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.
Highlights
Mutations in the progranulin gene (GRN) are the most frequent cause of autosomic dominant frontotemporal lobar degeneration (FTLD)
Additional evidence of a clinical overlap between psychiatric disorders and genetically determined FTLD comes from the recent description of a patient with heterosexual pedophilia [6] who was a carrier of a gene progranulin (GRN) mutation and developed behavioural variant of frontotemporal dementia (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 bipolar disorder (BPD) history [7]
Considering each single nucleotide polymorphism (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, Odds Ratio (OR):0.63, 95%Confidence Interval (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)
Summary
Mutations in the progranulin gene (GRN) are the most frequent cause of autosomic dominant frontotemporal lobar degeneration (FTLD). As well as clinical phenotypes associated with such mutations are extremely wide, even in the same family [1] and include, besides the classical FTLD syndromes behavioural variant of frontotemporal dementia (bvFTD), progressive non fluent aphasia and semantic dementia [2,3,4], additional presentations such as corticobasal syndrome and progressive supranuclear palsy (PSP). Additional evidence of a clinical overlap between psychiatric disorders and genetically determined FTLD comes from the recent description of a patient with heterosexual pedophilia [6] 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 [7]. 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 [1,9,10,11]
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