitive function (estimated IQ, verbal fluency, attention, working memory and executive function). Results Significantly lower scores on the SPQ-B (p=0.0005) and the Interpersonal Deficit subscale (p=0.0005) in carriers of the A-risk allele were detected. There were no differences in any of the cognitive variables between groups. Conclusions The results indicate that genetic variation of the DTNBP1 genotype might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level.

[1]  C. Stefanis,et al.  Effect of Schizotypy on Cognitive Performance and Its Tuning by COMT val 158 Met Genotype Variations in a Large Population of Young Men , 2007, Biological Psychiatry.

[2]  Birgit Funke,et al.  Association of the DTNBP1 locus with schizophrenia in a U.S. population. , 2004, American journal of human genetics.

[3]  Heather C Whalley,et al.  A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms , 2006, Nature Neuroscience.

[4]  Kirwin,et al.  Behavioral and Brain Functions Failure to Confirm Allelic and Haplotypic Association between Markers at the Chromosome 6p22.3 Dystrobrevin-binding Protein 1 (dtnbp1) Locus and Schizophrenia , 2022 .

[5]  R. de Graaf,et al.  Neuroticism and low self-esteem as risk factors for psychosis , 2002, Social Psychiatry and Psychiatric Epidemiology.

[6]  Thomas G Schulze,et al.  The DTNBP1 (dysbindin) gene contributes to schizophrenia, depending on family history of the disease. , 2003, American journal of human genetics.

[7]  P. DeRosse,et al.  Dysbindin genotype and negative symptoms in schizophrenia. , 2006, The American journal of psychiatry.

[8]  M. Martínez-González,et al.  Neuroticism and low self-esteem as risk factors for incident eating disorders in a prospective cohort study. , 2003, The International journal of eating disorders.

[9]  E. J. van den Oord,et al.  Relationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia. , 2005, The American journal of psychiatry.

[10]  C. Stefanis,et al.  Variation in catechol-o-methyltransferase val158 met genotype associated with schizotypy but not cognition: A population study in 543 young men , 2004, Biological Psychiatry.

[11]  Costas N. Stefanis,et al.  Impact of Schizophrenia Candidate Genes on Schizotypy and Cognitive Endophenotypes at the Population Level , 2007, Biological Psychiatry.

[12]  Mark J Daly,et al.  Analysis of high-resolution HapMap of DTNBP1 (Dysbindin) suggests no consistency between reported common variant associations and schizophrenia. , 2006, American journal of human genetics.

[13]  J. Strauss,et al.  An independent analysis of the Copenhagen sample of the Danish adoption study of schizophrenia. II. The relationship between schizotypal personality disorder and schizophrenia. , 1981, Archives of general psychiatry.

[14]  P. Vernon,et al.  Heritability of the big five personality dimensions and their facets: a twin study. , 1996, Journal of personality.

[15]  Margot Albus,et al.  Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. , 2003, American journal of human genetics.

[16]  K. Kendler,et al.  The Roscommon Family Study. I. Methods, diagnosis of probands, and risk of schizophrenia in relatives. , 1993, Archives of general psychiatry.

[17]  P. Costa,et al.  Domains and facets: hierarchical personality assessment using the revised NEO personality inventory. , 1995, Journal of personality assessment.

[18]  Robert A. Bornstein,et al.  The Wechsler Memory Scale—Revised , 1990 .

[19]  A. Hoes.  Case-control studies. , 1995, The Netherlands journal of medicine.

[20]  D. Blake,et al.  Dysbindin, a Novel Coiled-coil-containing Protein That Interacts with the Dystrobrevins in Muscle and Brain* , 2001, The Journal of Biological Chemistry.

[21]  Ivan Nikolov,et al.  Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria , 2004, Biological Psychiatry.

[22]  R. Bagby,et al.  Relationship between the five-factor model of personality and unipolar, bipolar and schizophrenic patients , 1997, Psychiatry Research.

[23]  T. Goldberg,et al.  Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia. , 1997, Archives of general psychiatry.

[24]  R. Straub,et al.  Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. , 2002, American journal of human genetics.

[25]  Marcia A. Bockbrader,et al.  Personality traits in schizophrenia and related personality disorders , 2005, Psychiatry Research.

[26]  Birgit Funke,et al.  Genetic variation in DTNBP1 influences general cognitive ability. , 2006, Human molecular genetics.

[27]  Adrian Raine,et al.  The SPQ-B: A brief screening instrument for schizotypal personality disorder. , 1995 .

[28]  Gerome Breen,et al.  Genetic Variation , 2020, Population Genetics with R.

[29]  P. Sullivan,et al.  Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families. , 2003, Molecular Psychiatry.

[30]  Richard Coppola,et al.  The G72/G30 Gene Complex and Cognitive Abnormalities in Schizophrenia , 2006, Neuropsychopharmacology.

[31]  Paul J. Harrison,et al.  Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence , 2005, Molecular Psychiatry.

[32]  Takahisa Taguchi,et al.  Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. , 2004, Human molecular genetics.

[33]  M C O'Donovan,et al.  The molecular genetics of schizophrenia: new findings promise new insights , 2004, Molecular Psychiatry.

[34]  Derek J. Blake,et al.  Different Dystrophin-like Complexes Are Expressed in Neurons and Glia , 1999, The Journal of cell biology.

[35]  Luba Kalaydjieva,et al.  Genetic evidence for a distinct subtype of schizophrenia characterized by pervasive cognitive deficit. , 2005, American journal of human genetics.

[36]  M. Schlossberg.  The Halstead-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation. , 1986 .

[37]  M. Gill,et al.  Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study , 2007, Neuropsychologia.

[38]  G. Feng,et al.  Family-based association study of DTNBP1 in 6p22.3 and schizophrenia , 2003, Molecular Psychiatry.

[39]  I. Skre,et al.  Schizotypal personality disorder inside and outside the schizophrenic spectrum , 2002, Schizophrenia Research.

[40]  David Goldman,et al.  DISC1 and neurocognitive function in schizophrenia , 2005, Neuroreport.

[41]  Michele Tansella,et al.  Association study of dysbindin gene with clinical and outcome measures in a representative cohort of Italian schizophrenic patients , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[42]  W. Maier,et al.  Personality variations in healthy relatives of schizophrenics , 1994, Schizophrenia Research.

[43]  J. Endicott,et al.  Crossing the border into borderline personality and borderline schizophrenia. The development of criteria. , 1979, Archives of general psychiatry.

[44]  Daniel R Weinberger,et al.  Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. , 2004, Archives of general psychiatry.

[45]  Dysbindin-1 and schizophrenia: from genetics to neuropathology. , 2004, The Journal of clinical investigation.

[46]  Lin He,et al.  Association study between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia: A meta-analysis , 2007, Schizophrenia Research.

[47]  J. M. Digman.  PERSONALITY STRUCTURE: EMERGENCE OF THE FIVE-FACTOR MODEL , 1990 .

[48]  Birgit Funke,et al.  DTNBP1 genotype influences cognitive decline in schizophrenia , 2007, Schizophrenia Research.

[49]  Michael J Owen,et al.  Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia? , 2005, Schizophrenia bulletin.

[50]  C. Stefanis,et al.  Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele , 2002, Molecular Psychiatry.

[51]  R. Straub,et al.  Significant correlation in linkage signals from genome-wide scans of schizophrenia and schizotypy , 2007, Molecular Psychiatry.

[52]  J. Waddington,et al.  Susceptibility genes for schizophrenia: Characterisation of mutant mouse models at the level of phenotypic behaviour , 2007, Neuroscience & Biobehavioral Reviews.

[53]  Danielle Posthuma,et al.  A genomewide scan for intelligence identifies quantitative trait loci on 2q and 6p. , 2005, American journal of human genetics.

[54]  J. Coyle,et al.  Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis , 2006, Cellular and Molecular Neurobiology.

[55]  Frank Baas,et al.  Association between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings , 2007, Behavioral and Brain Functions.

[56]  Hai-Gwo Hwu,et al.  Neuregulin 1 gene and variations in perceptual aberration of schizotypal personality in adolescents , 2005, Psychological Medicine.

[57]  Raquel E Gur,et al.  Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. , 2004, The Journal of clinical investigation.

[58]  H. Berenbaum,et al.  Schizophrenia and personality: exploring the boundaries and connections between vulnerability and outcome. , 1994, Journal of abnormal psychology.

[59]  I Daum,et al.  Memory dysfunction of the frontal type in normal ageing. , 1996, Neuroreport.

[60]  J. Angst,et al.  Premorbid personality of depressive, bipolar, and schizophrenic patients with special reference to suicidal issues. , 1986, Comprehensive psychiatry.

[61]  R. Brickenkamp,et al.  D2 Test of Attention , 1998 .