Progranulin Gene Variability and Plasma Levels in Bipolar Disorder and Schizophrenia

Abstract

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). Mean±SEM progranulin plasma levels were significantly decreased in BPD patients, either Germans or Italians, as compared with controls (89.69±3.97 and 116.14±5.80 ng/ml, respectively, versus 180.81±18.39 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.

The behavioural variant frontotemporal dementia (bvFTD) syndrome in psychiatry

“…67 Psychotic 68 and bipolar 50 syndromes have been associated with GRN mutations, and recent studies indicate that different polymorphisms of GRN may contribute to schizophrenia and BPD, thus suggesting the possibility of shared pathophysiological mechanisms between FTD and some psychotic disorders. 69 This notion is further supported by the fact that plasma levels of progranulin were found to be lower in patients with BPD (without GRN mutations) compared with controls in two different study populations. 69 70 It is important to mention that we have focused our review on patients who received a DSM-compatible primary psychiatric diagnosis and were later found to have bvFTD, therefore suggesting that the psychopathological changes that led to a primary psychiatric diagnosis were actually the earliest clinical manifestations of FTLD.…”

Potential Roles of Microglial Cell Progranulin in HIV-Associated CNS Pathologies and Neurocognitive Impairment

“…For example, plasma PGRN protein levels were reportedly decreased in children with autism (Al-Ayadhi and Mostafa, 2011). Plasma PGRN levels also were reported to be low in people with bipolar disorder (Galimberti et al, 2012). Again, while larger studies are necessary to confirm these findings, the available preliminary reports suggest that PGRN expression could play a role in the pathogenesis of abnormal brain function observed in certain neuropsychiatric conditions.…”

CSF protein changes associated with hippocampal sclerosis risk gene variants highlight impact of GRN/PGRN

“…Whereas multiple GRN mutations cause FTLD-TDP (184–188), rs5848 is apparently a disease-modifying allele that alters the manifestation of multiple different diseases rather than affecting FTLD or HS-Aging specifically. For example, rs5848 has been linked to AD, Parkinson’s disease, C9ORF72 neurodegeneration, and bipolar disorder (Chang et al, 2013, Galimberti et al, 2012, Kamalainen et al, 2013, Pickering-Brown et al, 2008, Rademakers et al, 2008, van Blitterswijk et al, 2014). Moreover, the SNAP profile – biomarker indication of a neurodegenerative process despite lack of Aβ-type amyloidogenesis – is linked to multiple different brain conditions.…”

“…The GRN SNP was subsequently linked to other dementia-inducing disorders (Chang et al, 2013, Galimberti et al, 2012, Kamalainen et al, 2013, Pickering-Brown et al, 2008, Rademakers et al, 2008). Genome-wide association studies (GWAS) using large datasets have implicated two genes that encode potassium channel regulators — ABCC9 (rs704180) and KCNMB2 (rs9637454) – in HS-Aging pathology (Beecham et al, 2014, Nelson et al, 2014).…”