Genetic professionals' reports of nondisclosure of genetic risk information within families

Patients attending genetic clinics are often the main gatekeepers of information for other family members. There has been much debate about the circumstances under which professionals may have an obligation, or may be permitted, to pass on personal genetic information about their clients but without their consent to other family members. We report findings from the first prospective study investigating the frequency with which genetics professionals become concerned about the failure of clients to pass on such information to their relatives. In all, 12 UK and two Australian regional genetic services reported such cases over 12 months, including details of actions taken by professionals in response to the clients' failure to disclose information. A total of 65 cases of nondisclosure were reported, representing

Understanding New Product Project Performance

Purpose – The purpose of this paper is to summarize the accumulated body of knowledge on the performance of new product projects and provide directions for further research. Design/methodology/approach – Using a refined classification of antecedents of new product project performance the research results are meta-analyzed in the literature in order to identify the strength and stability of predictor-performance relationships. Findings – The results reveal that 22 variables have a significant relationship with new product project performance, of which only 12 variables have a sizable relationship. In order of importance these factors are the degree of organizational interaction, R&D and marketing interface, general product development proficiency, product advantage, financial/business analysis, technical proficiency, management skill, marketing proficiency, market orientation, technology synergy, project manager competency and launch activities. Of the 34 variables 16 predictors show potential for moderator effects. Research limitations/implications – The validity of the results is constrained by publication bias and heterogeneity of performance measures, and directions for the presentation of data in future empirical publications are provided. Practical implications – This study helps new product project managers in understanding and managing the performance of new product development projects. Originality/value – This paper provides unique insights into the importance of predictors of new product performance at the project level. Furthermore, it identifies which predictor-performance relations are contingent on other factors.

Association Analysis of the PIP4K2A Gene on Chromosome 10p12 and Schizophrenia in the Irish Study of High Density Schizophrenia Families (ISHDSF) and the Irish Case-Control Study of Schizophrenia (ICCSS)

Molecular studies support pharmacological evidence that phosphoinositide signaling is perturbed in schizophrenia and bipolar disorder. The phosphatidylinositol-4-phosphate-5-kinase type-II alpha (PIP4K2A) gene is located on chromosome 10p12. This region has been implicated in both diseases by linkage, and PIP4K2A directly by association. Given linkage evidence in the Irish Study of High Density Schizophrenia Families (ISHDSF) to a region including 10p12, we performed an association study between genetic variants at PIP4K2A and disease. No association was detected through single-marker or haplotype analysis of the whole sample. However, stratification into families positive and negative for the ISHDSF schizophrenia high-risk haplotype (HRH) in the DTNBP1 gene and re-analysis for linkage showed reduced amplitude of the 10p12 linkage peak in the DTNBP1 HRH positive families. Association analysis of the stratified sample showed a trend toward association of PIP4K2A SNPs rs1417374 and rs1409395 with schizophrenia in the DTNBP1 HRH positive families. Despite this apparent paradox, our data may therefore suggest involvement of PIP4K2A in schizophrenia in those families for whom genetic variation in DTNBP1 appears also to be a risk factor. This trend appears to arise from under-transmission of common alleles to female cases. Follow-up association analysis in a large Irish schizophrenia case-control control sample (ICCSS) showed significant association with disease of a haplotype comprising these same SNPs rs1417374-rs1409395, again more so in affected females, and in cases with negative family history of the disease. This study supports a minor role for PIP4K2A in schizophrenia etiology in the Irish population. (C) 2009 Wiley-Liss, Inc.

Genetic Variation in the Serotonin 2A Receptor and Suicidal Ideation in a Sample of 270 Irish High-Density Schizophrenia Families

Genetic variation in the serotonin 2A receptor (HTR2A) has been associated with both schizophrenia and suicidal behavior. Our sample comprised 270 Irish high-density schizophrenia families (n = 1,408 subjects, including 755 with psychotic illness). Diagnoses were generated using a modified SCID. All patients who had at least one episode of psychosis were rated on the Operation Criteria Checklist for Psychotic Illness (OPCRIT). Lifetime history of suicidal ideation was determined from medical records and psychiatric interviews and was scored in the OPCRIT. Twelve SNPs were selected for study. Ten of these were tagSNPs derived from HapMap data, along with His452Tyr and T102C. We tested for association with psychotic illness as a whole, as well as stratified by the presence of suicidal ideation, using FBAT and PDTPHASE. Single-marker as well as haplotype-based tests using a

Novel linkage to chromosome 20p using latent classes of psychotic illness in 270 Irish high-density families

Background: Several lines of evidence suggest that the clinical heterogeneity of schizophrenia is due to genetic heterogeneity. Genetic heterogeneity may decrease the signal-to-noise ratio in linkage and association studies. Therefore, linkage studies of clinically homogeneous classes of psychotic illness may result in greater power to detect at least some loci.

AKT1 Is Associated with Schizophrenia Across Multiple Symptom Dimensions in the Irish Study of High Density Schizophrenia Families

Background: The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients. 
 Methods: The association of DTNBP1 in the Irish Study of High Density Schizophrenia Families (ISHDSF) prompted our investigation of AKT1 for association with disease in this sample. Eight single nucleotide polymorphisms spanning AKT1 were analyzed for association with schizophrenia across four definitions of affection and according to Operational Criteria Checklist of Psychotic Illness (OPCRIT) symptom scales. We examined expression of AKT1 messenger RNA from postmortem brain tissue of schizophrenic, bipolar, and control individuals. 
 Results: No single marker showed significant association, but the risk haplotype previously found over-transmitted to Caucasian schizophrenic patients was significantly under-transmitted in the ISHDSF (.01 < p < .05), across all OPCRIT symptom dimensions. Exploratory haplotype analysis confirmed association with schizophrenia toward the 5’ end of AKT1 (.008 < p < .049, uncorrected). We found significantly decreased RNA levels in prefrontal cortex of schizophrenic individuals, consistent with reduced AKT1 protein levels reported in schizophrenic brain. 
 Conclusions: The replication of association of AKT1 gene variants in a further Caucasian family sample adds support for involvement of AKT signaling in schizophrenia, perhaps encompassing a broader clinical phenotype that includes mood dysregulation. We show that AKT signaling might be compromised in schizophrenic and bipolar patients via reduced RNA expression of specific AKT isoforms.

Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia

Hereditary non-polyposis colorectal cancer (HNPCC), predominantly due to germline MLH1/MSH2 mutations, is the commonest form of hereditary colorectal cancer (CRC), but data in Asians are sparse. We sequenced the MLH1/MSH2 coding and promoter core regions in CRC patients diagnosed below age 40, and/or with multiple primary cancers or familial cancer clustering suggestive of HNPCC, and correlated deleterious mutations with clinical and tumour features. Forty-six Chinese, Malay and Indian kindreds participated. Of the 153 cancers reported in the 46 kindreds, stomach (14%) and urogenital cancers (13%) were the most common extracolonic cancers, whereas endometrial cancer comprised only 7%. Eleven different MLH1 and 12 MSH2 mutations were identified, including nine novel and four recurring mutations in the Chinese. One Indian was a compound heterozygote for an MLH1 and MSH2 mutation. The MLH1/MSH2 mutation data in the Malays and the Indians represents the first in these ethnic groups. Factors strongly associated with deleterious mutations were the Amsterdam criteria, family history of stomach or multiple primary cancers, and MSI-high tumours, whereas family history of endometrial cancer and young cancer age alone correlated poorly. Distinct clinical and molecular characteristics were identified among Asian HNPCC kindreds and may have important clinical implications.