Variations of Wnt/β‐catenin pathway‐related genes in susceptibility to knee osteoarthritis: A three‐centre case‐control study

Excessive activation of the Wnt signalling pathway in the articular cartilage is demonstrated to be related to the onset and severity of osteoarthritis (OA). However, few studies have investigated the association between variants in Wnt‐pathway‐related genes and the risk of OA by searching Pubmed and EMBASE. Totally, 471 knee OA patients and 532 controls were recruited from three hospitals to evaluate the associations of five genetic variants (rs61735963, rs2908004, rs10795550, rs1799986 and rs1127379) with the risk of knee OA. These polymorphisms were genotyped through polymerase chain reaction and Sanger sequencing. Genetic risk scores (GRSs) were calculated to evaluate the combined effect of these genetic variants. No significant association was found between OA risk and polymorphisms (rs61735963, rs10795550 or rs1127379). However, WNT16 rs2908004 polymorphism was correlated with a decreased risk of OA, especially among females, smokers, non‐drinkers and individuals with age < 60 years or BMI ≥ 25. This SNP was also associated with Kellgren‐Lawrence grade and CRP. Similarly, LRP1 rs1799986 polymorphism decreased the risk of OA among males, smokers, drinkers and individuals with age < 60 years or BMI ≥ 25. TT genotype was more frequent in the group of VAS ≥ 6 versus VAS < 6. A low GRS was positively correlated with a decreased risk of OA. In addition, rs2908004 or rs1799986 polymorphism reduces the expression of WNT16 or LRP1. In conclusion, two SNPs (rs2908004 and rs1799986) are associated with the decreased risk of OA by regulating the Wnt pathway.     

Differential brain development with low and high IQ in attention-deficit/hyperactivity disorder

Attention-Deficit/Hyperactivity Disorder (ADHD) and intelligence (IQ) are both heritable phenotypes. Overlapping genetic effects have been suggested to influence both, with neuroimaging work suggesting similar overlap in terms of morphometric properties of the brain. Together, this evidence suggests that the brain changes characteristic of ADHD may vary as a function of IQ. This study investigated this hypothesis in a sample of 108 children with ADHD and 106 typically developing controls, who participated in a cross-sectional anatomical MRI study. A subgroup of 64 children also participated in a diffusion tensor imaging scan. Brain volumes, local cortical thickness and average cerebral white matter microstructure were analyzed in relation to diagnostic group and IQ. Dimensional analyses investigated possible group differences in the relationship between anatomical measures and IQ. Second, the groups were split into above and below median IQ subgroups to investigate possible differences in the trajectories of cortical development. Dimensionally, cerebral gray matter volume and cerebral white matter microstructure were positively associated with IQ for controls, but not for ADHD. In the analyses of the below and above median IQ subgroups, we found no differences from controls in cerebral gray matter volume in ADHD with below-median IQ, but a delay of cortical development in a number of regions, including prefrontal areas. Conversely, in ADHD with above-median IQ, there were significant reductions from controls in cerebral gray matter volume, but no local differences in the trajectories of cortical development.In conclusion, the basic relationship between IQ and neuroanatomy appears to be altered in ADHD. Our results suggest that there may be multiple brain phenotypes associated with ADHD, where ADHD combined with above median IQ is characterized by small, more global reductions in brain volume that are stable over development, whereas ADHD with below median IQ is associated more with a delay of cortical development.     

Saitohin Q7R polymorphism is associated with late‐onset Alzheimer's disease susceptibility among caucasian populations: a meta‐analysis

Saitohin (STH) Q7R polymorphism has been reported to influence the individual's susceptibility to Alzheimer's disease (AD); however, conclusions remain controversial. Therefore, we performed this meta‐analysis to explore the association between STH Q7R polymorphism and AD risk. Systematic literature searches were performed in the PubMed, Embase, Cochrane Library and Web of Science for studies published before 31 August 2016. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association using a fixed‐ or random‐effects model. Subgroup analyses, Galbraith plot and sensitivity analyses were also performed. All statistical analyses were performed with STATA Version 12.0. A total of 19 case–control studies from 17 publications with 4387 cases and 3972 controls were included in our meta‐analysis. The results showed that the Q7R polymorphism was significantly associated with an increased risk of AD in a recessive model (RR versus QQ+QR, OR = 1.27, 95% CI = 1.01–1.60, P = 0.040). After excluding the four studies not carried out in caucasians, the overall association was unchanged in all comparison models. Further subgroup analyses stratified by the time of AD onset, and the quality of included studies provided statistical evidence of significant increased risk of AD in RR versus QQ+QR model only in late‐onset subjects (OR = 1.56, 95% CI = 1.07–2.26, P = 0.021) and in studies with high quality (OR = 1.37, 95% CI = 1.01–1.86, P = 0.043). This meta‐analysis suggests that the RR genotype in saitohin Q7R polymorphism may be a human‐specific risk factor for AD, especially among late‐onset AD subjects and caucasian populations.     

Family‐based genome scan for age at onset of late‐onset Alzheimer's disease in whole exome sequencing data

Alzheimer's disease (AD) is a common and complex neurodegenerative disease. Age at onset (AAO) of AD is an important component phenotype with a genetic basis, and identification of genes in which variation affects AAO would contribute to identification of factors that affect timing of onset. Increase in AAO through prevention or therapeutic measures would have enormous benefits by delaying AD and its associated morbidities. In this paper, we performed a family‐based genome‐wide association study for AAO of late‐onset AD in whole exome sequence data generated in multigenerational families with multiple AD cases. We conducted single marker and gene‐based burden tests for common and rare variants, respectively. We combined association analyses with variance component linkage analysis, and with reference to prior studies, in order to enhance evidence of the identified genes. For variants and genes implicated by the association study, we performed a gene‐set enrichment analysis to identify potential novel pathways associated with AAO of AD. We found statistically significant association with AAO for three genes (WRN, NTN4 and LAMC3) with common associated variants, and for four genes (SLC8A3, SLC19A3, MADD and LRRK2) with multiple rare‐associated variants that have a plausible biological function related to AD. The genes we have identified are in pathways that are strong candidates for involvement in the development of AD pathology and may lead to a better understanding of AD pathogenesis.     

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

Spontaneous late‐onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early‐onset AD (EOAD) models that rely on forcible expression of AD‐associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials. In this study, we hypothesized that genomic instability facilitates development of LOAD and tested two genomic instability mice models in the brain pathology at the old age. Shugoshin‐1 (Sgo1) haploinsufficient (?) mice, a model of chromosome instability (CIN) with chromosomal and centrosomal cohesinopathy, spontaneously exhibited a major feature of AD pathology; amyloid beta accumulation that colocalized with phosphorylated Tau, beta‐secretase 1 (BACE), and mitotic marker phospho‐Histone H3 (p‐H3) in the brain. Another CIN model, spindle checkpoint‐defective BubR1^?/+ haploinsufficient mice, did not exhibit the pathology at the same age, suggesting the prolonged mitosis‐origin of the AD pathology. RNA‐seq identified ten differentially expressed genes, among which seven genes have indicated association with AD pathology or neuronal functions (e.g., ARC, EBF3). Thus, the model represents a novel model that recapitulates spontaneous LOAD pathology in mouse. The Sgo1^?/+ mouse may serve as a novel tool for investigating mechanisms of spontaneous progression of LOAD pathology, for early diagnosis markers, and for drug development.     

Early‐life environment,developmental immunotoxicology,and the risk of pediatric allergic disease including asthma

Incidence of childhood allergic disease including asthma (AD‐A) has risen since the mid‐20th century with much of the increase linked to changes in environment affecting the immune system. Childhood allergy is an early life disease where predisposing environmental exposures, sensitization, and onset of symptoms all occur before adulthood. Predisposition toward allergic disease (AD) is among the constellation of adverse outcomes following developmental immunotoxicity (DIT; problematic exposure of the developing immune system to xenobiotics and physical environmental factors). Because novel immune maturation events occur in early life, and the pregnancy state itself imposes certain restrictions on immune functional development, the period from mid‐gestation until 2 years after birth is one of particular concern relative to DIT and AD‐A. Several prenatal‐perinatal risk factors have been identified as contributing to a DIT‐mediated immune dysfunction and increased risk of AD. These include maternal smoking, environmental tobacco smoke, diesel exhaust and traffic‐related particles, heavy metals, antibiotics, environmental estrogens and other endocrine disruptors, and alcohol. Diet and microbial exposure also significantly influence immune maturation and risk of allergy. This review considers (1) the critical developmental windows of vulnerability for the immune system that appear to be targets for risk of AD, (2) a model in which the immune system of the DIT‐affected infant exhibits immune dysfunction skewed toward AD, and (3) the lack of allergy‐relevant safety testing of drugs and chemicals that could identify DIT hazards and minimize problematic exposure of pregnant women and children. Birth Defects Res (Part B) 2008. © 2008 Wiley‐Liss, Inc.     

Bin1 and CD2AP polarise the endocytic generation of beta‐amyloid

The mechanisms driving pathological beta‐amyloid (Aβ) generation in late‐onset Alzheimer's disease (AD) are unclear. Two late‐onset AD risk factors, Bin1 and CD2AP, are regulators of endocytic trafficking, but it is unclear how their endocytic function regulates Aβ generation in neurons. We identify a novel neuron‐specific polarisation of Aβ generation controlled by Bin1 and CD2AP. We discover that Bin1 and CD2AP control Aβ generation in axonal and dendritic early endosomes, respectively. Both Bin1 loss of function and CD2AP loss of function raise Aβ generation by increasing APP and BACE1 convergence in early endosomes, however via distinct sorting events. When Bin1 levels are reduced, BACE1 is trapped in tubules of early endosomes and fails to recycle in axons. When CD2AP levels are reduced, APP is trapped at the limiting membrane of early endosomes and fails to be sorted for degradation in dendrites. Hence, Bin1 and CD2AP keep APP and BACE1 apart in early endosomes by distinct mechanisms in axon and dendrites. Individuals carrying variants of either factor would slowly accumulate Aβ in neurons increasing the risk for late‐onset AD.     

Surface-Based Analysis on Shape and Fractional Anisotropy of White Matter Tracts in Alzheimer's Disease

Background

White matter disruption has been suggested as one of anatomical features associated with Alzheimer''s disease (AD). Diffusion tensor imaging (DTI), which has been widely used in AD studies, obtains new insights into the white matter structure.

Methods

We introduced surface-based geometric models of the deep white matter tracts extracted from DTI, allowing the characterization of their shape variations relative to an atlas as well as fractional anisotropy (FA) variations on the atlas surface through large deformation diffeomorphic metric mapping (LDDMM). We applied it to assess local shapes and FA variations of twenty-three deep white matter tracts in 13 patients with AD and 19 healthy control subjects.

Results

Our results showed regionally-specific shape abnormalities and FA reduction in the cingulum tract and the sagittal stratum tract in AD, suggesting that disruption in the white matter tracts near the temporal lobe may represent the secondary consequence of the medial temporal lobe pathology in AD. Moreover, the regionally-specific patterns of FA and shape of the white matter tracts were shown to be of sufficient sensitivity to robustly differentiate patients with AD from healthy comparison controls when compared with the mean FA and volumes within the regions of the white matter tracts. Finally, greater FA or deformation abnormalities of the white matter tracts were associated with lower MMSE scores.

Conclusion

The regionally-specific shape and FA patterns could be potential imaging markers for differentiating AD from normal aging.     

Joint Effect of Genetic and Lifestyle Risk Factors on Type 2 Diabetes Risk among Chinese Men and Women

More than 40 genetic susceptibility loci have been reported for type 2 diabetes (T2D). Recently, the combined effect of genetic variants has been investigated by calculating a genetic risk score. We evaluated 36 genome-wide association study (GWAS) identified SNPs in 2,679 T2D cases and 3322 controls in middle-age Han Chinese. Fourteen SNPs were significantly associated with T2D in analysis adjusted for age, sex and BMI. We calculated two genetic risk scores (GRS) (GRS1 with all the 36 SNPs and GRS2 with the 14 SNPs significantly associated with T2D). The odds ratio for T2D with each GRS point (per risk allele) was 1.08 (95% CI: 1.06–1.09) for GRS1 and 1.15 (95% CI: 1.13–1.18) for GRS2. The OR for quintiles were 1.00, 1.26, 1.69, 1.95 and 2.18 (P<0.0001) for GRS1 and 1.00, 1.33, 1.60, 2.03 and 2.80 (P<0.001) for GRS2. Participants in the higher tertile of GRS1 and the higher BMI category had a higher risk of T2D compared to those on the lower tertiles of the GRS1 and of BMI (OR = 11.08; 95% CI: 7.39–16.62). We found similar results when we investigated joint effects between GRS1 and WHR terciles and exercise participation. We finally investigated the joint effect between tertiles of GRSs and a composite high risk score (no exercise participation and high BMI and WHR) on T2D risk. We found that compared to participants with low GRS1 and no high risk factors for T2D, those with high GRS1 and three high risk factors had a higher risk of T2D (OR = 13.06; 95% CI: 8.65–19.72) but the interaction factor was of marginal significance. The association was accentuated when we repeated analysis with the GRS2. In conclusion we found an association between GRS and lifestyle factors, alone and in combination, contributed to the risk of and T2D among middle age Chinese.     

Genetic Risk Score of NOS Gene Variants Associated with Myocardial Infarction Correlates with Coronary Incidence across Europe

Coronary artery disease (CAD) mortality and morbidity is present in the European continent in a four-fold gradient across populations, from the South (Spain and France) with the lowest CAD mortality, towards the North (Finland and UK). This observed gradient has not been fully explained by classical or single genetic risk factors, resulting in some cases in the so called Southern European or Mediterranean paradox. Here we approached population genetic risk estimates using genetic risk scores (GRS) constructed with single nucleotide polymorphisms (SNP) from nitric oxide synthases (NOS) genes. These SNPs appeared to be associated with myocardial infarction (MI) in 2165 cases and 2153 controls. The GRSs were computed in 34 general European populations. Although the contribution of these GRS was lower than 1% between cases and controls, the mean GRS per population was positively correlated with coronary incidence explaining 65–85% of the variation among populations (67% in women and 86% in men). This large contribution to CAD incidence variation among populations might be a result of colinearity with several other common genetic and environmental factors. These results are not consistent with the cardiovascular Mediterranean paradox for genetics and support a CAD genetic architecture mainly based on combinations of common genetic polymorphisms. Population genetic risk scores is a promising approach in public health interventions to develop lifestyle programs and prevent intermediate risk factors in certain subpopulations with specific genetic predisposition.     

Blood‐based biomarkers for Down syndrome and Alzheimer's disease: A systematic review

Down syndrome (DS) occurs due to triplication of chromosome 21. Individuals with DS face an elevated risk for development of Alzheimer's disease (AD) due to increased amyloid beta (Aβ) resulting from the over‐expression of the amyloid precursor protein found on chromosome 21. Diagnosis of AD among individuals with DS poses particular challenges resulting in an increased focus on alternative diagnostic methods such as blood‐based biomarkers. The aim of this review was to evaluate the current state of the literature of blood‐based biomarkers found in individuals with DS and particularly among those also diagnosed with AD or in prodromal stages (mild cognitive impairment [MCI]). A systematic review was conducted utilizing a comprehensive search strategy. Twenty‐four references were identified, of those, 22 fulfilled inclusion criteria were selected for further analysis with restriction to only plasma‐based biomarkers. Studies found Aβ to be consistently higher among individuals with DS; however, the link between Aβ peptides (Aβ1‐42 and Aβ1‐40) and AD among DS was inconsistent. Inflammatory‐based proteins were more reliably found to be elevated leading to preliminary work focused on an algorithmic approach with predominantly inflammatory‐based proteins to detect AD and MCI as well as predict risk of incidence among DS. Separate work has also shown remarkable diagnostic accuracy with the use of a single protein (NfL) as compared to combined proteomic profiles. This review serves to outline the current state of the literature and highlights the potential plasma‐based biomarkers for use in detecting AD and MCI among this at‐risk population.     

Atopic dermatitis induces the expansion of thymus‐derived regulatory T cells exhibiting a Th2‐like phenotype in mice

Atopic dermatitis (AD) is a widespread inflammatory skin disease with an early onset, characterized by pruritus, eczematous lesions and skin dryness. This chronic relapsing disease is believed to be primarily a result of a defective epidermal barrier function associated with genetic susceptibility, immune hyper‐responsiveness of the skin and environmental factors. Although the important role of abnormal immune reactivity in the pathogenesis of AD is widely accepted, the role of regulatory T cells (T_regs) remains elusive. We found that the T_reg population is expanded in a mouse model of AD, i.e. mice topically treated with vitamin D3 (VitD). Moreover, mice with AD‐like symptoms exhibit increased inducible T‐cell costimulator (ICOS)‐, cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4)‐ and Glycoprotein‐A repetitions predominant receptor (GARP)‐expressing T_regs in skin‐draining lymph nodes. Importantly, the differentiation of T_regs into thymus‐derived T_regs is favoured in our mouse model of AD. Emigrated skin‐derived dendritic cells are required for T_reg induction and Langerhans cells are responsible for the biased expansion of thymus‐derived T_regs. Intriguingly, thymus‐derived T_regs isolated from mice with AD‐like symptoms exhibit a Th2 cytokine profile. Thus, AD might favour the expansion of pathogenic T_regs able to produce Th2 cytokines and to promote the disease instead of alleviating symptoms.     

Genetic Predisposition to Increased Blood Cholesterol and Triglyceride Lipid Levels and Risk of Alzheimer Disease: A Mendelian Randomization Analysis

Background

Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD.

Methods and Findings

We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n = 10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p<5×10⁻⁸ and trait specific scores using SNPs associated exclusively with each trait at p<5×10⁻⁸ were developed. We used logistic regression to investigate whether the GRSs were associated with LOAD in each study and results were combined together by meta-analysis. We found no association between any of the full GRSs and LOAD (meta-analysis results: odds ratio [OR] = 1.005, 95% CI 0.82–1.24, p = 0.962 per 1 unit increase in HDL-c; OR = 0.901, 95% CI 0.65–1.25, p = 0.530 per 1 unit increase in LDL-c; OR = 1.104, 95% CI 0.89–1.37, p = 0.362 per 1 unit increase in triglycerides; and OR = 0.954, 95% CI 0.76–1.21, p = 0.688 per 1 unit increase in total cholesterol). Results for the trait specific scores were similar; however, the trait specific scores explained much smaller phenotypic variance.

Conclusions

Genetic predisposition to increased blood cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. The observed epidemiological associations between abnormal lipid levels and LOAD risk could therefore be attributed to the result of biological pleiotropy or could be secondary to LOAD. Limitations of this study include the small proportion of lipid variance explained by the GRS, biases in case-control ascertainment, and the limitations implicit to Mendelian randomization studies. Future studies should focus on larger LOAD datasets with longitudinal sampled peripheral lipid measures and other markers of lipid metabolism, which have been shown to be altered in LOAD. Please see later in the article for the Editors'' Summary     

Independent Component Analysis-Based Identification of Covariance Patterns of Microstructural White Matter Damage in Alzheimer’s Disease

The existing DTI studies have suggested that white matter damage constitutes an important part of the neurodegenerative changes in Alzheimer’s disease (AD). The present study aimed to identify the regional covariance patterns of microstructural white matter changes associated with AD. In this study, we applied a multivariate analysis approach, independent component analysis (ICA), to identify covariance patterns of microstructural white matter damage based on fractional anisotropy (FA) skeletonised images from DTI data in 39 AD patients and 41 healthy controls (HCs) from the Alzheimer’s Disease Neuroimaging Initiative database. The multivariate ICA decomposed the subject-dimension concatenated FA data into a mixing coefficient matrix and a source matrix. Twenty-eight independent components (ICs) were extracted, and a two sample t-test on each column of the corresponding mixing coefficient matrix revealed significant AD/HC differences in ICA weights for 7 ICs. The covariant FA changes primarily involved the bilateral corona radiata, the superior longitudinal fasciculus, the cingulum, the hippocampal commissure, and the corpus callosum in AD patients compared to HCs. Our findings identified covariant white matter damage associated with AD based on DTI in combination with multivariate ICA, potentially expanding our understanding of the neuropathological mechanisms of AD.     

White Matter Changes in Patients with Amnestic Mild Cognitive Impairment Detected by Diffusion Tensor Imaging

Compared to normal aging adults, individuals with amnestic mild cognitive impairment (aMCI) have significantly increased risk for progressing into Alzheimer’s disease (AD). Autopsy studies found that most of the brains of aMCI cases showed anatomical features associated with AD pathology. The recent development of non-invasive neuroimaging technique, such as diffusion tensor imaging (DTI), makes it possible to investigate the microstructures of the cerebral white matter in vivo. We hypothesized that disrupted white matter (WM) integrity existed in aMCI. So we used DTI technique, by measuring fractional anisotropy (FA) and mean diffusivity (MD), to test the brain structures involved in patients with aMCI. DTI scans were collected from 40 patients with aMCI, and 28 normal controls (NC). Tract-based spatial statistics (TBSS) analyses of whole-brain FA and MD images in each individual and group comparisons were carried out. Compared to NC, aMCI patients showed significant FA reduction bilaterally, in the association and projection fibers of frontal, parietal, and temporal lobes, corpus callosum, bilateral corona radiation, right posterior thalamic radiation and right sagittal stratum. aMCI patients also showed significantly increased MD widespreadly in the association and projection fibers of frontal, parietal and temporal lobes, and corpus callosum. Assessment of the WM integrity of the frontal, parietal, temporal lobes, and corpus callosum by using DTI measures may aid early diagnosis of aMCI.     

Homocysteine modulates 5‐lipoxygenase expression level via DNA methylation

Elevated levels of homocysteinemia (Hcy), a risk factor for late‐onset Alzheimer's disease (AD), have been associated with changes in cell methylation. Alzheimer's disease is characterized by an upregulation of the 5‐lipoxygenase (5LO), whose promoter is regulated by methylation. However, whether Hcy activates 5LO enzymatic pathway by influencing the methylation status of its promoter remains unknown. Brains from mice with high Hcy were assessed for the 5LO pathway and neuronal cells exposed to Hcy implemented to study the mechanism(s) regulating 5LO expression levels and the effect on amyloid β formation. Diet‐ and genetically induced high Hcy resulted in 5LO protein and mRNA upregulation, which was associated with a significant increase of the S‐adenosylhomocysteine (SAH)/S‐adenosylmethionine ratio, and reduced DNA methyltrasferases and hypomethylation of 5‐lipoxygenase DNA. In vitro studies confirmed these results and demonstrated that the mechanism involved in the Hcy‐dependent 5LO activation and amyloid β formation is DNA hypomethylation secondary to the elevated levels of SAH. Taken together these findings represent the first demonstration that Hcy directly influences 5LO expression levels and establish a previously unknown cross talk between these two pathways, which is highly relevant for AD pathogenesis. The discovery of such a novel link not only provides new mechanistic insights in the neurobiology of Hcy, but most importantly new therapeutic opportunities for the individuals bearing this risk factor for the disease.     

Gray matter deficits in bipolar disorder are associated with genetic variability at interleukin‐1 beta gene (2q13)

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.