New concepts for distinguishing the hidden patterns of linkage disequilibrium which underlie association between genotypes and complex phenotypes

A disappointing feature of conventional methods for detecting association between DNA variation and a phenotype of interest is that they tell us little about the hidden pattern of linkage disequilibrium (LD) with the functional variant that is actually responsible for the association. This limitation applies to case-control studies and also to the transmission/disequilibrium test (TDT) and other family-based association methods. Here we present a fresh perspective on genetic association based on two novel concepts called 'LD squares' and 'equi-risk alleles'. These describe and characterize the different patterns of gametic LD which underlie genetic association. These concepts lead to a general principle - the Equi-Risk Allele Segregation Principle - which captures the way in which underlying LD patterns affect the transmission patterns of genetic variants associated with a phenotype. This provides a basis for distinguishing the hidden LD patterns and might help to locate the functional variants responsible for the association.

The v-MFG test: Investigating maternal, offspring and maternal-fetal genetic incompatibility effects on disease and viability

The MFG test is a family-based association test that detects genetic effects contributing to disease in offspring, including offspring allelic effects, maternal allelic effects and MFG incompatibility effects. Like many other family-based association tests, it assumes that the offspring survival and the offspring-parent genotypes are conditionally independent provided the offspring is affected. However, when the putative disease-increasing locus can affect another competing phenotype, for example, offspring viability, the conditional independence assumption fails and these tests could lead to incorrect conclusions regarding the role of the gene in disease. We propose the v-MFG test to adjust for the genetic effects on one phenotype, e.g., viability, when testing the effects of that locus on another phenotype, e.g., disease. Using genotype data from nuclear families containing parents and at least one affected offspring, the v-MFG test models the distribution of family genotypes conditional on offspring phenotypes. It simultaneously estimates genetic effects on two phenotypes, viability and disease. Simulations show that the v-MFG test produces accurate genetic effect estimates on disease as well as on viability under several different scenarios. It generates accurate type-I error rates and provides adequate power with moderate sample sizes to detect genetic effects on disease risk when viability is reduced. We demonstrate the v-MFG test with HLA-DRB1 data from study participants with rheumatoid arthritis (RA) and their parents, we show that the v-MFG test successfully detects an MFG incompatibility effect on RA while simultaneously adjusting for a possible viability loss.

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25 000 single-nucleotide polymorphisms (SNPs) located within approximately 14 000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

Phylogeny, molecular and fossil dating, and biogeographic history of Annonaceae and Myristicaceae (Magnoliales)

Annonaceae and Myristicaceae, the two largest families of Magnoliales, are pantropical groups of uncertain geographic history. The most recent morphological and molecular phylogenetic analyses identify the Asian-American genus Anaxagorea as sister to all other Annonaceae and the ambavioids, consisting of small genera endemic to South America, Africa, Madagascar, and Asia, as a second branch. However, most genera form a large clade in which the basal lines are African, and South American and Asian taxa are more deeply nested. Although it has been suggested that Anaxagorea was an ancient Laurasian line, present data indicate that this genus is basically South American. These considerations may mean that the family as a whole began its radiation in Africa and South America in the Late Cretaceous, when the South Atlantic was narrower, and several lines dispersed from Africa-Madagascar into Laurasia as the Tethys closed in the Tertiary. This scenario is consistent with the occurrence of annonaceous seeds in the latest Cretaceous of Nigeria and the Eocene of England and with molecular dating of the family. Based on distribution of putatively primitive taxa in Madagascar and derived taxa in Asia, it has been suggested that Myristicaceae had a similar history. Phylogenetic analyses of Myristicaceae, using morphology and several plastid regions, confirm that the ancestral area was Africa-Madagascar and that Asian taxa are derived. However, Myristicaceae as a whole show strikingly lower molecular divergence than Annonaceae, indicating either a much younger age or a marked slowdown in molecular evolution. The fact that the oldest diagnostic fossils of Myristicaceae are Miocene seeds might be taken as evidence that Myristicaceae are much younger than Annonaceae, but this is implausible in requiring transoceanic dispersal of their large, animal-dispersed seeds.

Sperm ultrastructure of the Actinocyclidae (Mollusca, Nudibranchia) and homology of the terminal region of nudibranch sperm

Sperm ultrastructure is examined and described for the actinocyclidid nudibranchs Actinocyclus verrucosus, Hallaxa iju and Hallaxa indecora. Although general characteristics were consistent with previously described heterobranch observations, present investigations revealed ultrastructural synapomorphies for the family based on the morphology of the terminal region of the spermatozoon. In actinocyclidids, the axonemal microtubules penetrate for some distance beyond the annulus, and the annular accessory body elongates to completely seal the terminal region. Chromodoris also has an annular accessory body that completely seals the axoneme and terminal region, but it does not extend far beyond the annulus, and it is possible that these states were derived independently. Cytochemical staining confirmed that there was no glycogen present in the posterior region of the sperm for H. indecora or Chromodoris kuniei. However, representatives of other chromodoridid genera (Noumea, Risbecia) have an axoneme that penetrates through the entire annular complex, after which it is sheathed by a glycogen deposit. Similarities in the acrosomal complex support the proposed sister group relationship between the Actinocyclidae and Chromodorididae.

Application of DNA parentage analyses for determining relative growth rates of Penaeus japonicus families reared in commercial ponds

The ability to track large numbers of individuals and families is a key determinant of the power and precision of breeding programs, including the capacity to quantify interactions between genotypes and their environment. Until recently, most family based selective breeding programs for shrimp, and other highly fecund aquaculture species, have been restricted by the number of animals that can be physically tagged and individually selected. Advances in the development of molecular markers, such as microsatellite loci, are now providing the means to track large numbers of individuals and families in commercial production systems. In this study microsatellites, coupled with DNA parentage analyses, were used to determine the relative performance of 22 families of R japonicus reared in commercial production ponds. In the experimental design 6000 post-larvae from each of 22 families, whose maternal parents had been genotyped at 8 microsatellite loci, were stocked into each of four I ha ponds. After 6 months the ponds were harvested and a total of 6000 individuals were randomly weighed from each pond. Mean wet weight of the shrimp from one pond was significantly lower than that of the other three ponds demonstrating a possible pond effect on growth rate. The representation of families in the top 10% of each pond's weight distribution was then determined by randomly genotyping up to 300 individuals from this upper weight class. Parentage analyses based on individual genotypic data demonstrated that some families were over-represented in the top 10% in all ponds, while others were under-represented due to slower growth rates. The results also revealed some weak, but significant, male genotype x environment (G x E) interactions in the expression of shrimp growth for some families. This indicates that G x E effects may need to be factored into future R japonicus selective breeding programs. This study demonstrated the utility of DNA parentage analyses for tracking individual family performance in communally stocked shrimp pond populations and, its application to examining G x E effects on trait expression under commercial culture conditions. Crown Copyright (c) 2005 Published by Elsevier B.V. All rights reserved.

Development of a web-service-agents-based family wealth management system

The roiling financial markets, constantly changing tax law and increasing complexity of planning transaction increase the demand of aggregated family wealth management (FWM) services. However, current trend of developing such advisory systems is mainly focusing on financial or investment side. In addition, these existing systems lack of flexibility and are hard to be integrated with other organizational information systems, such as CRM systems. In this paper, a novel architecture of Web-service-agents-based FWM systems has been proposed. Multiple intelligent agents are wrapped as Web services and can communicate with each other via Web service protocols. On the one hand, these agents can collaborate with each other and provide comprehensive FWM advices. On the other hand, each service can work independently to achieve its own tasks. A prototype system for supporting financial advice is also presented to demonstrate the advances of the proposed Webservice- agents-based FWM system architecture.

What the family brings: Gathering evidence for strengths-based work

Families attending child and adolescent mental health (CAMH) services are often assumed to have problems in key areas such as communication, belonging/acceptance and problem-solving. Family therapy is often directed towards addressing these difficulties. With increasing emphasis in family therapy and human services fields over the last decade on identifying and building from strengths, a different starting point has been advocated. This paper describes a large survey of the self-reported pre-therapy functioning of children and families using a public CAMH service (n = 416). Before commencing family therapy parents identified family strengths across a range of key areas, despite the burden of caring for children with moderate to severe mental health problems. This evidence supports theoretical and clinical work that advocates a strengths perspective, and highlights how resilience framed in family (and social) rather than individual terms enables a greater appreciation of how strengths may be harnessed in therapeutic work.

A national case-control study of Ewing's sarcoma family of tumours in Australia

Limited population-based epidemiologic information is available on Ewing's sarcoma family of tumours (ESFT), a rare group of neoplasms. Several associations have been noted on a few studies but results were not consistent, except for exposure to farming among cases and their parents. Here we present the non-farm findings of a nationwide case-control study of ESFT in children and young adults in Australia. The analysis included 106 persons with confirmed ESFT and 344 population-based controls selected randomly via telephone. Information was collected by interview (84% face to face). We found a strong and significant association of ESFT with hernias, in particular hernia repaired in hospital (OR = 5.6, 95% Cl 1.3-6.4). Among other factors, there was a near doubling of risk for males, and male cases had their pubertal signs earlier (started shaving earlier) than male controls. There was also an increased risk of ESFT at higher levels of self-assessed exercise, but no other factor really stood out. For pregnancy-related factors, there was a tripling of risk for glandular fever, a doubling of risk for urinary tract infection and a near doubling of risk for X-rays during or just before pregnancy, but these estimates were not significant. In addition, there was a large number of inverse associations with medical conditions (specifically bone disorders), case exposure to medications, vaccinations and X-rays, with ultrasound during the pregnancy having the most certain effects. We conclude that, although the aetiology of ESFT remains obscure, overall there is strong evidence of an association with inguinal hernia; this can now be added to the farm-associated risk reported by others and us. The other associations reported here await replication and refinement in future studies. (C) 2003 Wiley-Liss, Inc.

Family average income and body mass index above the healthy weight range among urban and rural residents in regional Mainland China

Objective: To explore the relationship between family average income (FAI; an index of socio-economic status) and body mass index (BMI; a widely used, inexpensive indicator of weight status) above the healthy weight range in a region of Mainland China. Design: Population-based cross-sectional study, conducted between October 1999 and March 2000 on a sample of regular local residents aged 35 years or older who were selected by random cluster sampling. Setting: Forty-five administrative villages selected from three urban districts and two rural counties of Nanjing municipality, Mainland China, with a regional population of 5.6 million. Subjects: In total, 29 340 subjects participated; 67.7% from urban and 32.3% from rural areas; 49.8% male and 50.2% female. The response rate among eligible participants was 90.1%. Results: The proportion of participants classified as overweight was 30.5%, while 7.8% were identified as obese. After adjusting for possible confounding variables (age, gender, area of residence, educational level, occupational and leisure-time physical activity, daily vegetable consumption and frequency of red meat intake), urban participants were more likely to be overweight or obese relative to their rural counterparts, more women than men were obese, and participants in the lowest FAI tertile were the least likely to be above the healthy weight range. Conclusions: The proportion of adults with BMI above the healthy weight range was positively related to having a higher socio-economic status (indexed by FAI) in a regional Chinese population.

Parent management training and Asperger syndrome - A randomized controlled trial to evaluate a parent based intervention

This controlled trial of a parent management intervention aimed to increase parental competence in management of problem behaviours associated with Asperger syndrome. The intervention compared two formats, a 1 day workshop and six individual sessions. Measures were taken on three occasions: pre-intervention, at 4 weeks, and at 3 month follow-up. Variables of interest were number and intensity of problem behaviours, and parent evaluation of social interaction skills. Results showed parents reporting fewer and lower intensity of problem behaviours and increased social interactions at 4 weeks and 3 months. Results held across formats and suggest that parent management training can provide an effective intervention for parents of a child with Asperger syndrome. Group differences on outcome measures and in the use of strategies are discussed along with limitations of the study.

Introducing evidence-based family assessment and therapy in child and youth mental health services: Applying systemic principles to maintain, sustain and build capacity

The purpose of this article is to overview the context of the mental health service in which we work, and family therapy's status prior to and after the impact of changes wrought by the introduction of the National Mental Health Policy. We then explore some key issues that we think contribute to the persistence of the occlusion of family therapy in child psychiatric services; and the strategies that we developed and are continuing to develop to support change, finally, we describe the use of a family assessment instrument that we believe is central to our change strategy.