Objective: The etiology of delusional disorder is imperfectly understood. Involvement of biological factors has long been suspected. We examined the incidence of class I human leukocyte antigens (HLAs) in patients with delusional disorder to understand the role of HLA genes and explore a possible immunogenetic etiology for delusional disorder.
Methods: We used a nested case-control study design. Psychiatric reference data were available for 27 500 patients registered between 1998 and 2003. Initially, we enrolled 150 patients with delusional disorder from the India-born Bengali population, using DSM-IV diagnostic criteria. After longitudinal follow-up, 80 patients were found to have only delusional disorder, while the remaining 70 patients represented different illnesses with paranoid symptoms and were excluded. We performed serological typing on all 150 patients and applied the polymerase chain reaction-based high-resolution molecular typing method to the 80 patients with delusional disorder. Eighty healthy donors of the same ethnic background, matched for age, sex, and other socioeconomic variables, formed the control group.
Results: Some of the HLA alleles were associated with delusional disorder, and the gene HLA-A*03 was found to be significantly more frequent. This gene may influence patients' susceptibility to delusional disorder.
Conclusion: The study reveals important associations between HLA genes and delusional disorder. This preliminary observation may help our understanding of this disorder's genetic basis.
(Can J Psychiatry 2005;50:269-274)
Information on author affiliations appears at the end of the article.
Clinical Implications
* This preliminary study may help our understanding of the genetic basis of delusional disorder.
* The investigation may help others to understand whether human leukocyte antigen (HLA) genes are specifically related to certain etiologies.
* HLA-based studies may help to distinguish delusional entities present in a broad spectrum of psychiatric and medical conditions and may reduce possible diagnostic confusion.
Limitations
* The sample size was small, and the study needs to be repeated on a large cohort sample.
* We did not study the relations between drug efficacy and HLA genes.
* We did not perform family-based analyses.
Key Words: delusion, etiology, human leukocyte antigens, HLAs, association, paranoid symptoms
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, pharmacologie 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, immunologie 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 Methods
Subjects
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 IHLA 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).
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).
Results
As 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 (χ^sup 2^ = 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.
Discussion
Several studies have been done on the associations between HLA and schizophrenia as well as on reported associations of A9 or itsA24 subspecificity, A28, AlO, DRBl *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 ofHLA-AS 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 immunologie 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.
[Sidebar]
R�sum� : Une �tude des g�nes li�s aux antig�nes HLA dans un trouble psychotique monosymptomatique dans la population indienne bengalaise
Objectif : L'�tiologie du trouble d�lirant est imparfaitement comprise. La participation des facteurs biologiques est soup�onn�e depuis longtemps. Nous avons examin� l'incidence des antig�nes d'histocompatibilit� (HLA) de classe I chez les patients souffrant de trouble d�lirant, pour comprendre le r�le des g�nes HLA et explorer la possibilit� d'une �tiologie immunog�n�tique du trouble d�lirant.
M�thodes : Nous avons utilis� un mod�le de cas-t�moins embo�t�s. Les donn�es de r�f�rence psychiatriques �taient disponibles pour 27 500 patients, enregistr�es entre 1998 et 2003. Au d�part, nous avons inscrit 150 patients souffrant de trouble d�lirant de la population indienne bengalaise, � l'aide des crit�res diagnostiques du DSM-IV. Apr�s un suivi longitudinal, 80 patients n'avaient que le trouble d�lirant, alors que les 70 patients restants pr�sentaient diff�rentes maladies avec des sympt�mes parano�des, et ont �t� exclus. Nous avons proc�d� � un typage s�rologique sur tous les 150 patients, et appliqu� une m�thode de typage mol�culaire haute r�solution � base de r�action en cha�ne de la polym�rase aux 80 patients souffrant de trouble d�lirant. Quatre-vingts donneurs en sant� de la m�me origine ethnique, assortis selon l'�ge, le sexe et d'autres variables socio-�conomiques, formaient le groupe t�moin.
R�sultats : Certains des all�les HLA �taient associ�s au trouble d�lirant, et l'on a constat� que le g�ne HLA-A *03 �tait significativement plus �lev� en fr�quence. Ce g�ne peut influencer la susceptibilit� des patients au trouble d�lirant.
Conclusion : L'�tude r�v�le d'importantes associations entre les g�nes HLA et le trouble d�lirant. Cette observation pr�liminaire peut nous aider � comprendre le fondement g�n�tique de ce trouble.
[Reference]
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[Author Affiliation]
Monojit Debnath, MSc1, Sujit K Das, MBBS, DPM, MD (Psy)2, Nirmal K Bera, MBBS, MD (Psy)3, Chitta R Nayak, MSc, Dip (Operation Research)4, Tapas K Chaudhuri, MSc, PhD5
[Author Affiliation]
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
