Mapping loci influencing blood pressure in the Framingham pedigrees using model-free LOD score analysis of a quantitative trait

This paper presents a method of performing model-free LOD-score based linkage analysis on quantitative traits. It is implemented in the QMFLINK program. The method is used to perform a genome screen on the Framingham Heart Study data. A number of markers that show some support for linkage in our study coincide substantially with those implicated in other linkage studies of hypertension. Although the new method needs further testing on additional real and simulated data sets we can already say that it is straightforward to apply and may offer a useful complementary approach to previously available methods for the linkage analysis of quantitative traits

The effect of increasingly stringent diagnostic criteria on sex differences in schizophrenia

Sex differences in premorbid function and symptomatology were examined as increasingly stringent criteria for schizophrenia were applied to 182 male and 139 female . psychotic patients. The male/female ratio rose from 1.6 among those meeting the CATEGO 'broad' criteria for schizophrenia to 3.7 among those satisfying DSM-III criteria. Of 76 women meeting the former criteria, 53 were excluded by the latter, the majority rediagnosed as affective or schizo-affective psychosis. Consequently, although women meeting CATEGO 'broad' criteria showed more affective and fewer typical schizophrenic symptoms than their male counterparts, these differences were abolished by DSM-III criteria. Among CATEGO 'broad' schizophrenics, men were more likely than women to have received special education, and had shown worse childhood social adjustment and worse adult social achievement than women. These differences disappeared among DSM-III schizophrenics, but women continued to have fewer premorbid schizoid and schizotypal traits, a greater likelihood of marriage, and a later age of onset

Strategies for the Study of Neuropsychiatric Disorders Using Endophenotypes in Developing Countries: A Potential Databank from China

Endophenotypic research can be considered to be one of the most promising strategies to bridge the gap between genomic complexity and the phenotypic heterogeneity observed in neuropsychiatric disorders. However, despite the promising and systematic work initiated by our western counterparts, this research strategy is still not well known in developing countries. Thus, the purpose of this paper is to argue the merits and promise of a potentially useful database on phenotypes and endophenotypes for developing countries

The genetic basis of onset age in schizophrenia: evidence and models

Schizophrenia is a heritable neurocognitive disorder affecting about 1% of the population, and usually has an onset age at around 21–25 in males and 25–30 in females. Recent advances in genetics have helped to identify many common and rare variants for the liability to schizophrenia. Earlier evidence appeared to suggest that younger onset age is associated with higher genetic liability to schizophrenia. Clinical longitudinal research also found that early and very-early onset schizophrenia are associated with poor clinical, neurocognitive, and functional profiles. A recent study reported a heritability of 0.33 for schizophrenia onset age, but the genetic basis of this trait in schizophrenia remains elusive. In the pre-Genome-Wide Association Study (GWAS) era, genetic loci found to be associated with onset age were seldom replicated. In the post-Genome-Wide Association Study era, new conceptual frameworks are needed to clarify the role of onset age in genetic research in schizophrenia, and to identify its genetic basis. In this review, we first discussed the potential of onset age as a characterizing/subtyping feature for psychosis, and as an important phenotypic dimension of schizophrenia. Second, we reviewed the methods, samples, findings and limitations of previous genetic research on onset age in schizophrenia. Third, we discussed a potential conceptual framework for studying the genetic basis of onset age, as well as the concepts of susceptibility, modifier, and “mixed” genes. Fourth, we discussed the limitations of this review. Lastly, we discussed the potential clinical implications for genetic research of onset age of schizophrenia, and how future research can unveil the potential mechanisms for this trait

An association study of ADSS gene polymorphisms with schizophrenia

<p>Abstract</p> <p>Background</p> <p>Adenylosuccinate synthase (ADSS) catalyzes the first committed step of AMP synthesis. It was suggested that the blood-derived RNA of ADSS was down-regulated in schizophrenia (SZ) and one of the eight putative biomarker genes to discriminate SZ from normal controls. However, it remains unclear whether the reduction of ADSS RNA is due to the polymorphisms of the gene or not.</p> <p>Methods</p> <p>We attempted to examine the association of ADSS gene with schizophrenia in a Chinese population of 480 schizophrenics and 502 normal controls. Genotyping was performed by the Sequenom platform.</p> <p>Results</p> <p>The 6 marker SNPs (rs3102460, rs3127459, rs3127460, rs3127465, rs3006001, and rs3003211) were genotyped. The frequencies of alleles, genotypes, and haplotypes were tested between cases and controls. There was no significant difference of genotypic, allelic, or haplotypic distributions of the 6 SNPs between the two groups.</p> <p>Conclusion</p> <p>Our data did not support ADSS gene as a susceptibility gene for SZ in Chinese Han population. Large sample size study is needed to validate or replicate our association study, especially from other ethnic populations.</p

Sacral agenesis: a pilot whole exome sequencing and copy number study

Background: Caudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes. Method: Whole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations. Results: In this pilot study, exome sequencing and copy number variation (CNV) analyses implicate a number of candidate genes, including SPTBN5, MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous). Importantly, predicted damaging mutations in PTEN (heterozygous), in its direct regulator GLTSCR2 (compound heterozygous) and in VANGL1 (heterozygous) were identified. These genes had previously been linked with the CRS phenotype. Two CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype. Conclusion: Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients

Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes

Background: Congenital dilatation of the bile-duct (CDD) is a rare, mostly sporadic, disorder that results in bile retention with severe associated complications. CDD affects mainly Asians. To our knowledge, no genetic study has ever been conducted. Methods: We aim to identify genetic risk factors by a “trio-based” exome-sequencing approach, whereby 31 CDD probands and their unaffected parents were exome-sequenced. Seven-hundred controls from the local population were used to detect gene-sets significantly enriched with rare variants in CDD patients. Results: Twenty-one predicted damaging de novo variants (DNVs; 4 protein truncating and 17 missense) were identified in several evolutionarily constrained genes (p &#60; 0.01). Six genes carrying DNVs were associated with human developmental disorders involving epithelial, connective or bone morphologies (PXDN, RTEL1, ANKRD11, MAP2K1, CYLD, ACAN) and four linked with cholangio- and hepatocellular carcinomas (PIK3CA, TLN1 CYLD, MAP2K1). Importantly, CDD patients have an excess of DNVs in cancer-related genes (p &#60; 0.025). Thirteen genes were recurrently mutated at different sites, forming compound heterozygotes or functionally related complexes within patients. Conclusions: Our data supports a strong genetic basis for CDD and show that CDD is not only genetically heterogeneous but also non-monogenic, requiring mutations in more than one genes for the disease to develop. The data is consistent with the rarity and sporadic presentation of CDD

Circulating Levels of Adipocyte and Epidermal Fatty Acid–Binding Proteins in Relation to Nephropathy Staging and Macrovascular Complications in Type 2 Diabetic Patients

OBJECTIVE—To investigate the relationships of serum adipocyte fatty acid–binding protein (A-FABP) and epidermal fatty acid–binding protein (E-FABP) with renal dysfunction and macrovascular complications in type 2 diabetic patients

A central resource for accurate allele frequency estimation from pooled DNA genotyped on DNA microarrays

Analysing pooled DNA on microarrays is an efficient way to genotype hundreds of individuals for thousands of markers for genome-wide association. Although direct comparison of case and control fluorescence scores is possible, correction for differential hybridization of alleles is important, particularly for rare single nucleotide polymorphisms. Such correction relies on heterozygous fluorescence scores and requires the genotyping of hundreds of individuals to obtain sufficient estimates of the correction factor, completely negating any benefit gained by pooling samples. We explore the effect of differential hybridization on test statistics and provide a solution to this problem in the form of a central resource for the accumulation of heterozygous fluorescence scores, allowing accurate allele frequency estimation at no extra cost

Predicting prognosis in hepatocellular carcinoma after curative surgery with common clinicopathologic parameters

<p>Abstract</p> <p>Background</p> <p>Surgical resection is one important curative treatment for hepatocellular carcinoma (HCC), but the prognosis following surgery differs substantially and such large variation is mainly unexplained. A review of the literature yields a number of clinicopathologic parameters associated with HCC prognosis. However, the results are not consistent due to lack of systemic approach to establish a prediction model incorporating all these parameters.</p> <p>Methods</p> <p>We conducted a retrospective analysis on the common clinicopathologic parameters from a cohort of 572 ethnic Chinese HCC patients who received curative surgery. The cases were randomly divided into training (n = 272) and validation (n = 300) sets. Each parameter was individually tested and the significant parameters were entered into a linear classifier for model building, and the prediction accuracy was assessed in the validation set</p> <p>Results</p> <p>Our findings based on the training set data reveal 6 common clinicopathologic parameters (tumor size, number of tumor nodules, tumor stage, venous infiltration status, and serum α-fetoprotein and total albumin levels) that were significantly associated with the overall HCC survival and disease-free survival (time to recurrence). We next built a linear classifier model by multivariate Cox regression to predict prognostic outcomes of HCC patients after curative surgery This analysis detected a considerable fraction of variance in HCC prognosis and the area under the ROC curve was about 70%. We further evaluated the model using two other protocols; leave-one-out procedure (n = 264) and independent validation (n = 300). Both were found to have excellent prediction power. The predicted score could separate patients into distinct groups with respect to survival (p-value = 1.8e-12) and disease free survival (p-value = 3.2e-7).</p> <p>Conclusion</p> <p>This described model will provide valuable guidance on prognosis after curative surgery for HCC in clinical practice. The adaptive nature allows easy accommodation for future new biomarker inputs, and it may serve as the foundation for future modeling and prediction for HCC prognosis after surgical treatment.</p