M. Ruggeri

Large recurrent microdeletions associated with schizophrenia.

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

At-Risk Variant in TCF7L2 for Type II Diabetes Increases Risk of Schizophrenia

BACKGROUNDnSchizophrenia is associated with increased risk of type II diabetes and metabolic disorders. However, it is unclear whether this comorbidity reflects shared genetic risk factors, at-risk lifestyle, or side effects of antipsychotic medication.nnnMETHODSnEleven known risk variants of type II diabetes were genotyped in patients with schizophrenia in a sample of 410 Danish patients, each matched with two healthy control subjects on sex, birth year, and month. Replication was carried out in a large multinational European sample of 4089 patients with schizophrenia and 17,597 controls (SGENE+) using Mantel-Haenszel test.nnnRESULTSnOne type II diabetes at-risk allele located in TCF7L2, rs7903146 [T], was associated with schizophrenia in the discovery sample (p = .0052) and in the replication with an odds ratio of 1.07 (95% confidence interval 1.01-1.14, p = .033).nnnCONCLUSIONnThe association reported here with a well-known diabetes variant suggests that the observed comorbidity is partially caused by genetic risk variants. This study also demonstrates how genetic studies can successfully examine an epidemiologically derived hypothesis of comorbidity.

Replication study and meta-analysis in European samples supports association of the 3p21.1 locus with bipolar disorder

BACKGROUNDnCommon genetic polymorphisms at chromosome 3p21.1, including rs2251219 in polybromo 1 (PBRM1), have been implicated in susceptibility to bipolar affective disorder (BP) through genome-wide association studies. Subsequent studies have suggested that this is also a risk locus for other psychiatric phenotypes, including major depression and schizophrenia.nnnMETHODSnTo replicate the association, we studied 2562 cases with BP and 25,439 control subjects collected from seven cohorts with either genome-wide association or individual genotyping of rs2251219 and tagging single nucleotide polymorphisms across the PBRM1 gene. Results from the different case-control groups were combined with the inverse variance weighting method.nnnRESULTSnIn our dataset, rs2251219 was associated with BP (odds ratio [OR] = .89, p = .003), and meta-analysis of previously published data with our nonoverlapping new data confirmed genome-wide significant association (OR = .875, p = 2.68 × 10(-9)). Genotypic data from the SGENE-plus consortium were used to examine the association of the same variant with schizophrenia in an overall sample of 8794 cases and 25,457 control subjects, but this was not statistically significant (OR = .97, p = .21).nnnCONCLUSIONSnThere is strong evidence of association of rs2251219 with BP. However, our data do not support association of this marker with schizophrenia. Because the region of association has high linkage disequilibrium, forming a large haplotype block across many genes, it is not clear which gene is causally implicated in the disorder.

Brain Perfusion Characterizes First Episode of Psychosis Patients in Respect to Healthy Controls.

Introduction Vascular changes in the brain are relevant in schizophrenia [e.g. 1] and in bipolar disorder [2]. The study of first episode psychosis (FEP) allows the analysis of brain morphology and function without confounds due to chronicity. Objectives To characterize brain perfusion in FEP. Aims To see if FEP exhibit modified perfusion in respect to healthy controls (HC), and identify the most affected brain areas. Methods We acquired T1 and DSC images of 35 FEP patients (45 +/- 10 years old) and 35 HC (42 +/- 8), using Gadolinium (0.1 mmol/Kg). We computed cerebral blood volume (CBV), cerebral blood flow (CBF) and mean transit time (MTT) [3] in the whole brain and in left and right frontal, parietal, temporal and occipital lobes, insula, caudate and cerebellum Results Mean values of all quantities resulted lower in patients, up to 12% for CBV in right frontal lobe, 11% for CBF in left cerebellum and 16% for MTT in right frontal lobe. We used a support vector machine (SVM) to classify subjects on the basis of the histogram of perfusion values. We found that the classification reached accuracies over 80%, especially in the frontal brain areas. Conclusions FEP show altered perfusion parameters, which allow automatic classification with good accuracy, showing that brain vascular characteristics can be considered as marker of psychosis.n [1] Peruzzo et al (2011). J Neural Transm, 118, 4:563-70. [2] Agarwal et al (2008). J Affect Disord, 110, 1-2:106-14. [3] Ostergaard et al (1996). Magn Reson Med, 36, 5:715-25.