A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population
Introduction
The dimensional view of schizophrenia suggests that schizotypal personality traits, which are present in the normal population, are genetically related to schizophrenia (Lenzenweger and Loranger, 1989, Kendler et al., 1993, Tsuang et al., 1999). A number of studies have shown that schizotypal traits may reflect a spectrum of variation describing a predisposition to psychotic disorders (Claridge, 1987, Tyrka et al., 1995). Studies of schizotypal traits may thus facilitate the dissection of genetic components of schizophrenia (Winterer et al., 2001).
Several questionnaires or scales have been developed to assess schizotypal traits (Eysenck and Eysenck, 1975, Nielsen and Petersen, 1976, Chapman et al., 1976, Chapman et al., 1978, Claridge and Broks, 1984, Raine, 1991). Among them, the self-report Schizotypal Personality Questionnaire (SPQ) was developed from the DSM-III-R criteria for schizotypal personality disorder (Raine, 1991). The SPQ is a 74-item self-reported questionnaire with a true or false response to each item. Scores on nine schizotypal components or subscales can be assigned by summating related items (Raine, 1991). Factor analysis of the SPQ showed that questionnaire items of schizotypal traits can be reduced to three latent factors (cognitive–perceptual, interpersonal, and disorganized) (Raine et al., 1994, Vollema and Hoijtink, 2000). Extensive studies using community and college samples showed the SPQ is a sound psychometric and multidimensional questionnaire for assessing schizotypal traits (Raine, 1991). Furthermore, subjects with high SPQ scores demonstrate deficits similar to those observed in schizophrenia (Daneluzzo et al., 1998), a finding that suggests the SPQ could be an indicator of the genetic vulnerability to schizophrenia.
Studies attempting to identify susceptibility genes for schizophrenia have suggested the presence of schizophrenia-related gene(s) on the chromosome 22q region (Collier and Li, 2003). Two genes in this region, catechol-O-methyltransferase (COMT) and proline dehydrogenase (PRODH) in 22q11.2, have attracted considerable attention. COMT is an enzyme that plays an important role in the metabolism of dopamine, and dopamine has long been thought to play an important role in the pathogenesis of schizophrenia. Several family studies have shown the high activity allele of the functional Val-158-Met polymorphism to be preferentially transmitted to schizophrenic offspring (Li et al., 1996, Li et al., 2000, Kunugi et al., 1997, Egan et al., 2001) though some negative studies have also been reported (Strous et al., 1997, Karayiorgou et al., 1998, Wei and Hemmings, 1999). Furthermore, Avramopoulos et al. found that healthy young males with the COMT high activity allele of the Val158Met polymorphism had higher scores on the SPQ (Avramopoulos et al., 2002). The PRODH gene has also been previously reported to be in linkage disequilibrium (LD) with schizophrenia (Liu et al., 2002, Li et al., 2004) though some studies failed to support the association (Fan et al., 2003, Williams et al., 2003). In addition, hyperprolinemia due to PRODH gene deletions were found in a subset of schizophrenic patients (Jacquet et al., 2002).
The brain-derived neurotrophic factor (BDNF) gene, located on 11p13, is a member of the neurotrophic factor family which plays important roles in the development of the brain (Hanson et al., 1992). It has critical effects on the development of dopaminergic related systems. BDNF also interacts with the mesolimbic DA system and is implicated in the response to antipsychotic drugs (Guillin et al., 2001). Durany et al. reported changes in the expression of BDNF in the brain of patients with schizophrenia (Durany et al., 2001). A number of studies also found evidence that a valine-to-methionine variation at codon 66 of the BDNF gene coding sequence (rs6265) is associated with psychotic disorders (Neves-Pereira et al., 2002, Neves-Pereira et al., 2005, Szekeres et al., 2003, Egan et al., 2003, Sklar et al., 2002). Jönsson et al. (2006) did not find significant association between the BDNF Val66Met polymorphism and schizophrenia in their own case-control study. However, a meta-analysis that combined data from 11 published case-control studies (6217 subjects in total) showed a significant association between Val66Met homozygosity and schizophrenia, suggesting the need for further study (Jönsson et al., 2006).
These studies have suggested that COMT, PRODH and BDNF are possible susceptibility genes for schizophrenia, though there is still no consensus regarding their association with the disease. Extensive genetic replication, the assessment of gene–environment interaction and functional biological analysis will be needed to identify robustly associated haplotypes and causal alleles. In addition, exploring the influence of these and other genes on schizotypal traits, which are both heritable and genetically related to schizophrenia, may facilitate the understanding of its genetic etiology. To test the hypothesis that the COMT, PRODH and BDNF genes are associated with schizotypy, we genotyped five single nuclear polymorphisms (SNPs) in these genes, all of which have been previously associated with schizophrenia, and performed association analyses between alleles, genotypes, or haplotypes of these, and quantitative schizotypal trait scores in a Chinese healthy population.
Section snippets
Subjects
A stratified random sampling procedure was used to recruit 465 healthy community dwelling adults from five urban districts in Chengdu city, Sichuan province, China. The sample were representative of the urban population in China according to the year 2000 Chinese census in terms of gender, age and years of education. Written informed consent was obtained from all subjects after full explanation of the study aims and procedures. A history of medical and psychiatric problems was obtained from
Demographic characteristics
There were 231 male and 234 female participants. Their ages ranged from 16 to 75 years old (34.90 ± 12.80), and years of education from 1 to 23 years (10.17 ± 3.74). There were 454 right-handed subjects, 4 left-handed subjects, and 7 mixed-handed subjects. General demographic characteristics of all participants and distributions of three SPQ dimensions scores and total SPQ score were presented in Table 1. There were no significant differences between males and females regarding age, education
Discussion
In the current study we tested the hypothesis that the COMT, PRODH and BDNF genes are associated with schizotypy, using SNPs in these genes and quantitative schizotypal trait scores in a healthy Chinese population. We found that education had an effect on seven out of nine schizotypal subscales, three schizotypal factors and the total scores of the SPQ, which contributed to 1.3–8.6% of the variance (Table 2). In addition, gender had small effects on two of the schizotypal subscales (odd or
Acknowledgements
This work was partly supported by funding from the Chinese National Natural Science Foundation (TL, Outstanding Youth Award), the Wellcome Trust (TL, DAC, PS), NARSAD (TL), and the Schizophrenia Research Fund (TL).
References (61)
- et al.
A general test of association for quantitative traits in nuclear families
American Journal of Human Genetics
(2000) - et al.
Schizotype and hemisphere function. I. Considerations and the measurement of schizotype
Personality and Individual Differences
(1984) - et al.
The genetics of schizophrenia: glutamate not dopamine?
European Journal of Pharmacology
(2003) - et al.
Schizotypal Personality Questionnaire and Wisconsin Card Sorting Test in a population of DSM-III-R schizophrenic patients and control subjects
Comprehensive Psychiatry
(1998) - et al.
A family-based association study of T1945C polymorphism in the praline dehydrogenase gene and schizophrenia in the Chinese population
Neuroscience Letters
(2003) - et al.
The human BDNF gene maps between FSHB and HVBS1 at the boundary of 11p13–p14
Genomics
(1992) - et al.
No linkage or linkage disequilibrium between brain-derived neurotrophic factor (BDNF) dinucleotide repeat polymorphism and schizophrenia in Irish families
Psychiatry Research
(1998) - et al.
An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients
Neuroscience Letters
(2003) - et al.
Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: an association study
Progress in Neuro-Psychopharmacology & Biological Psychiatry
(2006) - et al.
Identification of sequence variants and analysis of the role of the catechol-O-methyl-transferase gene in schizophrenia susceptibility
Biological Psychiatry
(1998)
Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder
Neuroscience Letters
The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study
American Journal of Human Genetics
Molecular genetics of affective disorders
Progress in Neuro-Psychopharmacology & Biological Psychiatry
A highly significant association between a COMT haplotype and schizophrenia
American Journal of Human Genetics
Variation in catechol-O-methyltransferase val158 met genotype associated with schizotypy but not cognition: a population study in 543 young men
Biological Psychiatry
Lack of association of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia
Biological Psychiatry
The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia
Schizophrenia Research
Association study of schizophrenia with polymorphisms at six candidate genes
Schizophrenia Research
An association between reduced interhemispheric EEG coherence in the temporal lobe and genetic risk for schizophrenia
Schizophrenia Research
Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele
Molecular Psychiatry
Scales for physical and social anhedonia
Journal of Abnormal Psychology
Body image aberration in schizophrenia
Journal of Abnormal Psychology
The schizophrenias as nervous types' revisited
British Journal of Psychiatry
Genomic scan for genes predisposing to schizophrenia
American Journal of Medical Genetics
Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenia psychoses
Schizophrenia Research
Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia
Proceedings of the National Academy of Sciences of the United States of American
Schizophrenia, III: brain-derived neurotropic factor and genetic risk
American Journal of Psychiatry
Manual of the Eysenck Personality Questionnaire
A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12. Schizophrenia Collaborative Linkage Group (Chromosome 22)
American Journal of Medical Genetics
Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies
The American Journal of Psychiatry
Cited by (45)
Interaction of multiple gene variants and their effects on schizophrenia phenotypes
2016, Comprehensive PsychiatryTemperament and character in remitted and symptomatic patients with schizophrenia: Modulation by the COMT Val158Met genotype
2014, Journal of Psychiatric ResearchDisentangling the molecular genetic basis of personality: From monoamines to neuropeptides
2014, Neuroscience and Biobehavioral ReviewsCitation Excerpt :In the context of schizotypy, studies by Avramopoulos et al. (2002), Smyrnis et al. (2007) and Grant et al. (2013) point toward the homozygous Val/Val variant being associated with highest schizotypal trait scores. Other studies reported either the contrary finding or rather weak effects, which turned out to be of relevance for males only (Ma et al., 2007; Sheldrick et al., 2008). In addition to the COMT gene, the genes encoding for dopamine D2 (Reuter et al., 2006; Smillie et al., 2010; Tsuchimine et al., 2012) and dopamine D4 receptors (Munafò et al., 2008), as well the dopamine transporter (DAT; Felten et al., 2011; Kazantseva et al., 2011) have been strongly investigated in personality research.
Evidence of a dimensional relationship between schizotypy and schizophrenia: A systematic review
2013, Neuroscience and Biobehavioral ReviewsSchizophrenia and Affective Disorders
2013, Emery and Rimoin's Principles and Practice of Medical GeneticsSchizophrenia and related disorders
2012, Core Psychiatry: Third Edition