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Delusional disorder is characterized by monosymptomatic paranoid symptoms, and in contemporary classifications of mental disorders, delusions are considered as cornerstone symptoms for the diagnosis of psychotic disorders. Since the beginning of psychiatry, delusional disorder has been a central subject of attention and continues to engender controversy right up to the present. Delusional formation is a fascinating and enigmatic psychic process that has been the subject of numerous scientific debates and theoretical models; however, surprisingly few empirical studies have been done (1,2). Delusions are understood to mean intersubjectively disconcerting convictions, with a tendency toward subjective certainty, that lose their disconcerting character when made the object of psychiatric analysis. Delusions involve thought contents and, as such, tend to be idiosyncratic and richly varied. Delusional disorder comprises an uncommon and probably heterogeneous group of illnesses; it is complicated by more than 100 conditions and agents, including neurologic disorders, metabolic and endocrine disorders, infections, pharmacologic agents, alcohol and other substances, and psychiatric disorders (3). Although its prevalence is low, delusional disorder is not rare (4). Recent studies have revealed that delusional disorder is underdiagnosed, which results in poor anticipation of its implications (5). The underlying etiologic mechanism and the pathophysiology of delusional disorder are poorly understood. Etiologic explanations range from theories based on individual life history factors (6) to biological theories based on organic brain factors (7). Although epidemiologic and clinical studies suggest that certain risk factors, such as advanced age, sensory impairment, personality features (8), and family history (9) may be relevant to etiology, the strength of their associations with delusional disorder varies. Familial aggregation of the disease has been proposed by many investigators (10); however, the exact role of hereditary factors in the etiology of delusional disorder remains controversial. Since delusional disorder is characterized by monosymptomatic paranoid symptoms, several investigators have suggested that delusional disorder is a naturally occurring model psychosis based on abnormalities of the dopaminergic temporolimbic system (11). Molecular genetic evidence for this dopamine hypothesis of delusional disorder has been supported by a few studies on D2 receptor variation (12) and D4 receptor Exon 3 variation (13). However, many other studies do not support these findings (14). They indicate that, although such variation may be connected with delusional symptomatology, the variations do not play a major role in conferring susceptibility to delusional disorder on patients (15). In the apparent absence of a single pathogenic mutation, the human leukocyte antigen (HLA) system has been considered to test whether HLA proteins confer susceptibility to delusional disorder on patients. Several significant associations have been found between HLA proteins and different diseases. In many diseases, but not in all, immunologic abnormalities are evident. Many psychiatric conditions, such as psychosis, depression, and anxiety, have been considered as autoimmune disorders (16). Researchers have postulated that autoimmune mechanisms account in part for schizophrenia and have found that schizophrenia patients with an affected first-degree relative are significantly more likely to have a parent or sibling with an autoimmune disease (17). So far, there is not a single report available regarding the involvement of immune abnormality in patients with delusional disorder. Considering the uniqueness of delusional disorder and the above-noted advances in the arena of biological psychiatry, we were stimulated to explore a possible immunogenetic etiology by conducting a study of the association of HLAs with delusional disorder. Materials and MethodsSubjects We recruited subjects from an India-born Bengali population referred to the psychiatric outpatient department at North Bengal Medical College and Hospital. On average, 1500 new patients with various psychiatric illnesses and about 4000 recurrent follow-up cases attend the outpatient department every year. We recruited 150 unrelated patients (82 women and 68 men) with the symptom of delusions and studied them for 5 years. All subjects were screened independently by 2 psychiatrists using the Structured Clinical Interview for DSM-IV (SCID) to determine a diagnosis of delusional disorder (18). After longitudinal follow-up, we made the following diagnostic assessments: 80 patients represented genuine cases of delusional disorder of various subtypes; 40 patients turned out to have paranoid schizophrenia; 8 patients showed the features of dementia; 14 patients were suffering from alcohol withdrawal; and 8 patients had mood-congruent delusions. We compared delusional disorder patients with and without comorbid diagnoses to investigate whether the presence of another psychiatric disorder influenced the clinical features of the illness. The distribution of delusional disorder subtypes, as defined by DSM-IV criteria, was as follows: 62.5% persecutory, 12.5% mixed, 12.5% jealous, 6.25% somatic, 3.75% erotomanic, and 2.5% grandiose. Most patients were clustered between the ages of 25 and 55 years. Of the initial 150 patients, we excluded from the patient group the 70 patients suffering from psychiatric conditions other than delusional disorder. Eighty healthy individuals belonging to the same ethnic group as the patients were used as control subjects. Control subjects were mainly selected from the university as well as from hospital employees. We also recruited some of the healthy donors from members of the psychiatric outpatient department who accompanied the patients from time to time. We screened the control subjects for a recent history of intercurrent infections and allergies and excluded those with a past history of autoimmune or psychiatric disorders. All the patients and control subjects gave informed consent and were matched for sex, age, and other socioeconomic variables. The subjects were mostly from middle-class urban and semirural society and belonged to a nuclear family. The above-mentioned medical college is one of the rural medical institutes in India; the scenario has changed, in that formerly extended Indian families are becoming nuclear. Methodology We obtained approximately 5 mL of blood from each individual. Serological typing of class I HLA antigens was done with the standard 2-stage microlymphocytotoxicity assay in 72-well Terasaki trays (19). We used 37 antigen specificities to detect the frequency of different class I antigens in the initial 150 patients. We performed molecular typing only on the final 80 patients with delusional disorder and the equal number of healthy control subjects. We obtained DNA from peripheral mononuclear cells in ethylene diamine tetra acetate anticoagulant, using a salting out procedure (20). We carried out molecular typing using polymerase chain reaction sequence-specific primer (PCR-SSP) technique to detect HLA class I genes (Figure 1). The primers, Taq polymerase, nucleotides, and other reagents were obtained from Bangalore Genei, India, and the typing and sequence information on primers were taken from Bunce and colleagues (21). Figure 1 Electrophoregram showing the results of HLA- A*03, A*11, A*24, 
Statistical Analysis We calculated the phenotype frequencies by direct count. We compared the frequency of each antigen in the patient group as a whole with that of the control population, using the chi-square test followed by Fisher’s exact test. Testing for a large number of antigens can reveal at least one positive association where none really exists; to be statistically significant, therefore, the P values from each Fisher’s exact test had to be less than the Bonferroni P (0.05 divided by the number of antigens tested [n = 37] minus 2 degrees of freedom [1 for each of the 2 loci examined], which equals 0.0014). We estimated relative risk (RR) as recommended by Svejgaard and colleagues (22). ResultsAs noted above, serological typing was done for all 150 patients first enrolled for the study; however, molecular typing was done for only the final 80 patients with delusional disorder. The data shown in Table 1 are the results of molecular typing because for allele assignment this typing provides better resolution than does serological typing. The results demonstrate a marked elevation (60%) of the frequency of HLA-A*03 (c2 = 32.66, P < 0.01) in patients with delusional disorder, compared with healthy control subjects (15%); the P value after Bonferroni correction was significant. In addition, we also observed an increased frequency of HLA-A*11 (28.75 % vs 15%) in the patients with delusional disorder, although it was not significant after Bonferroni correction.
DiscussionSeveral studies have been done on the associations between HLA and schizophrenia as well as on reported associations of A9 or its A24 subspecificity, A28, A10, DRB1*01, and DRw6 with schizophrenia as a whole (23). Paranoid (delusional) disorders are usually thought to overlap with schizophrenic disorders, and a continuum may exist, especially with paranoid schizophrenia (24). At least 7 studies have shown HLA-A9 to be elevated in patients with paranoid schizophrenia (25). The diagnostic value of delusional phenomena is still a controversial issue in psychiatry. This problem is related to the fact that the specific link between certain delusional symptoms and particular etiologies has not yet been completely clarified. To our knowledge, the present investigation is the first report on possible associations between delusional disorder and HLA. We found a significant association between delusional disorder and HLA-A*03. When the strength of association was measured by cross-product ratio or the RR of developing a disease, A*03 showed a high value (that is, RR 8.5) reflecting a strong positive association. However, the exact nature of the mechanism underlying the empirically observed association between the HLA-A*03 antigen and delusional disorder is not fully understood. This result could not be an artifact arising from inadvertent ethnic mismatching of patients and control subjects because there is no ethnic group known for which the HLA-A*03 frequency is higher than about 19%. The pattern of HLA-A3 prevalence in various ethnic groups on the Indian subcontinent and in several other countries is as follows: 15.5% in a South African San population, 4.8% in a Mongolian population, 12.9% in an Italian population, 6.6% in Australian Aborigines, and 6.0% in Indian tribes (26). More interestingly, the frequency of the A3 antigen in 2 other major populations in our region is 18.52% (in a Rajbanshi population, 27) and 12% (in a Gurkha population, 28). Several findings suggest that immunologic dysfunctions may have relevant implications for the etiology of schizophrenia. It has also been postulated that viral infections and (or) autoimmune reactions against central nervous structures may play an important role in the disease pathogenesis (29). A few studies have also correlated the associations of HLA and the influence of prenatal infections and winter birth with schizophrenia (30). Currently, we are not in a position to propose the autoimmune pathogenicity of delusional disorder, but we can assume the possible existence of a susceptibility locus within the HLA region. It is premature to conclude that the HLA-A*03 gene is the sole determinant of delusional disorder; however, this significant association may contribute to the disease risk, or there may be a separate susceptibility gene in strong linkage disequilibrium with the A*03 gene. The presence of A*24 (subtype of A9) is not statistically significant in patients with delusional disorder. However, without Bonferroni correction, we observed a moderately strong association of A*11 in these patients; this coincided with the findings of Alexander and colleagues, who reported an association between HLA-A11 and paranoid schizophrenia (31). Considering the data and strength of the association, it is too early to propose that delusional disorder has any etiologic similarity with paranoid schizophrenia. The diagnostic criteria for paranoid schizophrenia are strictly defined. However, as far as diagnosis is concerned, the diagnostic criteria of DSM-IV are more reliable in defining the phenotypic specificity of delusional disorder. Our result is preliminary and, so far, is not correlated with parameters like birth status, viral infections, or prenatal infections. Extensive further study is presently underway in our laboratory, concerning the pattern of HLA haplotype inheritance in affected families and also in different clinical subgroups. Findings from that research will help to determine the validity and specificity of the A*03 gene as a genetic marker for delusional disorder. References1. Butler RW, Braff DL. Delusions: a review and integration. Schizophr Bull 1991;17:633–47. 2. Berrios GE. Delusions as ‘wrong beliefs’: a conceptual history. Br J Psychiatry 1991;159(Suppl 14):6–13. 3. Manchreck TC. Delusional disorder and shared psychotic disorder. In: Saddock BJ, Saddock VA, editors. Comprehensive textbook of psychiatry. Hagerstown (MD): Lippincott Williams & Wilkins; 1999. p 1243–64. 4. Manchreck TC. Delusional disorder: the recognition and management of paranoia. J Clin Psychiatry 1996;57:32–8. 5. Ulzen TP, Carpentier R. The delusional parent family and multisystemic issues. Can J Psychiatry 1997;42:617–22. 6. Gabriel E. Continental view points on the concept of reactive psychoses. Psychopathology1987;20:87–91. 7. Munro A. Delusional (paranoid) disorders: etiologic and taxonomic considerations. I. The possible significance of organic brain factors in etiology of delusional disorders. Can J Psychiatry 1988;33:171–4. 8. Kendler KS, Hays P. Paranoid psychosis (delusional disorder) and schizophrenia. A family history study. Arch Gen Psychiatry1981;38:547–51. 9. Kaplan HI, Saddock BJ, Grebb JA. Delusional disorder. In: Kaplan HI, Saddock BJ, editors. Synopsis of psychiatry. 7th ed. New Delhi (India): BI Waverly Pvt Ltd; 1994. p 503–9. 10. Winokur G. Classification of chronic psychoses including delusional disorders and schizophrenia. Psychopathology 1986;19:30–4. 11. Munro A. Delusional disorders are a naturally occurring ‘experimental psychosis’. Psychopathology 1994;27:247–50. 12. Serretti A, Lattuada E, Lorenzi C, Lilli R, Smeraldi E. Dopamine receptor D2Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses. Mol Psychiatry 1999;5:270–4. 13. Serretti A, Lilli R, Lorenzani C, Lattuada E, Smeraldi E. DRD4 Exon 3 variants associated with delusional symptomatology in major psychoses: a study on 2,011 affected subjects. Am J Med Genet 2001;105:283–90. 14. Serretti A, Lilli R, Di Bella D, Bertelli S, Nobile M, Novelli E, and others. Dopamine receptor D4 gene is not associated with major psychoses. Am J Med Genet 1999;88:486–91. 15. Morimoto K, Miyatake R, Nakamura M, Watanabe T, Hirao T, Suwaki H. Delusional disorder: molecular genetic evidence for dopamine psychosis. Neuropsychopharmacology 2002;26:794–801. 16. Denburg SD, Carbotte RM, Denburg JA. Psychological aspects of systemic lupus erythematosus: cognitive function, mood, and self-report. J Rheumatology 1997;24:998–1003. 17. Wright P, Sham PC, Gilvary CM, Jones PB, Cannon M, Sharma T, and others. Autoimmune diseases in the pedigrees of schizophrenia and control subjects. Schizophr Res 1996;20:261–7. 18. American Psychiatric Association. Delusional disorder. In: Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): American Psychiatric Association; 1994. p 296–301. 19. Terasaki PI, McCelland JD. Microdroplet assay of human serum cytotoxins. Nature 1964;204:998–1000. 20. Miller SA, Dikes DED, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215. 21. Bunce M, O’Neill CM, Barnardo MCNM, Krausa P, Browning MJ, Morris PJ, and others. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 and DQB1 by PCR with 144 primer mixes utilizing sequence specific primers (PCR-SSP). Tissue Antigens 1995;46:355–67. 22. Svejgaard A, Jersild C, Nielsen LS, Bodmer WF. HLA antigens and disease. Statistical and genetical considerations. Tissue Antigens 1974;4:95–105. 23. Wright P, Nimgaonkar VL, Donaldson PT, Murray RM. Schizophrenia and HLA: a review. Schizophr Res 2001;47:1–12. 24. Munro A. Delusional (paranoid) disorders: etiologic and taxonomic considerations. I. A possible relationship between delusional and affective disorders. Can J Psychiatry1988;33:175–8. 25. McGuffin P, Stuart E. Genetic markers in schizophrenia. Hum Hered 1986;36:65–88. 26. Imanishi T, Akaza A, Kimura A, Tokunaga K, Gojabori T. Allele and haplotype frequencies of HLA and complement loci in various ethnic groups. In: Tsuji K, Aizawa M, Sasazuki T, editors. HLA 1991. Proceedings of the 11th International Histocompatibility Workshop and Conference. Volume 1. Oxford (UK): Oxford University Press; 1992. p 1064–74. 27. Mandal BB, Chaudhuri TK. HLA profile of Rajbanshi and Gurkha: a comparative account. In: Ghosal SK, Ray D, editors. Recent advances of animal science research. Volume 1. Calcutta: Orion Press International WB; 2000. p 121–5. 28. Chaudhuri TK, Mandal TK, Sen TK, Taneja V. Distribution of HLA antigens in Indian Gurkha population. Ind J Med Res 1995;101:170–2. 29. Kirch DG. Infection and autoimmunity as etiologic factors in schizophrenia: a review and reappraisal. Schizophr Bull 1993;19:355–70. 30. Narita K, Sasaki T, Akaho R, Okazaki Y, Kusumi I, Kato T, and others. Human leukocyte antigen and season of birth in Japanese patients with schizophrenia. Am J Psychiatry 2000;157:1173–5. 31. Alexander RC, Coggiano M, Daniel DG, Wyatt RJ. HLA antigens in schizophrenia. Psychiatry Res 1990;31:221–33. Author(s)Manuscript received September 2003, revised, and accepted July 2004. 1. Senior Research Fellow, Cellular Immunology Laboratory, Department of Zoology, University of North Bengal, Siliguri, WB, India. 2. Professor and Head, Department of Psychiatry, North Bengal Medical College and Hospital, Siliguri, WB, India. 3. Assistant Professor, Department of Psychiatry, North Bengal Medical College and Hospital, Siliguri, WB, India. 4. Systems’ Engineer and Head, Computer Centre, University of North Bengal, Siliguri, WB, India. 5. Associate Professor, Cellular Immunology Laboratory, Department of Zoology, University of North Bengal, Siliguri, WB, India. Address for correspondence: Dr TK Chaudhuri, Cellular Immunology Laboratory, Department of Zoology, University of North Bengal, Siliguri-734430, WB, India e-mail: dr_tkc_nbu@rediffmail.com
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