Progranulin Gene Variability and Plasma Levels in
Bipolar Disorder and Schizophrenia
Daniela Galimberti1*, Bernardo Dell’Osso1, Chiara Fenoglio1, Chiara Villa1, Francesca Cortini1,
Maria Serpente1, Sarah Kittel-Schneider2, Johannes Weigl2, Maria Neuner2, Juliane Volkert2,
C. Leonhard2, David G. Olmes2, Juliane Kopf2, Claudia Cantoni1, Elisa Ridolfi1, Carlotta Palazzo1,
Laura Ghezzi , Nereo Bresolin , A. C. Altamura , Elio Scarpini , Andreas Reif
1Department of Neurological Sciences, University of Milan, IRCCS Fondazione Ca ` Granda, Ospedale Maggiore Policlinico, Milan, Italy, 2Bipolar Disorder Program,
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wu ¨rzburg, Wu ¨rzburg, Germany
Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might
share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German
population of patients with schizophrenia (n=271) or BPD (n=237) as compared with 574 age-, gender- and ethnicity-
matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian
BPD patients and 29 matched controls. A significantly decreased allelic frequency of the minor versus the wild-type allele
was observed for rs2879096 (23.2 versus 34.2%, P,0.001, OR:0.63, 95%CI:0.49–0.80), rs4792938 (30.7 versus 39.7%, P=0.005,
OR: 0.70, 95%CI: 0.55–0.89) and rs5848 (30.3 versus 36.8, P=0.007, OR: 0.71, 95%CI: 0.56–0.91). Mean6SEM progranulin
plasma levels were significantly decreased in BPD patients, either Germans or Italians, as compared with controls
(89.6963.97 and 116.1465.80 ng/ml, respectively, versus 180.81618.39 ng/ml P,0.001) and were not correlated with
age. In conclusion, GRN variability decreases the risk to develop BPD and schizophrenia, and progranulin plasma levels are
significantly lower in BPD patients than in controls. Nevertheless, a larger replication analysis would be needed to confirm
these preliminary results.
Citation: Galimberti D, Dell’Osso B, Fenoglio C, Villa C, Cortini F, et al. (2012) Progranulin Gene Variability and Plasma Levels in Bipolar Disorder and
Schizophrenia. PLoS ONE 7(4): e32164. doi:10.1371/journal.pone.0032164
Editor: Neil R. Smalheiser, University of Illinois-Chicago, United States of America
Received November 16, 2011; Accepted January 20, 2012; Published April 10, 2012
Copyright: ? 2012 Galimberti et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by grants from Monzino Foundation, Italian Ministry of Health (Programma Strategico RF 2007, conv. PS39, to DG and ES) and
the (DFG) German Research Foundation (Grant RE1632/1-1, /1-3 and /5 to AR, KFO 125 to AR, SFB TRR Z02 58 to AR, and RTG 1252/2, to AR). The funders had no
role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
Mutations in the progranulin gene (GRN) are the most frequent
cause of autosomic dominant frontotemporal lobar degeneration
(FTLD). Age at disease onset, as well as clinical phenotypes
associated with such mutations are extremely wide, even in the
same family  and include, besides the classical FTLD
syndromes behavioural variant of frontotemporal dementia
(bvFTD), progressive non fluent aphasia and semantic dementia
[2–4], additional presentations such as corticobasal syndrome and
progressive supranuclear palsy (PSP). In 2009, Velakoulis et al. 
presented a post mortem study of young patients, diagnosed ante
mortem with psychiatric illnesses including bipolar disorder (BPD)
and schizophrenia, and demonstrated the presence of protein
deposits [tau or TAR DNA Binding Protein (TDP)43] typical of
FTLD brains. Moreover, genetic analysis in one case revealed a
GRN mutation. Additional evidence of a clinical overlap between
psychiatric disorders and genetically determined FTLD comes
from the recent description of a patient with heterosexual
pedophilia  who was a carrier of a GRN mutation and
developed bvFTD over time, and from a second article reporting
two clinically different, apparently sporadic FTLD cases sharing
the previously described Thr272fs GRN mutation, who had had a
premorbid BPD history . Basing on the assumption that FTD
and schizophrenia might have a common aetiology in some
families in which both syndromes coexist, Schoder et al. 
analyzed the morbid risk for schizophrenia in first-degree relatives
of 100 FTD probands and compared it with first-degree relatives
of 100 Alzheimer’s disease (AD) relatives, showing that the morbid
risk for schizophrenia was significantly higher in relatives of FTD
probands than in relatives of AD probands. Notably, in one family,
a mutation in GRN was found . A major contribution to achieve
a correct diagnosis independent of the phenotypic presentation is
the demonstration that progranulin plasma levels are extremely
low in GRN mutation carriers [1,9–11].
Besides autosomic dominantly inherited GRN mutations, a
contribution of GRN genetic variability has been previously shown
in sporadic FTLD as well , even though another study did not
confirm these data . A further association analysis demon-
strated that a single nucleotide polymorphism (SNP) in the GRN
promoter influences the risk for FTLD . Besides the
susceptibility effect, GRN polymorphisms likely influence gene
expression. In this regard, Fenoglio et al.  demonstrated that
rs5848 TT genotype is associated with decreased GRN expression
levels in brains and peripheral blood mononuclear cells (PBMC)
from patients with AD. GRN is localized in a region of
PLoS ONE | www.plosone.org1 April 2012 | Volume 7 | Issue 4 | e32164
chromosome 17q21 previously shown to be associated with BPD
[16,17] and schizophrenia .
Given these premises, we carried out a GRN association study in
patients with BPD and schizophrenia compared with controls. In
addition, we measured progranulin plasma levels and correlated
them with genetic data.
Genetic variation within GRN was analyzed in a German
population of 508 patients with schizophrenia and BPD as
compared with 574 matched controls (Table 1). Both control
and case populations were in HWE for all SNPs studied.
Considering each SNP alone, a significantly decreased allelic
frequency of the minor versus the wild-type allele was observed for
rs2879096 (23.2 versus 34.2%, P,0.001, OR:0.63, 95%CI:0.49–
0.80, Table 2), rs4792938 (30.7 versus 39.7%, P=0.005, OR:
0.70, 95%CI: 0.55–0.89, Table 2) and rs5848 (30.3 versus 36.8%,
P=0.007, OR: 0.71, 95%CI: 0.56–0.91, Table 2). For all three
polymorphisms, there seemed to be an additive effect in that the
effect was stronger when carrying two polymorphic alleles (see
details in Table 2). Stratifying patients according to the diagnosis,
a significant association could still be seen in both schizophrenia
and BPD (Table 2). Regarding haplotype analysis, none of the
selected SNPs were in strong LD (D’ ranging from 0.1 to 0.9, data
not shown). Accordingly, none of upper CI values met the criteria
for haplotype analysis according to the method used .
Progranulin plasma levels were measured in 26 German BPD
patients. As one of them had levels below the reference range ,
GRN was sequenced, but no causal mutations were identified.
Although exceeding the lower cut-off level, mean progranulin
levels in patients were lower than previously published data
obtained in Italian controls . We thus evaluated progranulin
levels in an independent cohort of Italian volunteers (n=29) and
compared them with German cases (Table 3), again showing a
significant difference in means levels 6SEM (180,81618.39 ng/
ml in controls versus 89.6963.97 ng/ml in patients, P,0.001,
Figure 1). Similar levels were found also in an Italian population of
61 patients with BPD (116.1465.80 ng/ml versus controls,
P,0.001, Figure 1). Progranulin levels were not correlated with
age either in patients (r=0.07, P=0.568 in the Italian population,
r=0.17, P=0.662 in German patients, data not shown) or
controls (r=20.11, P=0.578, data not shown). Stratification
according to each of the SNPs studied, no significant differences in
progranulin plasma levels were shown (data not shown).
To our best knowledge, this is the first evidence that GRN
variability decreases the risk to develop BPD and schizophrenia. In
addition, progranulin plasma levels are significantly decreased in
patients as compared with controls. Despite both the SNPs and
progranulin levels were associated with the target phenotypes, no
association between such SNPs and progranulin levels were
observed. This could be due to a number of reasons, including the
possible regulation of translation by microRNA, the interaction of
additional variants not included in this study, or the effect of
medications taken at time of plasma sampling. Unfortunately, at
time of DNA sampling, no matched plasma samples were taken
from German controls. Therefore, these preliminary results need a
further confirmation in a larger and ethnically matched popula-
Progranulin and the various granulin peptides derived by
elastase cleavage are implicated in a range of biological functions,
including development, wound repair, inflammation and tumor-
igenesis . Whereas progranulin has anti-inflammatory prop-
erties, granulins display pro-inflammatory actions . Our
observation that progranulin levels are low in plasma from
patients with schizophrenia and BPD could imply that the balance
between progranulin and granulins is altered in favour of
granulins, that increase the degree of inflammation. A number
of findings suggest a role for inflammatory factors in schizophrenia
and BPD pathogenesis. Suvisaari et al.,  analyzed inflamma-
tory markers in psychotic disorders and their association with
metabolic comorbidity, antipsychotic medication, smoking, alco-
hol use, physical condition, and mood, showing that mononuclear
phagocyte system was mostly related to metabolic comorbidity and
antipsychotic medication use, whereas T-cell activation had a
more direct relationship with both psychotic disorders and
depressive symptoms. In addition, Interleukin (IL)-6 serum levels
were significantly increased in patients with schizophrenia as
compared with controls, whereas IL-10 concentration was
increased in both patients with schizophrenia and BPD .
To date, a number of Genome Wide Association Study (GWAS)
have been performed in patients with either schizophrenia or BPD
. Among these, an association with 17q21, the locus
containing GRN, has been shown in Latino populations with
schizophrenia  and in patients with BPD . Notably, this
locus has been implicated in several other neurological and
psychiatric pathologies of the central nervous system, including
FTLD (see  for review), PSP , and autism [29,30],
supporting the hypothesis of common pathogenic mechanisms
among these diseases. Regarding the occurrence of FTLD and
schizophrenia, in support of the hypothesis that these diseases
share a common aetiology, Schoder et al.  demonstrated that
the morbid risk for schizophrenia is significantly higher in relatives
of FTD probands than in relatives of Alzheimer’s disease
probands. In three mixed families, a causal GRN mutation was
found, even in family members diagnosed with schizophrenia .
In addition, TDP43 pathology was found in patients whose first
clinical presentation was consistent with schizophrenia or BPD .
Regarding our population, we did not have the opportunity to
Table 1. Characteristics of German individuals included in the association study.
Gender (M:F:unknown)230:341:3229:273:6146:120:5 83:153:1
Mean age, yrs6SEM (range)27.460.39 (18–68)28.3060.47 (9–72)*27.1360.59 (9–72)*30.1460.76 (14–63)*
*age at disease onset.
GRN Variability and Plasma Levels in BPD and SCZ
PLoS ONE | www.plosone.org2 April 2012 | Volume 7 | Issue 4 | e32164
follow up patients and their families to ascertain the development
In our study, the association observed in the whole population
was maintained after stratifying in patients with BPD and
schizophrenia, suggesting common pathogenic pathways. In line
with this hypothesis, two large GWAS in BPD and schizophrenia
patients, respectively, lead to the identification of the same
susceptibility genes [31,32]. Nevertheless, a replication analysis
should be carried out to confirm data described here.
Regarding progranulin levels, we acknowledge that the majority
of patients were treated at time of sampling, thus we can’t exclude
an influence of therapies on progranulin levels.
In conclusion, we demonstrated that GRN variability contributes
to schizophrenia and BPD development and that progranulin
Table 2. Allelic and genotype frequencies given as %(n) in German cases compared with age-, gender- and ethnicity matched
Genotype % (n)Allele % (n)
Controls574 46.7 (268) 38.2 (219)15.1 (87) 65.8 (755)34.2 (393)
BPD cases237 59.5 (141) 37.1 (88)3.4 (8)* 78.1 (370)21.9 (104)**
SZ cases 27157.6 (156) 36.5 (99) 5.9 (16)***75.8 (411) 24.2 (131)
All cases508 58.3 (296) 37.0 (188)4.7 (24)**** 76.8 (780)23.2 (236)*****
rs3785817 AAGA GGAG
Controls574 51.4 (295) 39.7 (228)8.9 (51) 71.3 (818)28.7 (330)
BPD cases 23759.1 (140)35.0 (83) 5.9 (14) 76.6 (363) 23.4 (111)
SZ cases 271 55.7 (151) 38.0 (103)6.3 (17) 74.7 (405)25.3 (137)
All cases 508 57.1 (290)36.8 (187)6.1 (31) 75.5 (767)24.5 (249)
Controls574 38.5 (221) 43.6 (250) 17.9 (103)60.3 (692) 39.7 (456)
BPD cases237 48.5 (115)43.9 (104) 7.6 (18)u
70.5 (334)29.5 (140)uu
SZ cases271 46.5 (126) 43.9 (119)9.6 (26)uuu
68.5 (371)31.5 (171)
All cases508 47.2 (240)44.1 (224)8.7 (44)uuuu
69.3 (704)30.7 (312)uuuuu
rs9897526 GG GA AAGA
Controls 574 76.3 (438)22.3 (128)1.4 (8) 87.5 (1004)12.5 (144)
BPD cases237 82.7 (196) 16.0 (38)1.3 (3)91.1 (432) 8.9 (42)
SZ cases 27176.7 (208) 21.8 (59) 1.5 (4)87.6 (475)12.4 (67)
All cases508 79.5 (404)19.1 (97) 1.4 (7)89.1 (905) 10.9 (111)
rs5848 CCCT TTCT
Controls574 39.9 (229) 46.5 (267)13.6 (78) 63.2 (725)36.8 (217)
BPD cases 23748.5 (115)41.3 (98) 10.2 (24)69.2 (328) 30.8 (146)
SZ cases 271 48.7 (132) 43.9 (119)7.4 (20)N
70.7 (383)29.3 (159)NN
All cases 50848.2 (245) 42.9 (218)8.9 (45)NNN
69.7 (708) 30.3 (308)NNNN
*P,0.001, OR: 0.20, 95%CI: 0.09–0.14.
**P=0.001, OR: 0.60, 95%CI: 0.44–0.81.
***P=0.0002, OR: 0.35, 95%CI: 0.20–0.61.
****P,0.001, OR: 0.28, 95%CI: 0.17–0.44.
*****P,0.001, OR: 0.63, 95%CI: 0.49–0.80.
uP=0.0003, OR: 0.37, 95%CI: 0.22–0.63.
uuP=0.01, OR: 0.66, 95%CI: 0.49–0.90.
uuuP=0.002, OR: 0.48, 95%CI: 0.31–0.77.
uuuuP,0.001, OR: 0.43, 95%CI: 0.30–0.63.
uuuuuP=0.005, OR: 0.70, 95%CI: 0.55–0.89.
NP=0.01, OR: 0.51, 95%CI: 0.30–0.85.
NNP,0.0001, OR: 0.53, 95%CI: 0.39–0.72.
NNNP=0.019, OR: 0.62, 95%CI: 0.42–0.91.
NNNNP=0.007, OR: 0.71, 95%CI: 0.56–0.91.
Table 3. Characteristics of Italian (I) and German (G) subjects
included in plasma level evaluation.
n 29 6126
Gender (M:F) 10:1925:369:17
Mean age at sampling, yrs6SEM
GRN Variability and Plasma Levels in BPD and SCZ
PLoS ONE | www.plosone.org3April 2012 | Volume 7 | Issue 4 | e32164
plasma levels are lower in patients with BPD than in controls,
although this findings need a replication in a larger cohort.
Materials and Methods
Five hundreds and eight patients with psychiatric disorders,
including 229 males, 273 females, and 6 gender unknown, mean
age6SEM at sampling: 48.9960.65 years (range 22–85), mean
age6SEM at disease onset: 28.306047 years (range: 9–72) were
recruited at the Department of Psychiatry, Psychosomatics and
Psychotherapy, University of Wu ¨rzburg, Germany. Two hundreds
seventy one patients, including 146 males, 120 females, and 5
gender unknown, mean age6SEM at sampling: 47.0060.84 years
27.1360.59years (range: 9–72) were diagnosed with schizophrenia
, whereas 237 patients including 83 males, 153 females and 1
gender unknown, mean age6SEM at sampling: 51.9661.00 years
(range: 25–85), mean age6SEM at disease onset: 30.1460.76
years (range: 14–63) were diagnosed with BPD (type 1: n=103,
type 2: n=78, not defined: n=56) .
The control group consisted of 574 German volunteers matched
for ethnic background and age (230 males, 341 females, 3 gender
unknown, mean age 6 SEM: 27.460.39 years, range 18–68) and
was recruited at the Department of Psychiatry, Psychosomatics
and Psychotherapy, University of Wu ¨rzburg, Germany. The age
of controls did not significantly differ from that of patients’ age at
disease onset (P.0.05). The control sample was composed of
blood donors, staff members, and volunteers all originating from
the Lower Franconia region. The sample was not systematically
screened for psychiatric disorders; however, all subjects were free
of medication, and the study was explained to them, so that the
likelihood of severe psychiatric disorders in the control sample was
low. Only subjects who gave written informed consent were
enrolled in the study, which complied with the Declaration of
Helsinki and was approved by the Ethics Committees of the
University of Wu ¨rzburg.
Plasma samples were collected in 26 German BPD patients,
including 9 males and 17 females, mean age6SEM at sampling:
42.2362.78 years (range 23–72). Additional plasma samples were
collected from 61 Italian patients with BPD, including 25 males
and 36 females, mean age6SEM at sampling: 52.3561.63 years
(range: 20–64) and 29 controls (10 males and 19 females), mean
age6SEM at sampling: 67.8961.83 years (range: 50–83) at the
University of Milan, Policlinico Hospital, Milan, Italy. Psychiatric
diagnoses were performed through the administration of a semi-
structured clinical interview for a DSM-IV-TR Axis 1 disorders
(SCID-I/P)  by trained psychiatrists.
This study has been approved by the Institutional Review board
of the Fondazione Ca ` Granda, IRCCS Ospedale Maggiore
Policlinico. Details of patients and controls are shown in Table 1.
DNA isolation and GRN SNPs analysis
High-molecular weight DNA was isolated from EDTA blood by
using a standard de-salting method. DNA samples were aliquoted
and stored at 220uC until use. For the association analysis, four
optimal tagging SNPs covering the GRN sequence were analyzed
(details in ). In addition, rs5848, located in the 39UTR and
previously shown to influence mRNA transcription through miR-
659 regulation , was included in the analysis as well.
Tagging SNPs were analyzed by using TaqMan methodology.
Each Taqman 59-nuclease assay employed 25 ng of genomic DNA
C_15835934_10, C_27482034_10, C_32346749_10, C_2548248
_10, C_7452046_10 were used for rs2879096, rs3785817,
rs4792938, rs9897526 and rs5848 genotyping respectively. Details
of the protocol used are given elsewhere .
GRN mutation scanning
The entire open reading frame including the noncoding exon 0
and exon-intron boundaries of exons 1–12 of the GRN gene was
sequenced using specific primers, as previously described  in
one patient with progranulin plasma levels under the normality
Allelic and genotypic frequencies were obtained by direct
counting. Chi square test was used to test for Hardy Weinberg
Equilibrium (HWE, http://www.husdyr.kvl.dk/htm/kc/popgen/
genetik/applets/kitest.htm). Chi2was used for differences in SNP
distribution between cases and controls. Bonferroni’s correction
was applied. The Odds Ratio (OR) was calculated along with its
95% Confidence Interval (CI). Haploview 3.2 software was used to
test for LD and for differences in haplotype distribution between
cases and controls. Statistical significance was estimated empiri-
cally using the bootstrap function in Haploview. Bootstrap P-
values are calculated using 10000 bootstrap samples. Calculation
of D’ is based on block definition by Gabriel et al. .
Progranulin levels were compared by using the Kurskall-Wallis
one way analysis of variance with Dunn’s method for multiple
We thank C. Gagel, J. Auer and T. To ¨pner for expert technical assistance.
Authors thank Dr. Andrea Arighi for his technical help.
Conceived and designed the experiments: DG CF. Performed the
experiments: CV FC MS CC ER. Analyzed the data: DG CF. Contributed
reagents/materials/analysis tools: BDO SKS JW MN JV CL DGO JK CP
LG NB ACA. Wrote the paper: DG AR ES.
Figure 1. Scattergram of progranulin plasma levels in BPD
patients and controls. Black lines represent mean values. G=Ger-
man. I=Italian. *P,0.001, patients versus controls.
GRN Variability and Plasma Levels in BPD and SCZ
PLoS ONE | www.plosone.org4 April 2012 | Volume 7 | Issue 4 | e32164
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PLoS ONE | www.plosone.org5April 2012 | Volume 7 | Issue 4 | e32164