Twin, family and recent molecular studies support the hypothesis of genetic overlapping between schizophrenia and bipolar disorder. Brain structural features shared by both psychiatric disorders might be the phenotypic expression of a common genetic risk background. Interleukin‐1 (IL‐1) cluster (chromosome 2q13) genetic variability, previously associated with an increased risk both for schizophrenia and for bipolar disorder, has been also associated with gray matter (GM) deficits, ventricular enlargement and hypoactivity of prefrontal cortex in schizophrenia. The aim of the present study was to analyze the influence of IL‐1 cluster on brain morphology in bipolar disorder. Genetic variability at IL‐1B and IL‐1RN genes was analyzed in 20 DSM‐IV ( Diagnostic and Statistical Manual of Mental Disorders ‐Fourth Edition) bipolar patients. Magnetic resonance imaging (MRI) measurements were obtained for whole‐brain GM and white matter, dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus, hippocampus and lateral ventricles. MRI data were corrected for age and cranial size using regression parameters from a group of 45 healthy subjects. A −511C/T polymorphism (rs16944) of IL‐1B gene was associated with whole‐brain GM deficits ( P = 0.031) and left DLPFCGM deficits ( P = 0.047) in bipolar disorder patients. These findings support the hypothesis of IL‐1 cluster variability as a shared genetic risk factor contributing to GM deficits both in bipolar disorder and in schizophrenia. Independent replication in larger samples would be of interest to confirm these results.

Results Genotypic frequencies in patients showed Hardy–Weinberg equilibrium and were similar to frequencies previously described in Spanish population despite the relative small sample size (Table 2). Table 2. Allelic and genotypic frequencies of −511C/T and 86 base pair VNTR polymorphisms of IL‐1B and IL‐1RN genes in bipolar disorder patients Genotypic frequencies Allelic frequencies IL‐1B: −511C/T N Allele*1/allele*1 Allele*1/allele*2 Allele*2/allele*2 Allele*1 Allele*2 20 8 (40.0%) 9 (45.0%) 3 (15.0%) 25 (62.5%) 15 (37.5%) IL‐1RN: VNTR N Allele*1/allele*1 Allele*1/allele*2 Allele*2/allele*2 Allele*1 Allele*2 20 10 (50.0%) 10 (50.0%) 0 (0.0%) 30 (75%) 10 (25%) In relation to IL‐1B gene polymorphism and according to previous reports (Meisenzahl et al. 2001), two subgroups were generated: risk allele*2 carriers (genotypes: allele*1/allele*2 and allele*2/allele*2; n = 12) and noncarriers (genotype: allele*1/allele*1; n = 8). Adjusted structural measurements of neuroanatomical variables according to these subgroups are displayed in Table 3. There were no differences in age (noncarriers: 43.28 ± 13.90; carriers: 43.25 ± 10.66, U = 45.5, Z = −0.19, P = not significant), sex distribution (noncarriers: four females and four males; carriers: six females and six males) or treatment (noncarriers: six with lithium; carriers: eight with lithium; χ2 = 0.16, df = 1, P = 0.53) between both subgroups. Both groups of patients also showed a similar profile in terms of anticonvulsant or antipsychotic treatment. Allele*2 carriers showed a longer time from onset than noncarriers, although this variable did not correlate with MRI measurements (Spearman’s rho between GM volume residuals and illness duration = 0.116, P = not significant). This coefficient was also nonsignificant for each of the subgroups. Five of 11 allele*2 carriers and 5 of 8 allele*2 noncarriers had a history of psychotic symptoms, while this was unknown for one carrier (χ2 = 0.54, df = 1, P = 0.46). Table 3. Structural measurements [mean (SD)] expressed as residuals after adjustment (see Methods) of all neuroanatomical variables analyzed in bipolar patients with respect to allele*2 carriage. These volumes represent a quantitative measure with respect to the control sample. Statistically significant differences between groups of patients are also indicated Noncarriers Allele*2 carriers Total GM* 14.64 (24.52) −10.67 (24.74) Total WM −17.23 (18.82) −22.64 (16.03) DLPFC GM left* 0.08 (3.89) −2.20 (2.88) DLPFC GM right −0.43 (2.52) −2.75 (2.88) Hippocampus left 0.05 (0.29) −0.16 (0.30) Hippocampus right 0.00 (0.33) −0.09 (0.27) STG GM left −0.03 (1.09) −0.31 (0.89) STG GM right −0.27 (0.70) −0.53 (0.33) Ventricle left 2.21 (6.21) 1.34 (3.17) Ventricle right 1.56 (5.45) 1.96 (2.93) After correction for age and intracranial volume, allele*2 carriers of IL‐1B polymorphism showed whole‐brain GM deficits (U = 20, z = −2.160, n = 20, P = 0.031) with respect to noncarriers (Fig. 1). In secondary analyses, these patients showed a borderline trend toward left DLPFC volume deficits (U = 22, z = −2.006, n = 20, P = 0.047; Fig. 1) compared with noncarriers. These comparisons were still significant in an ancova (total GM: F = 4.84, df = 1, 17, P = 0.04; left DLPFC: F = 4.25, df = 1, 17, P = 0.05). Figure 1 Open in figure viewer PowerPoint Scatterplot of whole‐brain GM and left dorsolateral prefrontal (DLPFC) GM adjusted volumes in bipolar patients. These volumes represent a quantitative measure of GM atrophy (if negative) with respect to a normal sample (see Methods). Patients who were allele*2 (−511T) carriers of IL‐1B gene polymorphism show a significant decrease in whole‐brain GM and left dorsolateral prefrontal GM. Nonparametric tests showed no effect of lithium treatment on whole‐brain GM (U = 40, z = −0.165, n = 20, P = 0.869) or left DLPFC GM (U = 33, z = −0.742, n = 20, P = 0.458) in the whole bipolar patients sample. With respect to IL‐1RN gene, we did not find any influence of its genetic variability on any of the ROIs.

Discussion To our knowledge, this is the first study analyzing the relationship between IL‐1 cluster and brain morphology in bipolar disorder. We report the association of a genetic variant (allele*2) at IL‐1B gene with generalized GM deficits in bipolar patients. The influence of this allele on these deficits seems to be mainly focused on the left DLPFC region. In this vein, it is interesting to highlight that the same allele has been previously associated with bifrontal–temporal GM deficits in schizophrenia (Meisenzahl et al. 2001) and that GM deficits in frontal regions have been described by neuroimaging studies both in schizophrenia and in bipolar disorder (Honea et al. 2008; Lyoo et al. 2004). A developmental model for functional psychoses (Murray et al. 2004) provides a framework for our results. Thereby IL‐1 cluster could be a genetic risk factor shared by schizophrenic patients and a subgroup of bipolar patients closely related to schizophrenia picture according to their brain structural features. Association between allele*2 and generalized GM decrease would also support this notion, although these generalized deficits have been reported in schizophrenia (Gur et al. 1999) but not in bipolar disorder. However, on the light of imaging evidences in bipolar disorder, the authors do not discard the possibility of progressive processes in the origin of these brain differences driven by early developmental and/or neurodegenerative events (Monkul et al. 2005). In this vein, recent follow‐up studies are starting to show the neurodevelopmental trajectory of these brain abnormalities in bipolar disorder (Gogtay et al. 2007). Considering these hypothetic neurodegenerative processes, it should be noted that IL‐1 is a key mediator in the brain damage derived from ischemia and there is evidence of this kind of lesion in at least some bipolar patients, mainly of late onset (Berthier et al. 1996). Therefore, the authors cannot discard that the role of IL‐1 in the risk to develop bipolar disorder might be mediated through these ischemic processes, although the similar age in both groups argues against this possibility. Likewise, the authors cannot discard (because of the lack of data regarding environmental stressors in these patients) that the effect of IL‐1B genetic polymorphism on bipolar disorder is driven by the role of IL‐1 as a modulator of hypothalamus–pituitary–adrenal (HPA) axis because (1) this neuroendocrine pathway is a key mediator of environmental stress and (2) this stress is a triggering event of psychotic symptoms in subjects at risk of developing a psychotic disorder (Post & Leverich 2006; Thompson et al. 2007). A major point is the possibility of the effect of lithium treatment on the GM volumes because lithium has been reported to increase GM volumes in prefrontal regions (Monkul et al. 2007). Although our results show no significant effect of lithium treatment on GM volumes in those areas, the authors cannot rule out an neuroprotective/osmotic effect that could not be detected because of the low sample size. There are some methodological limitations that require additional comments. In first place, sample size of this study may generate type II errors that could lead to a lack of power to detect genetic effects on MRI variables. However, our results suggest that −511C/T polymorphism has a strong influence on certain morphological variables. This influence has allowed us to detect this genetic effect in spite of our sample size. Second, it should be noted that statistical significance of our results would not resist a strict multiple comparisons adjustment. However, this correction seems too conservative in the context of our study because (1) selection of genetic polymorphisms, neuroanatomical areas of interest and their analyses has been performed according to a clear directional hypothesis taking into account previous data, (2) analyses include MRI measurements with an important degree of overlap and (3) only two functional polymorphisms of special interest have been chosen for analyses, avoiding a massive genetic screening of both candidate genes. In conclusion, our results reinforce the interest of IL‐1 cluster as a genetic risk factor shared by different nosological entities, confirming previous results obtained in linkage and association studies. It should be noted, however, that these preliminary results need independent replication because of the small sample size included in this study. Further research on IL‐1 family of cytokines (e.g. receptor regulation and biochemical signaling pathways) is required to identify processes filling the gap between genetic variability with functional repercussion and brain abnormalities described in functional psychoses. Once these issues were clarified, it would be probably easier to discern some of the elusive mechanisms which link brain structural changes with mental disease symptoms.

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