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Keywords:

  • ADHD;
  • catechol-O-methyltransferase gene;
  • schizotypy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHOD
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Abstract  Previous research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of Schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHOD
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

There is evidence of clinical and neurocognitive overlap between psychosis and attention deficit hyperactivity disorder (ADHD).1–4 For example, deficits on measures of attention are associated with increased risk of psychosis in children of a schizophrenic parent, and ADHD behaviors may be precursors of schizophrenia.5,6 Schizotypy, that is, the subclinical expression of schizophrenia signs and symptoms, is also associated with increased risk of psychosis.7 However, the relationship between ADHD and schizotypy has been little investigated.

One study found that schizophrenia patients’ relatives with ADHD had higher schizotypy levels than controls or relatives without DSM-IV Axis-I disorders.8 However, ADHD subjects in the sample had considerable comorbidity, making it difficult to estimate whether schizotypal traits stemmed from this comorbidity or were specifically associated with ADHD. Additionally, that study did not investigate whether the relationship is also found in individuals without increased genetic risk for schizophrenia.

One reason for the observed association between schizophrenia and ADHD might lie in dopaminergic (DA) mechanisms, given that changes in cortico-subcortical DA neurotransmission occur in both disorders.9,10 Also, DA gene polymorphisms are thought to confer vulnerability to both schizophrenia and ADHD. Among the most widely studied of these are polymorphisms on genes coding for the dopamine transporter (SLC6A3), catechol-O-methyltransferase (COMT), and dopamine receptors of the D3 (DRD3) and D4 type (DRD4). These genes have been implicated in schizophrenia and ADHD on the basis of their involvement in DA neurotransmission and in neurocognitive deficits seen in both conditions, such as executive dysfunction.10–12 COMT genotype was recently shown to be associated with ADHD features13 and schizotypy14 in healthy individuals.

We investigated the relationship between schizotypy and ADHD features. Additionally, we explored effects of polymorphisms in genes coding for proteins implicated in the dopamine system. We studied psychiatrically healthy men without a family history of schizophrenia or ADHD to exclude effects of these potential confounds.

METHOD

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHOD
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Participants

Caucasian men were recruited through advertisements at McGill University. Exclusion criteria were DSM-III Axis-I diagnosis,15 current physical illness, first-degree relatives with schizophrenia or ADHD,16 and current drug abuse (established using the Triage Drug of Abuse Panel, Biosite Diagnostics, San Diego, CA, USA) or any medication. Written, informed consent was obtained and ethical permission was granted (Douglas Hospital, McGill University).

Questionnaires

Participants completed the Rust Inventory of Schizotypal Cognitions (RISC17) and the World Health Organization Adult ADHD Self-Report Scale (ASRS18). One missing value each occurred for RISC and ASRS. The RISC is a 26-item measure of positive schizotypy, including items on abnormal perceptual experiences, thought disorder, and magical thinking. Each item is scored from 0 to 3. Higher scores indicate more schizotypal symptoms. The ASRS is an 18-item measure of the DSM-IV-TR criteria for ADHD. Each item is scored from 0 to 4. Higher scores indicate more ADHD-like features.

Genotyping

DNA was extracted from blood samples and processed using established protocols.19,20 The DRD4 variable number of tandem repeats (VNTR), DRD3 Ser9Gly, COMT Val158Met, and SLC6A3 VNTR polymorphisms were analyzed.19,20

Statistical analysis

Pearson correlation was used to investigate the relationship between the RISC and the ASRS. Partial correlation was used to explore this relationship while covarying for age and years of education. Analysis of variance (anova) was carried out for each polymorphism separately with genotype as the independent variable and psychometric scores as dependent variables. The alpha level was adjusted for multiple comparisons (0.05/8 = 0.00625). Significant effects were then followed up with independent samples t-tests adjusting the alpha level by the number of comparisons (e.g. for COMT: 0.05/3 = 0.0167).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHOD
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

The sample consisted of 31 participants (mean age: 26.93 ± 5.56 years; range: 19–37 years). Participants had a mean of 16 ± 1.08 years of full-time education. Descriptive statistics of questionnaire scores are summarized in Table 1.

Table 1.  Descriptive statistics of questionnaire scores
 MeanSDRange
  1. ASRS, Attention deficit hyperactivity disorder Self-Report Scale;18 RISC, Rust Inventory of Schizotypal Cognitions.17

RISC24.3710.916–44
ASRS21.77 6.618–33

RISC and ASRS scores were significantly correlated (r = 0.54, P = 0.003; Fig. 1). This correlation held when covarying for age and years of education (r = 0.56, P = 0.003).

image

Figure 1. Association between Rust Inventory of Schizotypal Cognitions17 (RISC) and ADHD Self-Report Scale18 (ASRS) scores (r = 0.54, P = 0.003).

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Allele frequencies for SLC6A3 were 22.58% (nine repeats) and 77.42% (10 repeats), distributed across the following genotypes: 9/9 (n = 2), 9/10 (n = 10), and 10/10 (n = 19; Table 2). Because of the small number of 9/9 homozygotes, we pooled nine-repeat allele carriers (n = 12) and compared these to 10-repeat homozygotes.

Table 2.  Descriptive statistics of schizotypy and ADHD scores by genotype
 SLC6A3DRD3DRD4COMT
9/9, 9/1010/10Ser/SerSer/GlyGly/Gly7-repeat carriersNon-carriersVal/ValVal/MetMet/Met
  1. ASRS, Attention deficit hyperactivity disorder Self-Report Scale;18 RISC, Rust Inventory of Schizotypal Cognitions.17

RISC23.00 (11.84)25.63 (10.55)22.50 (8.80)21.60 (11.33)34.83 (10.13)22.00 (10.03)25.64 (11.28)17.63 (9.26)25.42 (10.20)29.40 (10.96)
n = 11n = 19n = 14n = 10n = 6n = 8n = 22n = 8n = 12n = 10
ASRS21.58 (6.13)21.89 (7.09)19.15 (6.23)21.82 (5.83)27.33 (5.61)21.38 (7.29)21.91 (6.52)16.56 (4.93)22.55 (6.79)25.60 (4.88)
n = 12n = 18n = 13n = 11n = 6n = 8n = 22n = 9n = 11n = 10

Allele frequencies for DRD4 were 4.84% (two repeats), 77.42% (four repeats), 1.61% (five repeats), 1.61% (six repeats), 12.90% (seven repeats), and 1.61% (nine repeats), distributed across the following genotypes: 2/4 (n = 3), 4/4 (n = 19), 4/7 (n = 6), 4/9 (n = 1), 5/7 (n = 1) and 6/7 (n = 1; Table 2). We pooled carriers of the seven-repeat allele (n = 8) and compared these to seven-repeat allele non-carriers (n = 13).

For COMT, there were nine Val/Val, 12 Val/Met, and 10 Met/Met (Table 2). For DRD3, there were 14 Ser/Ser, 11 Ser/Gly, and six Gly/Gly (Table 2). Neither allele distribution differed significantly from the Hardy–Weinberg equilibrium.

The COMT genotype had a significant effect on the ASRS, F(2,29) = 6.18, P = 0.006: ASRS scores were highest in Met homozygotes, intermediate in heterozygotes, and lowest in Val homozygotes. The comparison between Met and Val homozygotes was significant (P = 0.005; all other comparisons P > 0.07). Val and Met homozygotes did not differ on age or years of education (both P > 0.20). anova revealed no significant effects of genotype on the RISC and no effects of DRD3, SLC6A3, or DRD4 on the ASRS using the aforementioned adjustment for multiple comparisons (all P > 0.03).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHOD
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

The present findings point to an association between subclinical schizophrenia-like and ADHD-like features in psychiatrically and medically healthy men. This finding extends a previous observation of increased levels of schizotypal personality traits in schizophrenia patients’ relatives with a diagnosis of ADHD.8 Importantly, the present design confirms the existence of this relationship in the absence of psychiatric diagnoses, genetic liability for schizophrenia or ADHD, and potential confounds such as drug abuse.

Future studies might investigate whether these dimensions reflect independent or overlapping predictors of psychosis by using prospective designs.6,7 Future research might also investigate whether the observed relationship may be accounted for by individual differences in neuroticism, which is known to be associated with a number of psychiatric symptom dimensions.21

We also explored the relationship between ADHD and schizotypy levels on the one hand and DA gene polymorphisms on the other hand. Although there was no significant relationship between schizotypy and polymorphisms in the present study, COMT Met homozygotes had higher levels of ADHD features than Val homozygotes; heterozygotes’ scores fell between the two homozygote groups. The relationship between COMT and ADHD features is consistent with a previous study of the genetic correlates of the ASRS.13 In that previous study of healthy Caucasian subjects, Met homozygotes scored higher than Val homozygotes or heterozygotes.13 The involvement of COMT genotype in ADHD is compatible with a large body of research suggesting dopaminergic mechanisms in the pathophysiology and treatment of ADHD.10 However, there is inconsistent evidence concerning a relationship between COMT genotype and full-blown ADHD.11

The primary limitation of the current study is the small sample size. Therefore, our findings should be interpreted with caution and need to be replicated using larger samples. Additionally, COMT allele frequencies differed slightly from previous large-scale studies,12,13 specifically in terms of the relatively low frequency of heterozygotes in the present study. This may suggest the possible operation of sampling bias in this highly selected sample of healthy Caucasian men.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHOD
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

This work was supported by a Richard H. Tomlinson Postdoctoral Research Fellowship (Dr Ettinger), a grant from the G.W. Stairs Memorial Fund (Dr Ettinger), a Canadian Institute of Health Research operating grant (Dr O’Driscoll) and a William Dawson Scholar Award (Dr O’Driscoll). Dr Ettinger is supported by the Leverhulme Trust (ECF/2004/0370) and ESRC/MRC (PTA-037-27-0002).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHOD
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES
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