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Background: Metabolic diseases such as obesity and diabetes are associated with changes in high-density lipoprotein (HDL) particles, including changes in particle size and protein composition, often resulting in abnormal function. Recent studies suggested that patients with non-alcoholic fatty liver disease (NAFLD), including individuals with non-alcoholic steatohepatitis (NASH), have smaller HDL particles when compared to individuals without liver pathologies. However, no studies have investigated potential changes in HDL particle protein composition in patients with NAFLD, in addition to changes related to obesity, to explore putative functional changes of HDL which may increase the risk of cardiovascular complications., Methods: From a cohort of morbidly obese females who were diagnosed with simple steatosis (SS), NASH, or normal liver histology, we selected five matched individuals from each condition for a preliminary pilot HDL proteome analysis. HDL particles were enriched using size-exclusion chromatography, and the proteome of the resulting fraction was analyzed by liquid chromatography tandem mass spectrometry. Differences in the proteomes between the three conditions (normal, SS, NASH) were assessed using label-free quantitative analysis. Gene ontology term analysis was performed to assess the potential impact of proteomic changes on specific functions of HDL particles., Results: Of the 95 proteins identified, 12 proteins showed nominally significant differences between the three conditions. Gene ontology term analysis revealed that severity of the liver pathology may significantly impact the anti-thrombotic functions of HDL particles, as suggested by changes in the abundance of HDL-associated proteins such as antithrombin III and plasminogen., Conclusions: The pilot data from this study suggest that changes in the HDL proteome may impact the functionality of HDL particles in NAFLD and NASH patients. These proteome changes may alter cardio-protective properties of HDL, potentially contributing to the increased cardiovascular disease risk in affected individuals. Further validation of these protein changes by orthogonal approaches is key to confirming the role of alterations in the HDL proteome in NAFLD and NASH. This will help elucidate the mechanistic effects of the altered HDL proteome on cardioprotective properties of HDL particles.

We undertook an RNA sequencing (RNAseq)-based transcriptomic profiling study on lymphoblastoid cell lines of a European ancestry sample of 529 schizophrenia cases and 660 controls, and found 1058 genes to be differentially expressed by affection status. These differentially expressed genes were enriched for involvement in immunity, especially the 697 genes with higher expression in cases. Comparing the current RNAseq transcriptomic profiling to our previous findings in an array-based study of 268 schizophrenia cases and 446 controls showed a highly significant positive correlation over all genes. Fifteen (18%) of the 84 genes with significant (false discovery rate<0.05) expression differences between cases and controls in the previous study and analyzed here again were differentially expressed by affection status here at a genome-wide significance level (Bonferroni P<0.05 adjusted for 8141 analyzed genes in total, or P<~6.1 × 10 -6 ), all with the same direction of effect, thus providing corroborative evidence despite each sample of fully independent subjects being studied by different technological approaches. Meta-analysis of the RNAseq and array data sets (797 cases and 1106 controls) showed 169 additional genes (besides those found in the primary RNAseq-based analysis) to be differentially expressed, and provided further evidence of immune gene enrichment. In addition to strengthening our previous array-based gene expression differences in schizophrenia cases versus controls and providing transcriptomic support for some genes implicated by other approaches for schizophrenia, our study detected new genes differentially expressed in schizophrenia. We highlight RNAseq-based differential expression of various genes involved in neurodevelopment and/or neuronal function, and discuss caveats of the approach.

Currently available methods for interrogating DNA-protein interactions at individual genomic loci have significant limitations, and make it difficult to work with unmodified cells or examine single-copy regions without specific antibodies. In this study, we describe a physiological application of the Hybridization Capture of Chromatin-Associated Proteins for Proteomics (HyCCAPP) methodology we have developed. Both novel and known locus-specific DNA-protein interactions were identified at the ENO2 and GAL1 promoter regions of Saccharomyces cerevisiae, and revealed subgroups of proteins present in significantly different levels at the loci in cells grown on glucose versus galactose as the carbon source. Results were validated using chromatin immunoprecipitation. Overall, our analysis demonstrates that HyCCAPP is an effective and flexible technology that does not require specific antibodies nor prior knowledge of locally occurring DNA-protein interactions and can now be used to identify changes in protein interactions at target regions in the genome in response to physiological challenges., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Populations and individuals differ in susceptibility to infections because of a number of factors, including host genetic variation. We previously demonstrated that differences in antibody titer, which reflect infection history, are significantly heritable. Here we attempt to identify the genetic factors influencing variation in these serological phenotypes. Blood samples from >1300 Mexican Americans were quantified for IgG antibody level against 12 common infections, selected on the basis of their reported role in cardiovascular disease risk: Chlamydia pneumoniae; Helicobacter pylori; Toxoplasma gondii; cytomegalovirus; herpes simplex I virus; herpes simplex II virus; human herpesvirus 6 (HHV6); human herpesvirus 8 (HHV8); varicella zoster virus; hepatitis A virus (HAV); influenza A virus; and influenza B virus. Pathogen-specific quantitative antibody levels were analyzed, as were three measures of pathogen burden. Genome-wide linkage and joint linkage and association analyses were performed using ~1 million SNPs. Significant linkage (lod scores >3.0) was obtained for HHV6 (on chromosome 7), HHV8 (on chromosome 6), and HAV (on chromosome 13). SNP rs4812712 on chromosome 20 was significantly associated with C. pneumoniae (P=5.3 × 10(-8)). However, no genome-wide significant loci were obtained for the other investigated antibodies. We conclude that it is possible to localize host genetic factors influencing some of these antibody traits, but that further larger-scale investigations will be required to elucidate the genetic mechanisms contributing to variation in antibody levels.

Increased immunoglobulin G (IgG) response to dietary antigens can be associated with gastrointestinal dysfunction and autoimmunity. The underlying processes contributing to these adverse reactions remain largely unknown, and it is likely that genetic factors play a role. Here, we estimate heritability and attempt to localize genetic factors influencing IgG antibody levels against food-derived antigens using an integrative genomics approach. IgG antibody levels were determined by ELISA in >1,300 Mexican Americans for the following food antigens: wheat gliadin; bovine casein; and two forms of bovine serum albumin (BSA-a and BSA-b). Pedigree-based variance components methods were used to estimate additive genetic heritability (h(2) ), perform genome-wide association analyses, and identify transcriptional signatures (based on 19,858 transcripts from peripheral blood lymphocytes). Heritability estimates were significant for all traits (0.15-0.53), and shared environment (based on shared residency among study participants) was significant for casein (0.09) and BSA-a (0.33). Genome-wide significant evidence of association was obtained only for antibody to gliadin (P = 8.57 × 10(-8) ), mapping to the human leukocyte antigen II region, with HLA-DRA and BTNL2 as the best candidate genes. Lack of association of known celiac disease risk alleles HLA-DQ2.5 and -DQ8 with antigliadin antibodies in the studied population suggests a separate genetic etiology. Significant transcriptional signatures were found for all IgG levels except BSA-b. These results demonstrate that individual genetic differences contribute to food antigen antibody measures in this population. Further investigations may elucidate the underlying immunological processes involved., (© 2014 WILEY PERIODICALS, INC.)

BACKGROUND- Intima-media thickness (IMT) of the common and internal carotid arteries is an established surrogate for atherosclerosis and predicts risk of stroke and myocardial infarction. Often IMT is measured as the average of these 2 arteries; yet, they are believed to result from separate biological mechanisms. The aim of this study was to conduct a family-based genome-wide association study (GWAS) for IMT to identify polymorphisms influencing IMT and to determine if distinct carotid artery segments are influenced by different genetic components. METHODS AND RESULTS- IMT for the common and internal carotid arteries was determined through B-mode ultrasound in 772 Mexican Americans from the San Antonio Family Heart Study. A GWAS using 931219 single-nucleotide polymorphisms was undertaken with 6 internal and common carotid artery IMT phenotypes using an additive measured genotype model. The most robust association detected was for 2 single-nucleotide polymorphisms (rs16983261, rs6113474; P=1.60e(-7)) in complete linkage disequilibrium on chromosome 20p11 for the internal carotid artery near wall, next to the gene PAX1. We also replicated previously reported GWAS regions on chromosomes 19q13 and 7q22. We found no overlapping associations between internal and common carotid artery phenotypes at P<5.0e(-6). The genetic correlation between the 2 carotid IMT arterial segments was 0.51. CONCLUSIONS- This study represents the first large-scale GWAS of carotid IMT in a non-European population and identified several novel loci. We do not detect any shared GWAS signals between common and internal carotid arterial segments, but the moderate genetic correlation implies both common and unique genetic components.

Infection with Epstein-Barr virus (EBV) is highly prevalent worldwide, and it has been associated with infectious mononucleosis and severe diseases including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal lymphoma, and lymphoproliferative disorders. Although EBV has been the focus of extensive research, much still remains unknown concerning what makes some individuals more sensitive to infection and to adverse outcomes as a result of infection. Here we use an integrative genomics approach in order to localize genetic factors influencing levels of Epstein Barr virus (EBV) nuclear antigen-1 (EBNA-1) IgG antibodies, as a measure of history of infection with this pathogen, in large Mexican American families. Genome-wide evidence of both significant linkage and association was obtained on chromosome 6 in the human leukocyte antigen (HLA) region and replicated in an independent Mexican American sample of large families (minimum p-value in combined analysis of both datasets is 1.4×10(-15) for SNPs rs477515 and rs2516049). Conditional association analyses indicate the presence of at least two separate loci within MHC class II, and along with lymphocyte expression data suggest genes HLA-DRB1 and HLA-DQB1 as the best candidates. The association signals are specific to EBV and are not found with IgG antibodies to 12 other pathogens examined, and therefore do not simply reveal a general HLA effect. We investigated whether SNPs significantly associated with diseases in which EBV is known or suspected to play a role (namely nasopharyngeal lymphoma, Hodgkin lymphoma, systemic lupus erythematosus, and multiple sclerosis) also show evidence of associated with EBNA-1 antibody levels, finding an overlap only for the HLA locus, but none elsewhere in the genome. The significance of this work is that a major locus related to EBV infection has been identified, which may ultimately reveal the underlying mechanisms by which the immune system regulates infection with this pathogen., Competing Interests: The authors have declared that no competing interests exist.

Individual differences in biological ageing (i.e., the rate of physiological response to the passage of time) may be due in part to genotype-specific variation in gene action. However, the sources of heritable variation in human age-related gene expression profiles are largely unknown. We have profiled genome-wide expression in peripheral blood mononuclear cells from 1240 individuals in large families and found 4472 human autosomal transcripts, representing ~4349 genes, significantly correlated with age. We identified 623 transcripts that show genotype by age interaction in addition to a main effect of age, defining a large set of novel candidates for characterization of the mechanisms of differential biological ageing. We applied a novel SNP genotype × age interaction test to one of these candidates, the ubiquilin-like gene UBQLNL, and found evidence of joint cis-association and genotype by age interaction as well as trans-genotype by age interaction for UBQLNL expression. Both UBQLNL expression levels at recruitment and cis genotype are associated with longitudinal cancer risk in our study cohort., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The delta-5 and delta-6 desaturases (D5D and D6D), encoded by fatty acid desaturase 1 (FADS1) and 2 (FADS2) genes, respectively, are rate-limiting enzymes in the metabolism of ω-3 and ω-6 fatty acids. The objective of this study was to identify genes influencing variation in estimated D5D and D6D activities in plasma and erythrocytes in Alaskan Eskimos (n = 761) participating in the genetics of coronary artery disease in Alaska Natives (GOCADAN) study. Desaturase activity was estimated by product: precursor ratio of polyunsaturated fatty acids. We found evidence of linkage for estimated erythrocyte D5D (eD5D) on chromosome 11q12-q13 (logarithm of odds score = 3.5). The confidence interval contains candidate genes FADS1, FADS2, 7-dehydrocholesterol reductase (DHCR7), and carnitine palmitoyl transferase 1A, liver (CPT1A). Measured genotype analysis found association between CPT1A, FADS1, and FADS2 single-nucleotide polymorphisms (SNPs) and estimated eD5D activity (p-values between 10(-28) and 10(-5)). A Bayesian quantitative trait nucleotide analysis showed that rs3019594 in CPT1A, rs174541 in FADS1, and rs174568 in FADS2 had posterior probabilities > 0.8, thereby demonstrating significant statistical support for a functional effect on eD5D activity. Highly significant associations of FADS1, FADS2, and CPT1A transcripts with their respective SNPs (p-values between 10(-75) and 10(-7)) in Mexican Americans of the San Antonio Family Heart Study corroborated our results. These findings strongly suggest a functional role for FADS1, FADS2, and CPT1A SNPs in the variation in eD5D activity.

Background: Gene identification using linkage, association, or genome-wide expression is often underpowered. We propose that formal combination of information from multiple gene-identification approaches may lead to the identification of novel loci that are missed when only one form of information is available., Methods: Firstly, we analyze the Genetic Analysis Workshop 16 Framingham Heart Study Problem 2 genome-wide association data for HDL-cholesterol using a "gene-centric" approach. Then we formally combine the association test results with genome-wide transcriptional profiling data for high-density lipoprotein cholesterol (HDL-C), from the San Antonio Family Heart Study, using a Z-transform test (Stouffer's method)., Results: We identified 39 genes by the joint test at a conservative 1% false-discovery rate, including 9 from the significant gene-based association test and 23 whose expression was significantly correlated with HDL-C. Seven genes identified as significant in the joint test were not independently identified by either the association or expression tests., Conclusion: This combined approach has increased power and leads to the direct nomination of novel candidate genes likely to be involved in the determination of HDL-C levels. Such information can then be used as justification for a more exhaustive search for functional sequence variation within the nominated genes. We anticipate that this type of analysis will improve our speed of identification of regulatory genes causally involved in disease risk.

The group that formed on the theme of linkage analyses of rheumatoid arthritis RA and related phenotypes (Group 10) in the Genetic Analysis Workshop 15 comprised 18 sets of investigators. Two data sets were available: one was a real set provided by the North American Rheumatoid Arthritis Consortium and collaborators in Canada, France (European Consortium Of Rheumatoid Arthritis Families) and the UK; the other was a simulated data set modelled after the real data set. Whereas a majority of the investigators analyzed the RA affection status as a binary phenotype, a few contributions considered data on correlated quantitative traits such as anti-cyclic citrullinated peptide and rheumatoid factor-immunoglobulin M. The different investigators applied a wide spectrum of linkage methods. As expected, most methods could identify the human leukocyfeantigen region on chromosome 6 as a major genetic factor for RA. In addition, some novel chromosomal regions provided significant evidence of linkage in multiple contributions in the group. In this report, we discuss the different strategies explored by the different investigators with the common goal of improving the power to detect linkage., (. (c) 2007 Wiley-Liss, Inc.)

The Hasemann-Elston method of linkage detection is based on the probabilities of a sib pair having 0, 1, or 2 alleles identical by descent (IBD) at a marker and a trait locus. These probabilities form a 3x3 matrix. Here, the characteristic values and characteristic vectors of this matrix were used to clarify the structure of the equations and to simplify calculations. As examples, the regression coefficients were derived for three genetic systems: a trait and a marker, two epistatic traits and two markers, and one trait locus and two markers. The last model was studied under the assumption of no crossover interference, the expression for allele IBD sharing at a trait locus was derived as a function of allele IBD sharing at two marker loci, and the regression is shown to be non-linear., (Copyright 1999 Academic Press.)

Methods of multiple comparisons were applied to linkage analysis in the case of genome scanning. Data for Problem 2A were used. p-Values were calculated for all 440,400 possible tests of linkage. Plots of distribution functions and false discovery rate are shown.

A genetic and epidemiological sample of 20-59-year-old males, Moscow residents (n = 3141), was surveyed. The authors obtained data on the prevalence of coronary heart disease from epidemiological criteria and genealogical data on cardiovascular diseases by the "Familial History" questionnaire in the first-degree relatives who were interviewed by using a genetic and mathematical monolocus diallelic model. It was found that out of the 10 possible variants under study a genetic and environmental variant with independent penetrance of 3 genotypes adequately describes the prevalence of coronary heart disease in the families and in the population. This suggest that both genetic and environmental factors have an influence on the prevalence of coronary heart disease and that there is a possible genetic polymorphism of the disease.

The ascertainment of probands according to place of residence in hospitals or in the community has enabled our sampling to be representative of whole subpopulations of patients. Probands from psychiatric hospitals are characterized by biased clinical parameters. Our sampling procedure provides important preliminary results which appear to be contradictory to those produced by conventional sampling methods.

Analysis of the character of the linear relation between the totality and some factors (the number of beds, psychiatrists working at hospitals and on an outpatient basis) that characterize the psychiatric services in 18 regions of Siberia and the Far East over 16 years as well as between the identification of new cases of schizophrenia, epilepsy, alcoholism, neuroses, psychoses and oligophrenia has demonstrated a high efficacy of the totality of factors. The differences have been shown between the regions in respect to the relation of the factors to the disease incidence, explained by the authors by the specificity of the organizational structure of the psychiatric services and by a number of other factors.

The method of estimation of parameters of monolocus diallele model (MDM) of qualitative trait on relative group data is described, these parameters being the number of affected and normal proband relatives of the arbitrary family degree and siblings in different matings types. For the case of single ascertainment, the expressions of corresponding probabilities have been taken as functions of MDM parameters using ITO matrixes and genetic transition matrix. Estimation of parameters was obtained by the maximum likelyhood method. Hardy-Weinberg equilibrium is not always necessary for this method; some weak requirement of stationarity is quite enough.

The article deals with the assessment of the main components and canonic correlations reflecting the relationship between the resources of psychiatric care (a number of beds and psychiatrists providing medical care in hospitals and in other settings) and the rate of identification and incidence of psychoses, schizophrenia, epilepsy, alcoholism, neuroses and oligophrenia in Siberia and Far East over a period of 16 years (from 1965 to 1981 excluding 1978). The first main component covered up to 80.1% of the dispersion range of the identification rate and 94.5% of the incidence rate, the second component covered up to 37.1% and 21% respectively. Canonic correlations proved higher for the incidence rate as against the identification rate. Although there were substantial differences in the studied interrelationship with regard to a number of territories, the main tendency was expressed in a marked linear correlation between a growth in the resources of psychiatric service and the time-course of the rates of the studied pathology.

Based on ITO matrices, a method for parameter estimation of the monolocus diallele model (MDM) of qualitative trait is described, taking account of non-genetic (environmental) factors. The model parameters, probabilities of relatives' affection, constructing the likelihood function and testing hypotheses of the effect of environmental factors on the penetrations of MDM genotypes are outlined. Examples are given, concerning estimation of epilepsy MDM parameters, taking account of two factors-harmfulness of antenatal ontogenesis period and harmfulness which provokes paroxysms.

The initial data for the analysis have resulted in epidemiologic (547 patients) and genetic-epidemiologic (365 patients) study of patients with diagnosis of epilepsy living in five districts of the Khabarovsk Territory. The population frequency of epilepsy was equal to 0.288%. With the use of data on numbers of sick and healthy first-third-degree relatives, and the method of maximum likelihood, the monolocus diallelic model (MDM) parameters of the family and population epilepsy prevalence were estimated. For each of 9 MDM variants two decisions were obtained, depending on the use of population probability of the feature. The analysis of 8 sets of initial data allowed to ascertain the influence of information about the first-third-degree relatives on parameter estimates. The calculation results are presented for one of initial data sets (set A). Three MDM variants were shown to predict the values of the relative affection probability, these being rather close to frequencies observed. The arguments are presented in favour of quasi-dominant variant with following parameters: frequency of mutant allele in a population - 5.28%, homozygote penetrance - 21.5% and that for heterozygote - 2.6%. According to parameter estimates within this model, the probability of offspring disease in the family with the known number of sick and healthy parents was calculated.

The authors have demonstrated the existence of linear correlation between the complex of three factors (the number of beds and psychiatrists in hospitals and outpatient clinics) and incidence rate (over a period of 16 years) of neuroses in 11 administrative areas, epilepsy, in 12 areas, psychoses, in 15, oligophrenia, in 17, alcoholism and schizophrenia in all 18 areas of Siberia and the Far East. Correlations of each of the three factors with the morbidity rate varied within a wide range in relation to both administrative areas and individual diseases. The authors draw attention to the importance of supplementing the growth of resources of psychiatric service with new forms and methods of work.