Mirella Ruggeri

Common variants conferring risk of schizophrenia

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Disruption of the neurexin 1 gene is associated with schizophrenia

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

Copy number variations of chromosome 16p13.1 region associated with schizophrenia

Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35 079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P=0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.

Common Variants at VRK2 and TCF4 Conferring Risk of Schizophrenia

Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).

Quality of life in patients with schizophrenia in five European countries: the EPSILON study

Objective: To compare subjective quality of life (QOL) and objective QOL indicators in patients with schizophrenia from five European sites: Amsterdam, Copenhagen, London, Santander and Verona.

Expanding the range of ZNF804A variants conferring risk of psychosis

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10−8) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10−7, and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10−8. In this study, using 5164 schizophrenia cases and 20 709 controls, we replicated the association with schizophrenia (odds ratio OR=1.08, P=0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N=609, OR=1.09, P=0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]—common and with low relative risk—may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39 481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P=0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P=0.0016 for association with the larger set of psychiatric disorders).

Determinants of subjective quality of life in patients attending community-based mental health services. The South-Verona Outcome Project 5

Objective: Investigate the relationship of various domains of quality of life (QoL) with socio‐demographics, clinical and social characteristics, service use and satisfaction in a representative sample of patients in contact with the South‐Verona community mental health service.

The perception of needs for care in staff and patients in community-based mental health services. The South-Verona Outcome Project 3.

Objective: The present study aims to assess needs for care rated by patients and staff and their agreement on needs assessment in a community‐based mental health service by using the Camberwell Assessment of Need (CAN).

Influence of perceived organisational factors on job burnout: survey of community mental health staff

BACKGROUND Staff burnout is a critical issue for mental healthcare delivery, as it can lead to decreased work performance and, ultimately, to poorer treatment outcomes. AIMS To explore the relative weight of job-related characteristics and perceived organisational factors in predicting burnout in staff working in community-based psychiatric services. METHOD A representative sample of 2000 mental health staff working in the Veneto region, Italy, participated. Burnout and perceived organisational factors were assessed by using the Organizational Checkup Survey. RESULTS Overall, high levels of job distress affected nearly two-thirds of the psychiatric staff and one in five staff members suffered from burnout. Psychiatrists and social workers reported the highest levels of burnout, and support workers and psychologists, the lowest. Burnout was mostly predicted by a higher frequency of face-to-face interaction with users, longer tenure in mental healthcare, weak work group cohesion and perceived unfairness. CONCLUSIONS Improving the workplace atmosphere within psychiatric services should be one of the most important targets in staff burnout prevention strategies. The potential benefits of such programmes may, in turn, have a favourable impact on patient outcomes.

Does Meeting Needs Improve Quality of Life

Background: This study investigated the relationship between patient-rated unmet needs and subjective quality of life using routine outcome data. Methods: 265 mental health service patients from South Verona were assessed using the Camberwell Assessment of Need, the Lancashire Quality of Life Profile, and other standardised assessments of symptoms, disability, function and service satisfaction. At 1-year follow-up, 166 patients were still in contact, of whom 121 patients (73%) were re-assessed. Results: Higher baseline quality of life was associated with being male, a diagnosis of psychosis, higher disability, higher satisfaction with care, fewer staff-rated or patient-rated unmet needs, and fewer patient-rated met needs (accounting for 40% of the variance). Specifically, fewer baseline patient-rated unmet needs were cross-sectionally associated with a higher quality of life (B = –0.08, 95% CI –0.12 to –0.04). Apart from its baseline value, the only baseline predictor of follow-up QoL was patient-rated unmet need (B = –0.08, 95% CI –0.21 to –0.09), accounting for 58% of the variance in follow-up quality of life. Graphical chain modelling confirmed this association. Conclusions: The association between high numbers of unmet needs and low subjective quality of life appears increasingly robust across several studies. Future research will need to investigate whether changes in needs precede changes in quality of life. This study provides further evidence that a policy of actively assessing and addressing patient-rated unmet needs may lead to improved quality of life.