Original Research

Genetic Associations Between Delusional Disorder and Paranoid Schizophrenia: A Novel Etiologic Approach
Monojit Debnath, MSc, PhD1, Sujit K Das, MBBS, DPM, MD(Psy)2, Nirmal K Bera, MBBS, MD(Psy), PhD3, Chitta R Nayak, MSc4, Tapas K Chaudhuri, MSc, PhD5
Objectives: Genetic associations between delusional disorder and paranoid schizophrenia are not well understood, although involvement of biological factors has been suspected. We investigated the incidence of human leukocyte antigen (HLA) class I alleles in patients with delusional disorder and paranoid schizophrenia, first, to explore a possible immunogenetic etiology of these paranoid disorders and, second, to determine whether they share similar etiologic mechanisms. Method: We employed a nested casecontrol study design. Psychiatric reference data were available for 38 500 patients attending a hospital-based psychiatric outpatient department between 1998 and 2005. We enrolled 100 patients with delusional disorder and 50 patients with paranoid schizophrenia as the subject cases, using DSM-IV criteria. We considered equivalent numbers of healthy volunteers matched for age and ethnic background as control subjects. All subjects came from an India-born Bengali population. We applied the polymerase chain reactionbased molecular typing method to all patients and healthy subjects. Results: The HLA-A*03 gene is significantly associated with delusional disorder as well as with paranoid schizophrenia. This HLA gene alone or in linkage disequilibrium with other HLA genes or other closely linked non-HLA genes may influence susceptibility to delusional disorder and paranoid schizophrenia. Conclusions: The study reveals important associations between HLA genes and paranoid disorders. Delusional disorder and paranoid schizophrenia may share similar etiologic mechanisms. This preliminary observation may help our understanding of the genetic basis of these paranoid disorders. (Can J Psychiatry 2006;51:342349) Information on funding and support and author affiliations appears at the end of the article.

Clinical Implications This preliminary study may help us to understand the genetic basis of delusional disorder and paranoid schizophrenia. This investigation may further help in understanding whether delusional disorder and paranoid schizophrenia bear similar etiologic mechanisms based on HLA associations. The study may strengthen our knowledge of the paranoid spectrum concept. Limitations The sample size was small, and the study needs to be replicated in a large sample. We studied the distribution of HLAs in delusional disorder as a whole, rather than by subtype. We did not study the familial clustering pattern of these HLA genes.

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Key Words: delusion, paranoid schizophrenia, etiology, human leukocyte antigens, association, paranoid symptoms aranoid symptoms are among the most dramatic and serious disturbances in psychiatry and medicine. Paranoid symptoms commonly seen in various psychiatric disorders are known as the paranoid spectrum (1). Kraepelin (1856 to 1926) clearly described paranoia and included it in a continuum of illnesses with delusional features, which also subsumed paraphrenia and paranoid schizophrenia (2). Since Kraepelins time, many psychiatrists have believed that paranoiadelusional disorder and paranoid schizophrenia are opposite ends of a continuum of psychotic disorders that have delusions as a prominent feature (2). However, controversy continues as to whether the paranoid (delusional) psychoses belong within, or are separate from, the schizophrenia disorders. The nosologic approaches to paranoid schizophrenia and paranoid psychosis differ substantially (3). Family studies have played a central role in the controversy over the nosologic status of paranoid psychosis or delusional disorder. In 1987, the revised third edition of the DSM distinguished d e lu s io n a l ( p a r a n o id ) d is o r d e r f r o m p a r a n o id schizophrenia (4).

suspiciousness, paranoid personality, and delusional disorder, compared with relatives of control subjects; however, the families have no increase in schizophrenia or mood disorders (8,9). Also, cases of schizophrenia-spectrum disorders were found to be strongly concentrated in the biological relatives of adoptees with schizophrenia. However, this pattern was not found for delusional disorder, suggesting that, from a genetic perspective, delusional disorder is not part of the schizophrenia spectrum. Despite these early and preliminary studies, the genetic associations between delusional disorder and paranoid schizophrenia remain enigmatic. Nevertheless, the strongest hypothesis holds that the entity of delusional disorder is one possible source of the heterogeneity within schizophrenia (10). Several significant associations have been found between HLAs and diseases. In many, but not all, of these disorders, immunologic abnormalities are evident. The HLA complex is the most diverse and polymorphic genetic system, with major functional and medical implications. The human MHC gene cluster spans a region of about 4000 kb on the short arm of chromosome 6 in the distal portion of the 6p21.3 band (11). Data from physical mapping, DNA cloning, and sequencing of the MHC region showed the presence of 224 gene loci, of which 128 are predicted to be expressed (12). Numerous investigators have suspected that chronic diseases of the central nervous system, including schizophrenia, have genetic, immunologic, and viral etiology (13,14). Many psychiatric conditions, such as psychosis, depression, and anxiety, have been considered in autoimmune disorders (15). More interestingly, one study showed significantly decreased production of interferon-gamma in acutely ill patients with paranoid schizophrenia, thereby indicating the possibility of immunologic dysfunctions in paranoid disorders (16). To date, there is no other research available regarding the immunogenetic basis of paranoid disorders. Considering the uniqueness of these conditions and the above-mentioned advancement in the field of biological psychiatry, we were stimulated to perform this HLA-association study of paranoid disorders to explore whether delusional disorder and paranoid schizophrenia bear similar etiologic mechanisms or result from distinct genetic underpinnings.

Delusional disorder, a psychosis previously called paraphrenia (5), is characterized by monosymptomatic paranoid symptoms. Delusions are considered as the basic factor responsible for the severity of many neuropsychiatric as well as medical conditions. However, research has not investigated the underlying psychopathology of such delusional manifestation in variable diseases. Many studies have explored the possibility of relating delusional disorder to other disorders such as schizophrenia and affective diseases. Delusional disorders are usually thought to overlap with schizophrenic disorders, and there may be a continuum with paranoid schizophrenia (6). Although paranoid schizophrenia is invariably grouped with other schizophrenia subtypes,there is still justification for Kraepelins original concept of its belonging with the delusional disorders (7). Huge controversy still exists, without any biological support. We feel it is worthwhile to investigate the biological basis of the paranoid spectrum. The underlying etiologic mechanism and the pathophysiology of these paranoid disorders are poorly understood. A few studies have shown that the relatives of probands with delusional disorder exhibit increased rates of jealousy,

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 different psychiatric conditions and about 4000 recurrent follow-up patients attend the department annually. For this study, we enrolled 100 (41 men and 59 women) unrelated patients with delusional disorder who attended between
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Abbreviations used in this article

HLA MHC RR human leukocyte antigen major histocompatibility complex relative risk

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1998 and 2005. The present study is an extension of our previous findings, published in the April 2005 issue of The Canadian Journal of Psychiatry (17). We added 20 more patients to our previous sample size. Two psychiatrists screened all patients with delusional disorder, using the Structured Clinical Interview for DSM-IV to confirm the diagnosis (18). The distribution of delusional disorder subtypes, as defined by DSM-IV criteria, was as follows: 57% persecutory, 13% jealous, 10% mixed, 10% somatic, 6% erotomanic, and 4% grandiose. Most patients ages were clustered between 25 and 55 years; however, the mean age was 39.8 years, SD 1.29, and the sex ratio was 69.4 men to 100 women. We considered a total of 100 healthy volunteers belonging to the same ethnic group to be control subjects. We also enrolled 50 (37 men and 13 women) unrelated patients with paranoid schizophrenia who attended the same psychiatric outpatient department. These patients were diagnosed independently by 2 psychiatrists according to the standard DSM-IV diagnostic criteria; the Schedule for Affective Disorders and Schizophrenia was used as a structured interview (19). The patients mean age was 34.96 years, SD 1.40, and the sex ratio was 284.6 men to 100 women. Again, we selected 50 healthy volunteers belonging to the same ethnic group as control subjects. Healthy control subjects were mainly selected from the university and from hospital employees. We screened all control subjects for a recent history of intercurrent infections and allergies, and we excluded those with a history of autoimmune or psychiatric disorders. All patients and control subjects gave informed consent and were matched for age. To collect blood samples, we obtained written permission from the appropriate authority of the medical college. Methodology We collected 2 mL of blood from each individual. We obtained DNA from peripheral mononuclear cells in ethylene diamine tetra acetate anticoagulant, using a salting out procedure (20). We performed molecular typing with the polymerase chain reaction technique (with sequence-specific primers) for detecting HLA class I genes. The primers, Taq polymerase, nucleotides, and other reagents were obtained from Bangalore Genei, India, and we used the typing and sequence information on primers developed by Bunce and colleagues (21). Statistical Analysis We calculated the phenotype frequencies by direct count. We compared the frequency of each allele in the patient group as a whole with the control population, using the chi-square test followed by Fishers exact test. We estimated RR as recommended by Svejgaard and colleagues (22). The haplotype frequency was estimated with an equation derived from Cavalli-Sforza and Bodmers research (23), and we used the
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chi-square test to calculate linkage disequilibrium (delta values) for 2 locus models.

Results
Table 1 presents the HLA class I allele profiles for the patients with delusional disorder, for those with paranoid schizophrenia, and for the healthy control subjects. The results demonstrate a marked elevation (60%) of the frequency of HLA-A*03 (2 = 43.20, P < 0.01) in patients with delusional disorder, compared with control subjects (15%). Statistically, this was highly significant. In addition, we observed a less significant increase in the frequency of HLA-A*11 (24% in the patients with delusional disorder, compared with 12% in control subjects). When we compared the frequency of B-locus alleles, we also noticed increased frequency of B*5001 in this patient group (25%, compared with 15% for the control subjects), but it did not reach statistical significance. Apart from this, several alleles, such as A*01 (3% for patients, compared with 12% for control subjects) and B*1501 (5% for patients, compared with 13% for control subjects), showed decreased frequency, although it was not statistically significant. When we compared the allele frequency of the patients with paranoid schizophrenia with that of the healthy control subjects, we found several alleles that showed high chi-square values, such as HLA-A*03 (50% and 14%, respectively), A*11 (32% and 14%, respectively), B*07 (22% and 6%, respectively), and B*13 (14% and 4%, respectively). In particular, the A*03 frequency (2 = 56.25, P < 0.01) was highly statistically significant. Conversely, alleles like A*02 (12% and 28%, respectively) and B*4001 (0% and 8%, respectively) showed significant values in the control subjects. When comparing the HLA profiles of the patients with delusional disorder with those of the patients with paranoid schizophrenia, we observed a high incidence of the HLA-A*03 allele in both patient groups (60% and 50%, respectively). In addition, several other HLA genes, such as A*11, and B*07, also showed relatively high values in both groups. However, there was a marked difference in the frequency of HLA-A*02 between the patient groups as well as between patient and control groups. Haplotype Estimation Significant HLA-A and HLA-B haplotypes among the patients with delusional disorder and the control subjects are shown in Table 2. Some of the prominent haplotypes we observed in the patients were not seen in the healthy control population. For example, we noticed A*24B*3701 and A*26B*08 only in the patients. However, only the A*02B*07 haplotype was common in both the groups. Similarly, some of the haplotype combinations that occurred in the healthy population did not appear in the patients.
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Table 1 Percentage of allele frequency, chi square, RR values, and probability of HLA-A and B loci alleles in the patients and healthy control subjects
Disease type Allele Allele frequency, % Patients Delusional disorder Patients n = 100 Control subjects n = 100 A*01 A*02 A*03 A*11 A*31 B*07 B*08 B*13 B*1501 B*27 B*35 B*44/4501 B*5001 Paranoid schizophrenia Patients n = 50 Control subjects n = 50 A*02 A*03 A*24 A*11 B*07 B*08 B*13 B*1501 B*35/*5301 B*4001 B*44/4501
**P < 0.01, *P < 0.05 ns = not significant.

c2

RR

Control subjects 12 23 15 12 8 10 9 6 13 11 10 5 15 28 14 16 14 6 6 4 16 14 8 8 5.8378* 0.0278 43.2000** 4.8780* 8.3333** 2.0980 1.2281 2.1978 3.9072* 2.4456 1.8018 1.2288 3.1250 10.6666** 56.2500** 3.5087 13.0434** 12.6984** 4.0000* 6.7750** 5.8275* 4.0000* 8.6956** 0.2710 0.2268 1.0572 8.5000 2.3157 0.0000 1.8433 1.6459 2.1363 0.3522 0.4258 0.4736 1.8791 1.8888 2.4812 6.1428 4.0476 4.5714 5.7619 2.8518 4.4722 2.8977 3.5064 0.0000 7.6190 ns ns significant ns ns ns ns ns ns ns ns ns ns ns significant ns ns ns ns ns ns ns ns ns

3 24 60 24 0 17 14 12 5 5 5 9 25 12 50 8 32 22 14 14 6 6 0 14

Table 3 represents the significant HLA-A and HLA-B haplotypes among the patients with paranoid schizophrenia and the control subjects. The pattern of haplotype distribution differed between the groups.

Discussion
Studying the immunogenetic aspect of a disease is most useful, not only for identifying the mode of inheritance of a particular disease process but also for understanding the immunopathogenic mechanisms underlying it. The discovery of HLA associations with a specific disease implies that at least part of the genetic basis lies in the MHC, thereby indicating the possibility of determining its etiology (24). A close study of different populations has shown that certain
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combinations of HLA alleles occur together more often than would be expected on the basis of their individual gene frequencies (24). This nonrandom association of the alleles of 2 HLA loci found together on the same HLA haplotype is termed linkage disequilibrium and is expressed in terms of delta values. One possible explanation for the association of HLAs with a disease is the existence of linkage disequilibrium between the alleles. Incidentally, most of the diseases that have shown strong associations with HLAssuch as various autoimmune and rheumatologic disordershave unknown etiology and mode of inheritance. Several researchers employing linkage analysis have found evidence for schizophrenia vulnerability genes on
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Table 2 Significant haplotypes and delta values per 10 000 among delusional disorder patients and healthy control subjects
Patients with delusional disorder Values Haplotype A*02 B*07 A*03 B*1801 A*24 B*5001 A*24 B*07 A*24 B*08 A*24 B*3701 A*26 B*08 A*26 B*44/4501 A*11 B*44 HF 234.03 248.19 128.38 101.22 113.01 124.16 180.59 137.06 147.58 Delta 119.97 98.11 31.06 36.61 60.25 83.04 139.48 110.98 68.19 c2 1.43 0.81 0.11 0.22 0.7 1.80 5.13 5.03 0.65 Haplotype A*01 B*1801 A*02 B*07 A*02 B*4001 A*03 B*1501 A*03 B*27/*7301 A*03 B*3701 A*23 B*35/*5301 A*24 B*4001 A*11 B*5001 HF 187.72 164.35 118.65 178.23 237.89 125.38 141.04 181.81 123.55 Healthy control subjects Values Delta 155.94 101.48 68.63 134.06 197.84 85.33 120.09 141.76 81.90 c2 8.2 1.81 1.03 4.42 10.67 1.96 7.30 5.44 1.73

Table 3 Significant haplotypes and delta values per 10 000 among paranoid schizophrenia patients and healthy control subjects
Patients with delusional disorder Values Haplotype A*01 B*13 A*02 B*5001 A*02 B*07 A*03 B*5001 A*03 B*44/4501 A*23 B*4901 A*26 B*07 A*29 B*08 HF 132.33 120.12 200.35 447.46 224.89 144.27 200.35 132.33 Delta 177.31 171.81 272.68 691.98 437.64 182.60 272.68 177.31 c2 2.11 1.52 3.11 5.35 1.49 2.93 3.11 2.11 Haplotype A*01 B*1801 A*02 B*07 A*02 B*4001 A*03 B*1501 A*03 B*27/*7301 A*03 B*3701 A*23 B*35/*5301 A*24 B*4001 HF 5.08 344.27 34.03 2.32 34.03 34.03 34.03 55.38 Healthy control subjects Values Delta 115.10 397.03 71.30 55.08 71.30 71.30 71.30 81.71 c2 0.00 12.58 0.16 0.00 0.16 0.16 0.11 0.61

chromosome 6p close to the HLA genetic region (25,26). Cazzullo and colleagues reported the first HLA-association study of schizophrenia in 1974 (27). More than 60 association studies have been reported since then. In the first review of HLA and schizophrenia, in 1979, McGuffin commented that the MHC was a logical place to search for genetic markers for schizophrenia (28). This was because schizophrenia subtypes showed several similar attributes, such as familial nature, an imperfectly understood etiology, and a postulated autoimmune pathogenesis, for which HLA association had already been established (29). Most of the previous studies on the involvement of the HLA system in schizophrenia have yielded inconsistent results because most considered schizophrenia as a whole. An association between HLA-A24 and
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schizophrenia has been reported (30). At least 7 studies have shown HLA-A9 to be elevated in patients with paranoid schizophrenia (31). Studies that divided HLA-A9 into subspecies found associations between schizophrenia and both HLA-A23 (32) and HLA-A24 (33). However, Alexander and colleagues found no association between either HLA-A23 or A24 and the paranoid subtype and expressed doubt about an association between HLA-A24 and schizophrenia (34).

Regarding the involvement of HLA genes in delusional disorder, our previous article (with a sample size of 80) reported the only published finding showing that delusional disorder was strongly associated with the HLA-A3 gene (17).
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Figure 1 Global distribution of HLA-A3

Australian Aborigine, 6.6 Italian, 12.9 Mongolian, 4.8

Patient, 60 South African San, 15.5

Toto, 11.11

Gurkha, 12 Bengali, 15

Rajbanshi, 18.52

To our knowledge, this is the first attempt to report on the possible genetic associations between delusional disorder and paranoid schizophrenia on the basis of HLA genetic studies. We found a significant association between delusional disorder and the HLA-A*03 allele. When we measured the strength of the association by the cross-product ratio or RR of developing a disease, A*03 showed a very high value (RR 8.5) reflecting a strong positive association. However, we also observed a strong association between HLA-A*03 and paranoid schizophrenia. When we measured the strength of this association by the same method, the A*03 gene again showed a high value (RR 6.14). We also observed a moderately strong association of the HLA-A*11 allele with paranoid schizophrenia, coinciding with Alexander and colleagues findings (34). Unlike some previous studies, however, we found no association with either HLA-A23 or A24 in our patient group. Several HLA-A and HLA-B haplotypes became significant in both groups of patients, as well as in control subjects, but they were extremely heterogeneous in nature. Only the A*02B*07 haplotype was common in all subjects, except for healthy control subjects matched with the paranoid schizophrenia group. According to these findings, we cannot assign any particular haplotype to the disease phenotype.

The exact nature of the mechanism underlying the empirically observed association of the HLA-A*03 gene with the delusional disorder and paranoid schizophrenia remains unknown; however, several genetic and environmental factors may be involved in such an association. HLA generally plays a critical role in the control of infectious and other immune functions. Also, it is widely accepted that a disturbance in neurodevelopment may be related to the development of schizophrenia. Research has also shown that an interaction between HLA and a perinatal or prenatal infection, which can affect neurodevelopment, may be associated with schizophrenia (35). At this point, we are not in a position to propose an autoimmune pathogenesis for delusional disorder and paranoid schizophrenia. Although there are reports on the etiologic role of several factors such as obstetric complications, low birth weight, reduced head circumference, prenatal underdevelopment, central nervous system damage, and maternal influenza infections in schizophrenia (36), such studies have not yet been conducted for delusional disorder. Our result is preliminary and so far not correlated with parameters such as birth status, viral infections, or prenatal infections. Nonetheless, we can assume the possible existence of a susceptible locus within the HLA region and that the HLA-A*03 gene may be the sole determinant of delusional disorder. This significant association may contribute to the disease risk, or else there may be a separate susceptibility gene in strong linkage disequilibrium with the A*03 gene. We also note that this result could not be an artifact arising from inadvertent ethnic mismatching of cases and control
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Our study shows that the frequency of the HLA-A*03 allele is significantly elevated in patients with delusional disorder as well as in those with paranoid schizophrenia. From this observation, we can suggest that these diseases may be linked etiologically or that there is an etiologic overlap between delusional disorder and paranoid schizophrenia.
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subjects, since there is no ethnic group known for which the HLA-A*03 frequency is higher than about 19%. Figure 1 illustrates the pattern of HLA-A3 distribution in various ethnic populations of the Indian subcontinent (including our Bengali patient population) as well as in a South African San population, a Mongolian population, an Italian population, and an Australian Aborigine population (37). Interestingly, the frequency of the A3 antigen in 2 other major populations in our region is 18.52% (Rajbanshi population) (38) and 12% (Gurkha population) (39). In conclusion, our study suggests that, at least in the Indian Bengali population, HLA may play a role in the development of delusional disorder and paranoid schizophrenia. The investigation also provides suggestive, but not conclusive, evidence for a genetic linkage between delusional disorder and paranoid schizophrenia.
Funding and Support This work was supported by a grant to Dr TK Chaudhuri from the Department of Science and Technology, Government of India (Grant No SP/SO/B58/99) .

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Manuscript received March 2005, revised, and accepted February 2006. 1 Formerly, Senior Research Fellow, Cellular Immunology Laboratory, Department of Zoology, University of North Bengal, Siliguri, WB, India; Now, Postdoctoral Fellow, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, Yunnan. 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, North Bengal Medical College and Hospital, Siliguri, WB, India. 5 Reader, 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; dr_tkc_nbu@rediffmail.com

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Rsum : Les associations gntiques entre le trouble dlirant et la schizophrnie paranode : une nouvelle approche tiologique
Objectifs : Les associations gntiques entre le trouble dlirant et la schizophrnie paranode sont mal comprises, bien que la participation de facteurs biologiques soit souponne. Nous avons recherch lincidence des allles de classe I de lantigne dhistocompatibilit (HLA) chez les patients souffrant de trouble dlirant et de schizophrnie paranode, premirement, pour explorer une tiologie immunogntique possible de ces troubles paranodes, et deuximement, pour dterminer sils partagent des mcanismes tiologiques semblables. Mthode : Nous avons employ une mthode dtude cas-tmoin embotements. Les donnes de rfrence psychiatrique taient disponibles pour 38 500 patients qui ont frquent une unit externe psychiatrique en milieu hospitalier entre 1998 et 2005. Nous avons inscrit comme sujets 100 patients souffrant de trouble dlirant et 50 patients souffrant de schizophrnie paranode, laide des critres du DSM-IV. Nous avons valu des nombres quivalents de donneurs en sant comme tmoins, jumels selon lge et les antcdents ethniques. Tous les sujets et tmoins provenaient dune population bengalaise originaire de lInde. Nous avons appliqu la mthode du typage molculaire bas sur la raction en chane de la polymrase aux patients et aux sujets en sant. Rsultats : Le gne HLA-A*03 est significativement associ au trouble dlirant ainsi qu la schizophrnie paranode. Ce gne HLA lui seul ou en dsquilibre de liaison avec dautres gnes HLA ou dautres gnes non-HLA troitement lis peut influencer la susceptibilit au trouble dlirant et la schizophrnie paranode. Conclusions : Ltude rvle dimportantes associations entre les gnes HLA et les troubles paranodes. Le trouble dlirant et la schizophrnie paranode peuvent partager des mcanismes tiologiques semblables. Cette observation prliminaire peut aider comprendre la base gntique de ces troubles paranodes.

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