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Bipolar Disorders 2014: 16: 769–772

BIPOLAR DISORDERS

Brief Report

Progranulin gene variability influences the risk for bipolar I disorder, but not bipolar II disorder Galimberti D, Prunas C, Paoli RA, Dell’Osso B, Fenoglio C, Villa C, Palazzo C, Cigliobianco M, Camuri G, Serpente M, Scarpini E, Altamura AC. Progranulin gene variability influences the risk for bipolar I disorder, but not bipolar II disorder. Bipolar Disord 2014: 16: 769–772. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objective: Recent data have shown that genetic variability in the progranulin (GRN) gene may contribute to the susceptibility to developing bipolar disorder (BD). However, in regard to patients with BD, no information is available on the role of genetic variability and plasma progranulin levels in different types of this disorder. Methods: In this study, we performed an association analysis of GRN in an Italian population consisting of 134 patients with BD and 232 controls to evaluate progranulin plasma levels. Results: The presence of the polymorphic variant of the rs5848 single nucleotide polymorphism is protective for the development of bipolar I disorder (BD-I) (odds ratio = 0.55, 95% confidence interval: 0.33–0.93; p = 0.024) but not bipolar II disorder (BD-II) (p > 0.05). In addition, plasma progranulin levels are significantly decreased in BD [mean  standard deviation (SD) 112  35 versus 183  93 ng/mL in controls; p < 0.001]. Conclusions: Regarding the influence of GRN variability on BD susceptibility, the predisposing genetic background differs between BD-I and BD-II, possibly implying that pathogenic mechanisms differ between the two subtypes of BD.

Mutations in the progranulin (GRN) gene are one of the most frequent causes of autosomic dominant frontotemporal lobar degeneration (FTLD). Clinical phenotypes associated with GRN mutations are extremely wide, even in the same family (1). In 2011, a carrier of a GRN mutation presenting with heterosexual paedophilia followed by behavioural variant frontotemporal dementia (bvFTD) was described (2), together with two clinically different, apparently

Daniela Galimbertia, Cecilia Prunasb, Riccardo A Paolib, Bernardo Dell’Ossob, Chiara Fenoglioa, Chiara Villaa, Carlotta Palazzob, Michela Cigliobiancob, Giulia Camurib, Maria Serpentea, Elio Scarpinia and A Carlo Altamurab a Neurology Unit, bPsychiatry Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca Granda, IRCCS Ospedale Policlinico, Milan, Italy

doi: 10.1111/bdi.12180 Key words: bipolar I disorder – bipolar II disorder – genetics – polymorphism – progranulin – risk factor – single nucleotide polymorphism Received 5 May 2013, revised and accepted for publication 16 October 2013 Corresponding author: Dr. Daniela Galimberti Neurology Unit Department of Pathophysiology and Transplantation University of Milan Fondazione Ca Granda IRCCS Ospedale Policlinico Milan 20122 Italy Fax: +39-2-50320430 E-mail: [email protected]

sporadic FTLD cases sharing the previously described Thr272fs GRN mutation, who had had a premorbid bipolar disorder (BD) history (3), underlining the clinical overlap between psychiatric disorders and genetically determined FTLD. In this regard, Velakoulis et al. (4) presented a postmortem study of young patients, diagnosed ante-mortem with psychiatric illnesses including BD and schizophrenia, and demonstrated the presence of protein deposits [tau or TAR DNA

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Galimberti et al. binding protein (TDP) 43] typical of FTLD brains. GRN variability decreases the risk of developing BD and schizophrenia (5). However, in regard to patients with BD, no information is available on the role of genetic variability and plasma progranulin levels in different types of BD. In the light of these findings, we performed an association study of GRN in patients with bipolar I disorder (BD-I) and bipolar II disorder (BD-II) compared with controls, and evaluated plasma levels.

Statistical analysis

Patients and methods

Results

Patients and controls

Both control and case populations were in HWE for all SNPs studied. The allelic and genotypic distributions of the three SNPs were not significantly different between patients and controls (p > 0.05) (Table 1). Nevertheless, when patients were stratified into BD-I and BD-II groups, a significantly decreased allelic frequency of the rs5848T allele was observed in the former (21.5% versus 32.5% in controls; OR = 0.55, CI: 0.33–0.93; p = 0.024) but not in the latter group (29.1%; p > 0.05 versus controls) (Table 1). The allele and genotype distributions were not influenced by sex (p > 0.05; data not shown). Progranulin plasma levels were evaluated in 80 patients (BD-I: n = 40; BD-II: n = 40) and 30 controls. Progranulin mean  SD plasma levels were significantly decreased in patients as compared with controls (112  35 versus 183  93 ng/mL, respectively; p < 0.001) (Fig. 1). No significant differences were found when comparing BD-I and BD-II (114  35 versus 111  35 ng/mL, respectively; p > 0.05). None of the SNPs analysed influenced progranulin plasma levels, and nor did age or sex (p > 0.05; data not shown).

One hundred and thirty-four patients with BD diagnosed according to DSM-IV-TR criteria [51 male and 83 female patients; mean  standard deviation (SD) age at sampling: 51.0  12.8 years, range: 20–74 years] and 232 healthy age-matched controls (87 male and 145 female individuals; mean  SD age at sampling: 54.0  15.3 years, range: 24–74 years) were included in the study. Seventy-nine patients were diagnosed with BD-I (36 male and 43 female patients; mean  SD age at sampling: 49.0  13.1 years, range: 20–74 years) and 55 with BD-II (15 male and 40 female patients; mean  SD age at sampling: 52.0  12.3 years, range: 33–74 years). This study was approved by the Institutional Review Board of the University of Milan, Fondazione Ca Granda, IRCCS Ospedale Maggiore Policlinico. All patients gave informed consent and underwent venipuncture in the morning, after overnight fasting. Blood was processed and plasma frozen within two hours. DNA extraction and genotyping

Genomic DNA was extracted from blood with a Flexigene kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. Tagging single nucleotide polymorphisms (SNPs) rs2879096 and rs4792938, along with rs5848, previously shown to be associated with BD and schizophrenia, were genotyped by allelic discrimination, as previously described (5–7). Progranulin plasma level evaluation

Plasma was obtained from blood and conserved at 30°C until use (80 samples from BD patients and 30 samples from controls). Progranulin plasma levels were evaluated with a specific enzyme-linked immunosorbent assay (ELISA) kit (Adipogen International, Liestal, Switzerland).

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Allelic and genotypic frequencies were obtained by direct counting. A chi-square test was used to test for Hardy–Weinberg equilibrium (HWE) (http:// www.husdyr.kvl.dk/htm/kc/popgen/genetik/applet s/kitest.htm) and for differences in SNP distribution between cases and controls, and Bonferroni’s correction was applied. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Progranulin plasma levels were analysed using ttests.

Discussion

Herein, we have shown that the GRN rs5848 SNP exerts a protective effect for the development of BD-I, decreasing the OR to 0.55, but not for the development of BD-II. Notably, when we considered the whole cohort of patients, no differences were observed, in line with results previously obtained in a German cohort of patients with BD, in which no such stratification was performed (5). In contrast to data obtained in that previous study (5), as regards rs2879096 and rs4792938, we did not observe an association in our population. An effect of ethnicity, or the interaction between different genetic and environmental factors, could, in part, explain the different results.

GRN variability in bipolar disorder Table 1. Allelic and genotypic frequencies given as n (%) in cases compared with age-, sex-, and ethnicity-matched controls SNP

N

rs2879096 Controls BD-I BD-II All cases rs4792938 Controls BD-I BD-II All cases rs5848 Controls BD-I BD-II All cases

Genotype, n (%)

Allele, n (%)

CC 136 (58.6) 44 (55.7) 30 (54.5) 74 (55.2) GG 106 (45.7) 37 (46.8) 23 (41.8) 60 (44.8) CC 110 (47.4) 49 (62.0) 28 (50.9) 77 (57.5)

232 79 55 134 232 79 55 134 232 79 55 134

CT 86 (37.1) 29 (36.7) 22 (40.0) 51 (38.1) GC 102 (44.0) 33 (41.8) 25 (45.4) 58 (43.3) CT 93 (40.0) 26 (32.9) 22 (40.0) 48 (35.8)

TT 10 (4.3) 6 (7.6) 3 (5.5) 9 (6.7) CC 24 (10.3) 9 (11.4) 7 (12.8) 16 (11.9) TT 29 (12.6) 4 (5.1) 5 (9.1) 9 (6.7)

C 358 (77.2) 117 (74.1) 82 (74.5) 199 (74.3) G 314 (67.7) 107 (67.7) 71 (64.5) 178 (66.4) C 313 (67.5) 124 (78.5) 78 (70.9) 202 (75.4)

T 106 (22.8) 41 (25.9) 28 (25.5) 69 (25.7) C 150 (32.3) 51 (32.3) 39 (35.5) 90 (33.6) T 151 (32.5) 34 (21.5)a 32 (29.1) 66 (24.6)

BD-I = bipolar I disorder; BD-II = bipolar II disorder; SNP = single nucleotide polymorphism. Odds ratio = 0.55, 95% confidence interval: 0.33–0.93; p = 0.024.

a

Progranulin plasma levels

400 350 300

ng/ml

250 200 150

*

100 50 0 CON

BD

BD-I

BD-II

Fig. 1. Scatterplot of progranulin plasma level in patients and controls (CON). Lines represent mean values. BD = bipolar disorder; BD-I = bipolar I disorder; BD-II = bipolar II disorder. *p < 0.001 versus CON.

In accordance with previous findings (5), we observed decreased levels of progranulin plasma levels in patients as compared with controls. As progranulin has anti-inflammatory properties, we could hypothesize that its decrease could promote inflammation in patients with BD. In this framework, it has been demonstrated that pro-inflammatory cytokines, such as interleukin 1 and 6, are over-expressed in blood cells from patients with BD and schizophrenia (8). According to Hsiung et al. (9), progranulin plasma levels are influenced by the T allele, and levels are significantly lower in TT versus CC carriers. Here, we did not observe significant differences among genotypes, but we acknowledge that the number of TT carriers found in patients was low (Table 1) and, therefore, we could not have reached the significance threshold due to a lack of power.

Our results suggest different predisposing genetic backgrounds in the two subtypes of BD and, possibly, different pathogenic mechanisms accounting for BD-I and BD-II. In support of this theory, previous data showed different degrees of DNA methylation at the promoter region of the brain-derived neurotrophic factor in patients with BD-I and BDII (10). Differences between BD-I and BD-II are also relevant when considering clinical features such as the frequency of depressive episodes, depressive symptoms, seasonality, rapid cycling course, and axis I and axis II comorbid conditions (11, 12). In conclusion, we demonstrated that GRN rs5848 is associated with BD-I, but not BD-II, raising the question of whether the two subtypes of BD should be considered separately in genetic studies, and possibly explaining the lack of replication in genome-wide analysis studies [see (13) for a review]. This study has, however, some limitations. First, the relatively small number of patients with BD-II could generate false-positive findings. Secondly, no correction for multiple testing was applied. Thirdly, we did not have information on the origin of patients, and it is known that northern and southern Italian populations can be different from one another at the SNP level. Therefore, a replication analysis in a larger independent population is needed to confirm these preliminary data. We also confirmed that progranulin plasma levels were decreased in patients with BD, although we did not consider the treatments that patients were taking, which could to some extent influence progranulin expression. In addition, in this study we did not observe a correlation between age and/ or sex and progranulin plasma levels, whereas, in a

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Galimberti et al. previous preliminary study in patients with Alzheimer’s disease, higher levels were found in elderly female patients (14). Therefore, the effect of aging on progranulin levels remains to be elucidated. Acknowledgements This work was supported by grants from the Monzino Foundation and the Italian Ministry of Health (Ricerca Corrente).

Disclosures The authors of this paper do not have any commercial associations that might pose a conflict of interest in connection with this manuscript.

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5. Galimberti D, Dell’Osso B, Fenoglio C et al. Progranulin gene variability and plasma levels in bipolar disorder and schizophrenia. PLoS ONE 2012: 7: e32164. 6. Rademakers R, Eriksen JL, Baker M et al. Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet 2008; 17: 3631–3642. 7. Galimberti D, Fenoglio C, Cortini F et al. GRN variability contributes to sporadic frontotemporal lobar degeneration. J Alzheimers Dis 2010; 19: 171–177. 8. Drexhage RC, Knijff EM, Padmos RC et al. The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert Rev Neurother 2010; 10: 59–76. 9. Hsiung GY, Fok A, Feldman HH et al. rs5848 polymorphism and serum progranulin level. J Neurol Sci 2011; 300: 28–32. 10. D’Addario C, Dell’Osso B, Palazzo MC et al. Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII. Neuropsychopharmacology 2012; 37: 1647–1655. 11. Baek JH, Park DY, Choi J et al. Differences between bipolar I and bipolar II disorders in clinical features, comorbidity, and family history. J Affect Disord 2011; 131: 59–67. 12. Bega S, Schaffer A, Goldstein B, Levitt A. Differentiating between bipolar disorder types I and II: results from the national epidemiologic survey on alcohol and related conditions (NESARC). J Affect Disord 2012; 138: 46–53. 13. Lee KW, Woon PS, Teo YY, Sim K. Genome wide association studies (GWAS) and copy number variation (CNV) studies of the major psychoses: what have we learnt? Neurosci Biobehav Rev 2012; 36: 556–571. 14. Piscopo P, Rivabene R, Galimberti D et al. Gender effects on plasma PGRN levels in patients with Alzheimer’s disease: a preliminary study. J Alzheimers Dis 2013; 35: 313– 318.

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Progranulin gene variability influences the risk for bipolar I disorder, but not bipolar II disorder.

Recent data have shown that genetic variability in the progranulin (GRN) gene may contribute to the susceptibility to developing bipolar disorder (BD)...
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