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The HLA system as a genetic marker of affective disorders
1328
BIOLPSYCHIATRY
Brief Reports
1985;20:1328-1331
The HLA System as a Genetic Marker of Affective Disorders Reports on a Population from Central Italy, with Comments on Methodology G. Bersani, M. Valeri, S. Cavallari, A. Piazza, N. Ciani, and C. U. Casciani
In recent years considerable interest has been shown in the suggestion that the antigens of the HLA system may play a role as a genetic marker in primary affective disorders (PADs). Weak associations between bipolar illness, unipolar depression, or affective illness in general on the one hand and antigens of the HLA-A, -B, or -C loci on the other hand have been found. An increased frequency of HLA-B16 was reported by Shapiro el al. (1976) in Danish PAD patients; Beckman et al. (1978) observed an increased frequency of HLA-A1 and HLA-B7 in Swedish unipolar patients. Majsky et al. (1978) reported increments of HLA-B40 and HLA-Cw4 in Czechoslovakian patients with PADs of bipolar and unipolar form, respectively. In a manicdepressive sample originating from northern Italy, Smeraldi et al. (1978b) found a significantly increased frequency of HLA-A29 and HLA-Bw22 and a decrement of HLA-A9 and HLA-A10. The aim of this study was to investigate the frequencies of various A-and-B-loci antigens, both in affective illness in general and in the bipolar and unipolar forms of the disorder, in a sample of PAD patients originating from central
Italy, whose genetic characters are markedly different from those of the northern Italian population.
From the Department of Psychiatry, University of Rome 1I (G.B., S.C., N.C.), and the Institute "Tipizzazione tissutale e problemi delia dialisi," L'Aquila, Italy (M.V., A.P., C.V.C.). Address reprint requests to Dr. G. Bersani, Via Giulia 102, 00186 Rome, Italy. Received March 2, 1984; revised May 20, 1985.
Results
Methods Eighty-four affectively ill patients selected according to the research diagnostic criteria for primary affective disorders were typed. The population consisted of both inpatients and outpatients treated at the psychiatric clinic of Rome University. All patients came from central Italy. They were divided according to the Perris diagnostic criteria into clinical bipolar (n = 58) and unipolar depressive (n = 26) subgroups. The controls were 321 unselected blood donors and volunteers with the same ethnographic background as the patients. HLA typing was performed on peripheral blood lymphocytes according to the standard microlymphocytotoxicity assay. The frequencies of the antigens in patients and controls were compared, using 2 x 2 contingency chi-square analysis, or using Fischer's exact test if any cell of the contingency involved fewer than five observations.
The percentages of antigens of the A and B loci are shown in Tables 1 and 2. The frequency of occurrence of HLA-B37 is higher in affective
Brief Reports
BIOLPSYCHIATRY
1329
1985;20:1328-1331
Table 1. HLA Types in Affective Illness: A-Locus Phenotype and Genotype Frequencies Controls (n = 321) Specificity AI A2 A3 A9 AI0 A11 A28 Awl9
Unipolar (n = 26)
Bipolar (n = 58)
Total patients (n = 84)
p
g
p
g
p
g
p
g
25.9 44.6 22.4 31.5 9.7 11.8 3.4 19.6
0.1392 0.2557 0.1191 0.1724 0.0497 0.0609 0.0171 0.1033
19.3 42.3 26.9 30.8 15.4 7.7 3.8 26.9
0.1017 0.2404 0.1450 0.1681 0.0802 0.0392 0.0192 0.1450
17.2 37.9 20.7 39.6 17.2 13.8 6.9 22.4
0.0901 0.2120 0.1095 0.2280 0.0901 0.0716 0.0351 0.1191
17.9 39.3 21.4 36.9 16.7 11.9 5.9 23.8
0.0939 0.2209 0.1134 0.2056 0.0873 0.0614 0.0299 0.1271
p, phenotype frequencies; g, genotype frequencies.
patients (5.9% vs. 1.2%;p < 0.025) than in the controls. This elevation is statistically significant in the bipolar patients (6.9% vs. 1.2%; p < 0.025). These differences, however, become nonsignificant when the probability value is multiplied by the number of antigens tested. A marked but nonsignificant (0.05 < p < 0.25) increment of HLA-A10 and a reduction of HLA-A 1 were observed in the total population of PAD patients, and in both subgroups. HLA-B5 and HLA-B16 frequencies (B5 30.8%, B 16 19.2%) were higher in the unipolar subgroup,
and HLA-B 16 was significantly increased compared with the bipolar subgroup.
Discussion The present study was conducted to find out whether an association of HLA types with primary affective disorders or subgroups could be confirmed. A significantly increased frequency of HLA-B37 was found in PAD patients (p < 0.025), particularly in the bipolar subgroup. This association has not been reported in earlier
Table 2. HLA Types in Affective Illness: B-Locus Phenotype and Genotype Frequencies Controls (n = 321) Specifity B5 B7 B8 BI2 BI3 B 14 BI5 B16 B17 BI8 B21 Bw22 B27 Bw35 B37 B40
Unipolar (n = 26)
Bipolar (n = 58)
p
g
p
g
23.4 10.6 6.8 14.6 9.4 11.5 7.2 8.4 7.2 19.3 13.7 4.1 5.6 32.7 1.2 9.7
0.1248 0.0545 0.0346 0.0759 0.0481 0.0593 0.0367 0.0429 0.0367 0.1017 0.0710 0.0207 0.0284 0.1796 0.0060 0.0497
30.8 7.7 3.8 15.4 3.8 11.5 3.8 19.2 7.7 19.2 11.5 3.8 -15.4 3.8 3.8
0.1681 0.0392 0.0192 0.0802 0.0192 0.0593 0.0192 0.1011 0.0393 0.1011 0.0593 0.0109 -0.0802 0.0192 0.0192
p, phenotype frequencies; g, genotype frequencies. °p < 0.025.
p 20.7 8.6 5.2 12.1 5.2 10.3 5.2 3.4 13.8 17.2 17.2 1.7 6.9 39.7 6.9 a 10.3
g 0.1095 0.440 0.0263 0.0625 0.0263 0.0529 0.0263 0.0171 0.0715 0.0901 0.0901 0.0085 0.0351 0.2235 0.0351 0.0529
Total Patients (n =84) p 23.8 8.3 4.8 13.1 4.8 10.7 4.8 8.7 11.9 17.8 15.5 2.4 4.8 32.2 5.9 ~ 8.3
g 0.1271 0.0424 0.0243 0.0678 0.0243 0.0550 0.0243 0.0445 0.0614 0.0934 0.0804 0.0121 0.0243 0.1766 0.0299 0.0428
1330
BIOL PSYCHIATRY 1985;20:1328-1331
studies. This suggests that the bipolar form may well implicate a linkage between H L A region, as genetic marker, and a PAD susceptibility locus; nevertheless, the association is not significant when corrected for the number of comparisons tested. The decreased frequency of HLAAl is in agreement with Smeraldi's (1978b) data concerning northern Italian PAD patients, whereas the increment of HLA-A10 contrasts with his findings. This fact may be explained by ethnographic and probable genetic differences between the populations of northern and central Italy. The increased frequency of HLAB 16 (19.2%) in the unipolar depressive patients is in agreement with Shapiro's (1976) data in a Danish population and with Propcrt's (1981) data in an Australian population. In conclusion, no consistent association between HLA antigens and PAD emerged in our study. As the HLA-B37 antigen is a low frequency antigen in controls, errors due to stratification effects in the PAD population are more likely to produce spurious results than in the case of more common antigens. As in the preceding reports, the association between PAD and HLA antigens is quite weak, even when statistically significant. This result, and the different distribution of the antigens in the unipolar and bipolar forms, suggest some methodological corrections are necessary in future studies. Since a biological heterogeneity in affective pathology was demonstrated, not always concordant with the clinical forms, it will be necessary to carry out future studies on samples of affective patients selected according to biological markers more directly correlated with probable genetic features, such as urinary and CSF levels of catabolites of neurotransmitters (3.4-methoxyhydroxyphenylglycol, 5-hydroxyindoleacetic acid), neuroendocrine responses (dexamethasone suppression test, thyrotropin-releasing hormone test, insulin tolerance test), or therapeutic response to antidepressant treatments with specific noradrenergic or serotoninergic agents. References Beckman L, Perris C, et al (1978): HLA antigens and affective disorders. Hum Hered 28:96-99.
Brief
Reports
Bersani G, Cavallari S, et al (1985): Sistema HLA e disturbi affettivi maggiori: Stato della ricerca e dati relativi alla popolazione della Italia Centrale. Psichiatria e Psicoterapia Analitica 4( 1) :71-80. Bersani G, Valeri M, et al (1982): II sistema HLA come possibile marker genetico della patologia affettiva primaria: Dati preliminari in una popolazione dell'Italia Centrale. Rivista di Psichiatria 17(4):332-340. Govaerts A, Mendelewicz J, et al (1977): Manicdepressive illness and HLA. Tissue Antigens 10:6ff4i2. Johnson GFS (1978): HLA antigens and manic-depressive disorders. Biol Psychiatry 13:409-412. Majsky A, Zvolsky P, et al (1978): Primary affective disorders and HLA antigens. 11:190-191. Mendlewicz J, Fleiss JL (1974): Linkage studies with x-chromosome markers in bipolar (manic-depressive) and unipolar (depressive) illness. Biol Psychiatry 9:261-294. Mendlewicz J, Verbanck P, et al (1978): HLA antigens in affective disorders. In Proceedings X1 C.I.N.P. Congress, pp 205-208. Mendlewicz J, Verbanck P, et al (1981): HLA antigens in affective disorders and schizophrenia. J Affect Dis 3:17-24. Perris C, Strandman E, et al (1978): HLA antigens in affective disorders and cycloid psychoses. In Proceedings XI C.I.N.P. Congress, pp 205-208. Propert DN, Tait BD, et al (1981): HLA antigens and affective illness. Tissue Antigens 18:335-340. Rafaelsen OJ, Kramp P, et al (1978): HLA antigens in manic-melancholic disorders. In Proceedings XI C.I.N.P. Congress, pp 209-213. Rosier M, Bellaire W, et al (1981): HLA antigens in schizophrenia, major depressive disorders and schizoaffective disorders. Med Microbiol lmmunol (Berl) 172:57-65. Rouquet JP, De Mouzon A, et al (1979): SystSme HLA chez les patients atteints de psychose maniaco-depressive. Nouv Presse Med 8(24): 2022-2023. Shapiro RW, Bock E, et al ( 1976): Histocompatibility antigens and manic-depressive disorders. Arch Gen Psychiatry. 33:823-825. Smeraldi E, Negri A, et al (1978a): HLA system and affective disorders: A sibship genetic study. Tissue Antigens 12:270-274. Smeraldi E, Negri F, et al (1978b): HLA typing in affective disorders: A study in the Italian population. Neuropsychobiology 4:344-352. Smeraldi E, Bellodi L (1981): Possible linkage between primary affective disorders susceptibilty 1o-
Brief Reports
BIOL PSYCHIATRY
1331
1985;20:1328-1331
cus and HLA haplotypes. Am J Psychiatry 138:1232-1234. Stember RH, Fieve RR (1977): Histocompatibility antigens in affective disorders. Clin lmmunol lmmunopathol 7:13-15. Suarez BK, Reich T (1984): HLA and major affective disorders. Arch Gen Psychiatry 51:22-27. Targum SD, Gershon ES, et al (1979): Human leukocyte antigen system not closely linked to or associated with bipolar manic-depressive illness. Biol Psychiatry 14:615~536. Terasaki P1, Vredevoe DL, et al (1967): Seroiyping for homotransplantation. Survival of 196 grafted
kidneys subsequent to typing. Transplantation 5:1057-1070. Weitkamp LR, Pardue LH, et al (1980): Genetic marker studies in a family unipolar depression. Arch Gen Psychiatry 10:1187-1192. Whalley LS, Roberts DF, et al (1982): Genetic factors in puerperal affective psychoses. Acta Psychiatr Scand 65:180-193. Winokur G, Tanna VL (1969): Possible role of xlinked dominant factor in manic-depressive disease. Dis Nerv Sys 30:89-92.
BIOLPSYCHIATRY
Brief Reports
1985;20:1328-1331
The HLA System as a Genetic Marker of Affective Disorders Reports on a Population from Central Italy, with Comments on Methodology G. Bersani, M. Valeri, S. Cavallari, A. Piazza, N. Ciani, and C. U. Casciani
In recent years considerable interest has been shown in the suggestion that the antigens of the HLA system may play a role as a genetic marker in primary affective disorders (PADs). Weak associations between bipolar illness, unipolar depression, or affective illness in general on the one hand and antigens of the HLA-A, -B, or -C loci on the other hand have been found. An increased frequency of HLA-B16 was reported by Shapiro el al. (1976) in Danish PAD patients; Beckman et al. (1978) observed an increased frequency of HLA-A1 and HLA-B7 in Swedish unipolar patients. Majsky et al. (1978) reported increments of HLA-B40 and HLA-Cw4 in Czechoslovakian patients with PADs of bipolar and unipolar form, respectively. In a manicdepressive sample originating from northern Italy, Smeraldi et al. (1978b) found a significantly increased frequency of HLA-A29 and HLA-Bw22 and a decrement of HLA-A9 and HLA-A10. The aim of this study was to investigate the frequencies of various A-and-B-loci antigens, both in affective illness in general and in the bipolar and unipolar forms of the disorder, in a sample of PAD patients originating from central
Italy, whose genetic characters are markedly different from those of the northern Italian population.
From the Department of Psychiatry, University of Rome 1I (G.B., S.C., N.C.), and the Institute "Tipizzazione tissutale e problemi delia dialisi," L'Aquila, Italy (M.V., A.P., C.V.C.). Address reprint requests to Dr. G. Bersani, Via Giulia 102, 00186 Rome, Italy. Received March 2, 1984; revised May 20, 1985.
Results
Methods Eighty-four affectively ill patients selected according to the research diagnostic criteria for primary affective disorders were typed. The population consisted of both inpatients and outpatients treated at the psychiatric clinic of Rome University. All patients came from central Italy. They were divided according to the Perris diagnostic criteria into clinical bipolar (n = 58) and unipolar depressive (n = 26) subgroups. The controls were 321 unselected blood donors and volunteers with the same ethnographic background as the patients. HLA typing was performed on peripheral blood lymphocytes according to the standard microlymphocytotoxicity assay. The frequencies of the antigens in patients and controls were compared, using 2 x 2 contingency chi-square analysis, or using Fischer's exact test if any cell of the contingency involved fewer than five observations.
The percentages of antigens of the A and B loci are shown in Tables 1 and 2. The frequency of occurrence of HLA-B37 is higher in affective
Brief Reports
BIOLPSYCHIATRY
1329
1985;20:1328-1331
Table 1. HLA Types in Affective Illness: A-Locus Phenotype and Genotype Frequencies Controls (n = 321) Specificity AI A2 A3 A9 AI0 A11 A28 Awl9
Unipolar (n = 26)
Bipolar (n = 58)
Total patients (n = 84)
p
g
p
g
p
g
p
g
25.9 44.6 22.4 31.5 9.7 11.8 3.4 19.6
0.1392 0.2557 0.1191 0.1724 0.0497 0.0609 0.0171 0.1033
19.3 42.3 26.9 30.8 15.4 7.7 3.8 26.9
0.1017 0.2404 0.1450 0.1681 0.0802 0.0392 0.0192 0.1450
17.2 37.9 20.7 39.6 17.2 13.8 6.9 22.4
0.0901 0.2120 0.1095 0.2280 0.0901 0.0716 0.0351 0.1191
17.9 39.3 21.4 36.9 16.7 11.9 5.9 23.8
0.0939 0.2209 0.1134 0.2056 0.0873 0.0614 0.0299 0.1271
p, phenotype frequencies; g, genotype frequencies.
patients (5.9% vs. 1.2%;p < 0.025) than in the controls. This elevation is statistically significant in the bipolar patients (6.9% vs. 1.2%; p < 0.025). These differences, however, become nonsignificant when the probability value is multiplied by the number of antigens tested. A marked but nonsignificant (0.05 < p < 0.25) increment of HLA-A10 and a reduction of HLA-A 1 were observed in the total population of PAD patients, and in both subgroups. HLA-B5 and HLA-B16 frequencies (B5 30.8%, B 16 19.2%) were higher in the unipolar subgroup,
and HLA-B 16 was significantly increased compared with the bipolar subgroup.
Discussion The present study was conducted to find out whether an association of HLA types with primary affective disorders or subgroups could be confirmed. A significantly increased frequency of HLA-B37 was found in PAD patients (p < 0.025), particularly in the bipolar subgroup. This association has not been reported in earlier
Table 2. HLA Types in Affective Illness: B-Locus Phenotype and Genotype Frequencies Controls (n = 321) Specifity B5 B7 B8 BI2 BI3 B 14 BI5 B16 B17 BI8 B21 Bw22 B27 Bw35 B37 B40
Unipolar (n = 26)
Bipolar (n = 58)
p
g
p
g
23.4 10.6 6.8 14.6 9.4 11.5 7.2 8.4 7.2 19.3 13.7 4.1 5.6 32.7 1.2 9.7
0.1248 0.0545 0.0346 0.0759 0.0481 0.0593 0.0367 0.0429 0.0367 0.1017 0.0710 0.0207 0.0284 0.1796 0.0060 0.0497
30.8 7.7 3.8 15.4 3.8 11.5 3.8 19.2 7.7 19.2 11.5 3.8 -15.4 3.8 3.8
0.1681 0.0392 0.0192 0.0802 0.0192 0.0593 0.0192 0.1011 0.0393 0.1011 0.0593 0.0109 -0.0802 0.0192 0.0192
p, phenotype frequencies; g, genotype frequencies. °p < 0.025.
p 20.7 8.6 5.2 12.1 5.2 10.3 5.2 3.4 13.8 17.2 17.2 1.7 6.9 39.7 6.9 a 10.3
g 0.1095 0.440 0.0263 0.0625 0.0263 0.0529 0.0263 0.0171 0.0715 0.0901 0.0901 0.0085 0.0351 0.2235 0.0351 0.0529
Total Patients (n =84) p 23.8 8.3 4.8 13.1 4.8 10.7 4.8 8.7 11.9 17.8 15.5 2.4 4.8 32.2 5.9 ~ 8.3
g 0.1271 0.0424 0.0243 0.0678 0.0243 0.0550 0.0243 0.0445 0.0614 0.0934 0.0804 0.0121 0.0243 0.1766 0.0299 0.0428
1330
BIOL PSYCHIATRY 1985;20:1328-1331
studies. This suggests that the bipolar form may well implicate a linkage between H L A region, as genetic marker, and a PAD susceptibility locus; nevertheless, the association is not significant when corrected for the number of comparisons tested. The decreased frequency of HLAAl is in agreement with Smeraldi's (1978b) data concerning northern Italian PAD patients, whereas the increment of HLA-A10 contrasts with his findings. This fact may be explained by ethnographic and probable genetic differences between the populations of northern and central Italy. The increased frequency of HLAB 16 (19.2%) in the unipolar depressive patients is in agreement with Shapiro's (1976) data in a Danish population and with Propcrt's (1981) data in an Australian population. In conclusion, no consistent association between HLA antigens and PAD emerged in our study. As the HLA-B37 antigen is a low frequency antigen in controls, errors due to stratification effects in the PAD population are more likely to produce spurious results than in the case of more common antigens. As in the preceding reports, the association between PAD and HLA antigens is quite weak, even when statistically significant. This result, and the different distribution of the antigens in the unipolar and bipolar forms, suggest some methodological corrections are necessary in future studies. Since a biological heterogeneity in affective pathology was demonstrated, not always concordant with the clinical forms, it will be necessary to carry out future studies on samples of affective patients selected according to biological markers more directly correlated with probable genetic features, such as urinary and CSF levels of catabolites of neurotransmitters (3.4-methoxyhydroxyphenylglycol, 5-hydroxyindoleacetic acid), neuroendocrine responses (dexamethasone suppression test, thyrotropin-releasing hormone test, insulin tolerance test), or therapeutic response to antidepressant treatments with specific noradrenergic or serotoninergic agents. References Beckman L, Perris C, et al (1978): HLA antigens and affective disorders. Hum Hered 28:96-99.
Brief
Reports
Bersani G, Cavallari S, et al (1985): Sistema HLA e disturbi affettivi maggiori: Stato della ricerca e dati relativi alla popolazione della Italia Centrale. Psichiatria e Psicoterapia Analitica 4( 1) :71-80. Bersani G, Valeri M, et al (1982): II sistema HLA come possibile marker genetico della patologia affettiva primaria: Dati preliminari in una popolazione dell'Italia Centrale. Rivista di Psichiatria 17(4):332-340. Govaerts A, Mendelewicz J, et al (1977): Manicdepressive illness and HLA. Tissue Antigens 10:6ff4i2. Johnson GFS (1978): HLA antigens and manic-depressive disorders. Biol Psychiatry 13:409-412. Majsky A, Zvolsky P, et al (1978): Primary affective disorders and HLA antigens. 11:190-191. Mendlewicz J, Fleiss JL (1974): Linkage studies with x-chromosome markers in bipolar (manic-depressive) and unipolar (depressive) illness. Biol Psychiatry 9:261-294. Mendlewicz J, Verbanck P, et al (1978): HLA antigens in affective disorders. In Proceedings X1 C.I.N.P. Congress, pp 205-208. Mendlewicz J, Verbanck P, et al (1981): HLA antigens in affective disorders and schizophrenia. J Affect Dis 3:17-24. Perris C, Strandman E, et al (1978): HLA antigens in affective disorders and cycloid psychoses. In Proceedings XI C.I.N.P. Congress, pp 205-208. Propert DN, Tait BD, et al (1981): HLA antigens and affective illness. Tissue Antigens 18:335-340. Rafaelsen OJ, Kramp P, et al (1978): HLA antigens in manic-melancholic disorders. In Proceedings XI C.I.N.P. Congress, pp 209-213. Rosier M, Bellaire W, et al (1981): HLA antigens in schizophrenia, major depressive disorders and schizoaffective disorders. Med Microbiol lmmunol (Berl) 172:57-65. Rouquet JP, De Mouzon A, et al (1979): SystSme HLA chez les patients atteints de psychose maniaco-depressive. Nouv Presse Med 8(24): 2022-2023. Shapiro RW, Bock E, et al ( 1976): Histocompatibility antigens and manic-depressive disorders. Arch Gen Psychiatry. 33:823-825. Smeraldi E, Negri A, et al (1978a): HLA system and affective disorders: A sibship genetic study. Tissue Antigens 12:270-274. Smeraldi E, Negri F, et al (1978b): HLA typing in affective disorders: A study in the Italian population. Neuropsychobiology 4:344-352. Smeraldi E, Bellodi L (1981): Possible linkage between primary affective disorders susceptibilty 1o-
Brief Reports
BIOL PSYCHIATRY
1331
1985;20:1328-1331
cus and HLA haplotypes. Am J Psychiatry 138:1232-1234. Stember RH, Fieve RR (1977): Histocompatibility antigens in affective disorders. Clin lmmunol lmmunopathol 7:13-15. Suarez BK, Reich T (1984): HLA and major affective disorders. Arch Gen Psychiatry 51:22-27. Targum SD, Gershon ES, et al (1979): Human leukocyte antigen system not closely linked to or associated with bipolar manic-depressive illness. Biol Psychiatry 14:615~536. Terasaki P1, Vredevoe DL, et al (1967): Seroiyping for homotransplantation. Survival of 196 grafted
kidneys subsequent to typing. Transplantation 5:1057-1070. Weitkamp LR, Pardue LH, et al (1980): Genetic marker studies in a family unipolar depression. Arch Gen Psychiatry 10:1187-1192. Whalley LS, Roberts DF, et al (1982): Genetic factors in puerperal affective psychoses. Acta Psychiatr Scand 65:180-193. Winokur G, Tanna VL (1969): Possible role of xlinked dominant factor in manic-depressive disease. Dis Nerv Sys 30:89-92.