Common Genetic Origin Research Articles

Pediatric cardiomyopathies: Assessment of genetic causes by next generation sequencing of cardiomyopathy genes and genotype-phenotype correlation

Cardiomyopathies (CM) are cardiac muscle diseases of the young adults. In 30–60% of cases, a genetic origin is observed with most often an autosomal dominant transmission. Except for syndromic and metabolic diseases, pediatric forms of primary cardiomyopathies remains poorly known regarding their genetic etiology, and frequently present a severe evolution. The aim of the work is to determine the genetic causes of a primary cardiomyopathy in a cohort of 57 children diagnosed under 15 years, sequenced on a custom panel of 52 cardiomyopathy genes and attempt to correlate the disease causing gene with the severity of the phenotype. This cohort was composed of 57 patients (31 males and 26 females) including 24 HCM, 20 DCM and 13 other sub-types (RCM, LVNC). The overall mutation rate was 61%. Age of onset was significantly earlier in the patients ( P = 0.02) with DCM (4 ± 3.5 years) and with others CM (3 ± 3.5 years) than in HCM patients (7 ± 5 years). In patients with DCM and other CMs, the mutation rate was higher (14/20, 70% and 8/13, 62%, respectively) than in patients with HCM (13/24, 54%). Similarly, the proportion of patients carrying 2 pathogenic variants was higher in patients with DCM (35%) and other CMs (62%) than in HCM patients (23%). The mutated genes were predominantly sarcomeric genes (13/21) (MYH7, MYCPB3, TNNC1 etc). A significant rate of de novo mutations (5/49, 10%) was observed in the cohort. We report a cohort of genotyped pediatric cardiomyopathies analyzed on a large panel of genes. We observed a molecular cause in 61% of patients including more than 23% of patients were carrier of two disease causing variants, suggesting that the early and severe phenotype could be explained by the cumulative effect of several pathogenic dominant variants. The predominance of sarcomeric gene supported the hypothesis of a common genetic origin between adult and pediatric cardiomyopathy cases. Our results support genetic testing in pediatric cardiomyopathies.

Clonality and heterogeneity of metachronous colorectal cancer.

Patients with metachronous colorectal cancer (CRC) have been diagnosed with primary CRC more than once. Given that the genetic and microenvironment is the same in these cases, metachronous CRC is an important model for studying colorectal tumorigenesis. We performed whole exome sequencing of seven freshly frozen tumors from three patients with metachronous CRC and compared their genetic profiles. In patients with metachronous tumors of distinct genetic origins, 3.74% and 0.20% of genes were ubiquitously mutated and candidate cancer genes mutated at different sites. Tumors from the same patients were clonally unrelated, and thus druggable genes differed. In contrast, in a patient with metachronous tumors of a common genetic origin, the ubiquitously mutated genes were 61.02%, with ubiquitously mutated genes and candidate cancer genes all mutated at the same sites, tumors were clonally related, and some druggable genes were the same. Therefore, two different clonal relationships between metachronous tumors exist in CRC, one is monoclonal and the other is polyclonal. Our findings may help to advance understanding of the differences in metachronous CRCs and the genetic mechanisms of which they originate, and provide new avenues for CRC treatment.

Shared genetic aetiology between cognitive performance and brain activations in language and math tasks

Cognitive performance is highly heritable. However, little is known about common genetic influences on cognitive ability and brain activation when engaged in a cognitive task. The Human Connectome Project (HCP) offers a unique opportunity to study this shared genetic etiology with an extended pedigree of 785 individuals. To investigate this common genetic origin, we took advantage of the HCP dataset, which includes both language and mathematics activation tasks. Using the HCP multimodal parcellation, we identified areals in which inter-individual functional MRI (fMRI) activation variance was significantly explained by genetics. Then, we performed bivariate genetic analyses between the neural activations and behavioral scores, corresponding to the fMRI task accuracies, fluid intelligence, working memory and language performance. We observed that several parts of the language network along the superior temporal sulcus, as well as the angular gyrus belonging to the math processing network, are significantly genetically correlated with these indicators of cognitive performance. This shared genetic etiology provides insights into the brain areas where the human-specific genetic repertoire is expressed. Studying the association of polygenic risk scores, using variants associated with human cognitive ability and brain activation, would provide an opportunity to better understand where these variants are influential.

Massively parallel sequencing of 165 ancestry informative SNPs in two Chinese Tibetan-Burmese minority ethnicities

The Tibeto-Burman language, one subfamily of the Sino-Tibetan languages, is spoken by over 60 million people all over East Asia. Yet the ethnic origin and genetic architecture of Tibeto-Burman speaking populations remain largely unexplored. In the present study, 169 Chinese individuals from Tibeto-Burman speaking populations (two ethnic groups: Tibetan and Yi) in four different geographic regions in western China were analyzed using the Precision ID Ancestry Panel (165 AISNPs) and the Ion PGM System. The performance and corresponding forensic statistical parameters of this AISNPs panel were investigated. Comprehensive population genetic comparisons (143 populations based on Kidd’ SNPs, 92 populations on the basis of Seldin’ SNPs and 31 populations based on the Precision ID Ancestry Panel) and ancestry inference were further performed. Sequencing performance demonstrated that the Precision ID Ancestry Panel is effective and robust. Forensic characteristics suggested that this panel not only can be used for ancestry estimation of Tibeto-Burman populations but also for individual identification. Tibetan and Yi shared a common genetic ancestry origin but experienced the complex history of gene flow, local adaptation, and isolation, and constructed the specific genetic landscape of human genetic diversity of Highlander and Lowlander populations. Tibetan-Burman populations and other East Asian populations showed sufficient genetic difference and could be distinguished into three distinct groups. Furthermore, analysis of population structure revealed that significant genetic difference was existed inter-continent populations and strong genetic affinity was observed within-continent populations. Additional population-specific AISNPs and a relatively more comprehensive database with sufficient reference population data remain necessary to get better-scale resolution within a geographically proximate populations in East Asia.

A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection

Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease–disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy.

Heritable aspects of biological motion perception and its covariation with autistic traits

The ability to detect biological motion (BM) and decipher the meaning therein is essential to human survival and social interaction. However, at the individual level, we are not equally equipped with this ability. In particular, impaired BM perception and abnormal neural responses to BM have been observed in autism spectrum disorder (ASD), a highly heritable neurodevelopmental disorder characterized by devastating social deficits. Here, we examined the underlying sources of individual differences in two abilities fundamental to BM perception (i.e., the abilities to process local kinematic and global configurational information of BM) and explored whether BM perception shares a common genetic origin with autistic traits. Using the classical twin method, we found reliable genetic influences on BM perception and revealed a clear dissociation between its two components-whereas genes account for about 50% of the individual variation in local BM processing, global BM processing is largely shaped by environment. Critically, participants' sensitivity to local BM cues was negatively correlated with their autistic traits through the dimension of social communication, with the covariation largely mediated by shared genetic effects. These findings demonstrate that the ability to process BM, especially with regard to its inherent kinetics, is heritable. They also advance our understanding of the sources of the linkage between autistic symptoms and BM perception deficits, opening up the possibility of treating the ability to process local BM information as a distinct hallmark of social cognition.

Disentangling the effects of genetic and environmental factors on movement behaviour

AbstractIndividual variability in animal movement behaviour is well documented for many species. However, it remains unclear whether this variability reflects genetic variation, environmental variation or a combination of the two. Here, we conduct a cross‐fostering experiment with the aim of investigating the role of these two components in movement patterns during the post‐fledging dependence period and early natal dispersal of 21 eagle owls Bubo bubo. Our experiment showed that cross‐fostering did not influence any of the movement parameters considered. Movement parameters were, however, affected by the age and sex of the owlets. We therefore suggest that individual variability and family resemblance in movement behaviour during the post‐fledging dependence period and early natal dispersal might not be due to the common genetic origin of siblings, but rather that it originates from factors related to the rearing environment.

Detección del Virus del mosaico de la caña de azúcar (SCMV) en Saccharum spp. en México y origen filogenético de un aislado de Jalisco

<p>El <em>Virus de mosaico de la caña de azúcar</em> (SCMV) es uno de los principales agentes virales que infectan a caña de azúcar (<em>Saccharum </em>spp.). En México la detección del SCMV se ha basado en sintomatología típica de la enfermedad, por lo que la información no es concluyente, además hay poca información sobre su origen filogenético. El objetivo del trabajo fue detectar mediante RTPCR La presencia y distribución del SCMV en las zonas cañeras de los estados de Colima, Jalisco y Nayarit, México y determinar el origen filogenético de un aislado de Jalisco. Los resultados obtenidos demuestran la amplia distribución del SCMV en la región cañera del Pacífico de México. De las 242 muestras analizadas se detectó al virus en 33 de ellas, lo que corresponde a un 13.63%. Las variedades Mex 69-290 y CP 72-2086 fueron las que presentaron los síntomas de mosaico más severos. El análisis filogenético con la secuencia parcial HC-Pro del SCMV aislado de Jalisco (JalMex-126) sugiere una estrecha relación con aislados de la India, Australia, China y Argentina, por lo que probablemente compartan un origen genético común y se hayan dispersado a través de germoplasma de caña de azúcar infectado.</p>

Introduction history overrides social factors in explaining genetic structure of females in Mediterranean mouflon.

Fine‐scale spatial genetic structure of populations results from social and spatial behaviors of individuals such as sex‐biased dispersal and philopatry. However, the demographic history of a given population can override such socio‐spatial factors in shaping genetic variability when bottlenecks or founder events occurred in the population. Here, we investigated whether socio‐spatial organization determines the fine‐scale genetic structure for both sexes in a Mediterranean mouflon (Ovis gmelini musimon × Ovis sp.) population in southern France 60 years after its introduction. Based on multilocus genotypes at 16 loci of microsatellite DNA (n = 230 individuals), we identified three genetic groups for females and two for males, and concurrently defined the same number of socio‐spatial units using both GPS‐collared individuals (n = 121) and visual resightings of marked individuals (n = 378). The socio‐spatial and genetic structures did not match, indicating that the former was not the main driver of the latter for both sexes. Beyond this structural mismatch, we found significant, yet low, genetic differentiation among female socio‐spatial groups, and no genetic differentiation in males, with this suggesting female philopatry and male‐biased gene flow, respectively. Despite spatial disconnection, females from the north of the study area were genetically closer to females from the south, as indicated by the spatial analysis of the genetic variability, and this pattern was in accordance with the common genetic origin of their founders. To conclude, more than 14 generations later, genetic signatures of first introduction are not only still detectable among females, but they also represent the main factor shaping their present‐time genetic structure.

P.62 - Genotype-phenotype correlations in a French cohort with Becker muscular dystrophy: focus on cognitive aspects

Becker muscular dystrophy (BMD) shares phenotypic similarities with Duchenne muscular dystrophy (DMD) because of their common genetic origin. Mutations involving Dp71 and Dp140 isoforms are known to be associated with mental retardation in DMD and BMD. The aim of our work was to study genotype- phenotype correlations in BMD patients with a particular interest to the cognitive functions. It was a bicentric, bispective, observational study in two French neuromuscular centers. Genetic, neurologic, cardiologic, respiratory data have been collected. Prospective part consisted on performing Montreal cognitive (MOCA) assessment to evaluate cognitive impairment. Statistics were performed with the R software. 54 patients were included in the retrospective study (mean age: 36 y.o; 5–63). 19 patients have been included in the prospective part. Half of patients who experienced first symptoms in adulthood were still ambulant. Non-ambulant patients have lost walking with a mean age of 38,2 years. 1/3 had cardiac involvement and 10% a respiratory failure. We did not find genotype-phenotype correlations for these features. 75% of pediatric patients had academic difficulties and the majority had adaptive schooling. For the prospective part, the average score in MOCA test was 25,1, which is lower than normal population (>26). There were no significant differences in these difficulties between patients who had mutations involving Dp71 and Dp140 mutations and the other ones. Although mutations affecting Dp71 and Dp140 are known in the literature to be associated with more prevalence of mental retardation in BMD, we could not find this association in our population. Physiopathology of cognitive impairment in dystrophinopathies is not well known. Nevertheless, we could confirm that it is a whole part of these diseases and should be evaluated and managed.

Characterizing cosmochemical materials with genetic affinities to the Earth: Genetic and chronological diversity within the IAB iron meteorite complex

The IAB iron meteorite complex consists of a main group (MG) and five chemical subgroups (sLL, sLM, sLH, sHL, and sHH). Here, mass-independent Mo and radiogenic 182W isotope compositions are reported for IAB complex meteorites to evaluate the genetics and chronology, respectively, of the MG and subgroups. Osmium isotopes are used to correct for cosmic ray exposure effects on isotopes of Mo and W. The MG and three subgroups (i.e., sLL, sLM, and sLH), characterized by low Au abundances, have the same Mo isotopic compositions within analytical uncertainty, consistent with a common genetic origin. These meteorites, together with winonaites, are the only cosmochemical materials yet identified with Mo isotopic compositions that are identical to Earth. The Mo isotopic compositions of two subgroups characterized by higher Au abundances (sHL and sHH) are identical to one another within uncertainty, but differ from the low Au subgroups, indicating derivation from genetically distinct materials.The MG has a 182W, post calcium–aluminum inclusion (CAI) formation model age of 3.4±0.7 Ma. One of the low Au subgroups (sLM) is ∼1.7 Ma younger, whereas the high Au subgroups are ∼1.5–3 Ma older. The new Mo–W data, coupled with chemical data, indicate that the MG and the low Au subgroups formed in different impact-generated melts, some of which evidently formed on a chemically disparate, but genetically identical parent body. The high Au subgroups likely formed via core-formation processes on separate, internally-heated parent bodies from other IAB subgroups. The IAB complex meteorites fall on a linear trend defined by 94Mo/96Mo vs. 95Mo/96Mo, along with most other iron meteorite groups. Variation along this line was caused by mixing between at least two nebular components. One component was likely a pure s-process enriched nucleosynthetic carrier, and the other a homogenized nebular component. Sombrerete, currently classified as an sHL iron, has a Mo isotopic composition that is distinct from all IAB complex meteorites analyzed here. Along with group IVB iron meteorites and some ungrouped iron meteorites, it falls on a separate line from other meteorites which may reflect addition of an r-process-enriched component, and it should no longer be classified as a IAB iron.

Light rare earth element systematics as a tool for investigating the petrogenesis of phoscorite-carbonatite associations, as exemplified by the Phalaborwa Complex, South Africa

In-situ trace element analyses of fluorapatite, calcite, dolomite, olivine, and phlogopite have been undertaken on representative phoscorite and carbonatite rocks of the Palaeoproterozoic Phalaborwa Complex. Textural and compositional characterization reveals uniformity of fluorapatite and calcite among most of the intrusions, and seems to favor a common genetic origin for the phoscorite-carbonatite association. Representing major repositories for rare earth elements (REE), fluorapatite and calcite exhibit tightly correlated light REE (LREE) abundances, suggesting that partitioning of LREE into these rock forming minerals was principally controlled by simple igneous differentiation. However, light rare earth element distribution in apatite and calcite cannot be adequately explained by equilibrium and fractional crystallization and instead favors a complex crystallization history involving mixing of compositionally distinct magma batches, in agreement with previously reported mineral isotope variability that requires open-system behaviour.

Genetic Correlation between Body Fat Percentage and Cardiorespiratory Fitness Suggests Common Genetic Etiology.

ObjectivesIt has long been discussed whether fitness or fatness is a more important determinant of health status. If the same genetic factors that promote body fat percentage (body fat%) are related to cardiorespiratory fitness (CRF), part of the concurrent associations with health outcomes could reflect a common genetic origin. In this study we aimed to 1) examine genetic correlations between body fat% and CRF; 2) determine whether CRF can be attributed to a genetic risk score (GRS) based on known body fat% increasing loci; and 3) examine whether the fat mass and obesity associated (FTO) locus associates with CRF.MethodsGenetic correlations based on pedigree information were examined in a family based cohort (n = 230 from 55 families). For the genetic association analyses, we examined two Danish population-based cohorts (ntotal = 3206). The body fat% GRS was created by summing the alleles of twelve independent risk variants known to associate with body fat%. We assessed CRF as maximal oxygen uptake expressed in millilitres of oxygen uptake per kg of body mass (VO2max), per kg fat-free mass (VO2maxFFM), or per kg fat mass (VO2maxFM). All analyses were adjusted for age and sex, and when relevant, for body composition.ResultsWe found a significant negative genetic correlation between VO2max and body fat% (ρG = -0.72 (SE ±0.13)). The body fat% GRS associated with decreased VO2max (β = -0.15 mL/kg/min per allele, p = 0.0034, age and sex adjusted). The body fat%-increasing FTO allele was associated with a 0.42 mL/kg/min unit decrease in VO2max per allele (p = 0.0092, age and sex adjusted). Both associations were abolished after additional adjustment for body fat%. The fat% increasing GRS and FTO risk allele were associated with decreased VO2maxFM but not with VO2maxFFM.ConclusionsOur findings suggest a shared genetic etiology between whole body fat% and CRF.

Identification by the DArTseq method of the genetic origin of the Coffea canephora cultivated in Vietnam and Mexico.

BackgroundThe coffee species Coffea canephora is commercially identified as “Conilon” when produced in Brazil, or “Robusta” when produced elsewhere in the world. It represents approximately 40 % of coffee production worldwide. While the genetic diversity of wild C. canephora has been well studied in the past, only few studies have addressed the genetic diversity of currently cultivated varieties around the globe. Vietnam is the largest Robusta producer in the world, while Mexico is the only Latin American country, besides Brazil, that has a significant Robusta production. Knowledge of the genetic origin of Robusta cultivated varieties in countries as important as Vietnam and Mexico is therefore of high interest.ResultsThrough the use of Sequencing-based diversity array technology-DArTseq method-on a collection of C. canephora composed of known accessions and accessions cultivated in Vietnam and Mexico, 4,021 polymorphic SNPs were identified. We used a multivariate analysis using SNP data from reference accessions in order to confirm and further fine-tune the genetic diversity of C. canephora. Also, by interpolating the data obtained for the varieties from Vietnam and Mexico, we determined that they are closely related to each other, and identified that their genetic origin is the Robusta Congo – Uganda group.ConclusionsThe genetic characterization based on SNP markers of the varieties grown throughout the world, increased our knowledge on the genetic diversity of C. canephora, and contributed to the understanding of the genetic background of varieties from very important coffee producers. Given the common genetic origin of the Robusta varieties cultivated in Vietnam, Mexico and Uganda, and the similar characteristics of climatic areas and relatively high altitude where they are grown, we can state that the Vietnamese and the Mexican Robusta have the same genetic potential to produce good cup quality.Electronic supplementary materialThe online version of this article (doi:10.1186/s12870-016-0933-y) contains supplementary material, which is available to authorized users.

A highly invasive subpopulation of MDA-MB-231 breast cancer cells shows accelerated growth, differential chemoresistance, features of apocrine tumors and reduced tumorigenicity in vivo.

The acquisition of an invasive phenotype is a prerequisite for metastasization, yet it is not clear whether or to which extent the invasive phenotype is linked to other features characteristic of metastatic cells. We selected an invasive subpopulation from the triple negative breast cancer cell line MDA-MB-231, performing repeated cycles of preparative assays of invasion through Matrigel covered membranes. The invasive sub-population of MDA-MB-231 cells exhibits stronger migratory capacity as compared to parental cells confirming the highly invasive potential of the selected cell line. Prolonged cultivation of these cells did not abolish the invasive phenotype. ArrayCGH, DNA index quantification and karyotype analyses confirmed a common genetic origin of the parental and invasive subpopulations and revealed discrete structural differences of the invasive subpopulation including increased ploidy and the absence of a characteristic amplification of chromosome 5p14.1-15.33. Gene expression analyses showed a drastically altered expression profile including features of apocrine breast cancers and of invasion related matrix-metalloproteases and cytokines. The invasive cells showed accelerated proliferation, increased apoptosis, and an altered pattern of chemo-sensitivity with lower IC50 values for drugs affecting the mitotic apparatus. However, the invasive cell population is significantly less tumorigenic in orthotopic mouse xenografts suggesting that the acquisition of the invasive capacity and the achievement of metastatic growth potential are distinct events.

Composition of Large Zoned Aluminum Phosphate Sulfate Minerals: Implications For Fluid Evolution In the Centennial Uranium Deposit Area, Athabasca Basin, Saskatchewan, Canada

Abstract Aluminum phosphate sulfate (APS) minerals associated with the Athabasca Basin are compositionally part of the alunite group. Typically 5–20 μm in size, they accompany the regional diagenetic-hydrothermal illite-kaolinite-dickite assemblage in the Athabasca Group sandstones, the illite-sudoite assemblage of the altered paleo-regolith, and alteration zones surrounding uranium deposits. In the vicinity of the Centennial deposit, where illite and sudoite replace coarse-grained aluminosilicate porphyroblasts in the basement phyllitic pelites, cubic APS crystals are as large as 80 μm. Detailed petrography indicates that the APS crystals form broadly coeval to illite. Backscattered electron imaging, elemental mapping, and compositional analysis reveal complex zoning as well as later hydrothermal alteration of the APS crystals. Growth-zoned crystals are a solid solution between crandallite-goyazite-svanbergite [Sr 0.17–0.32 Ca 0.0.18–0.28 LREE 0.0.25–0.46 (Al 2.78–2.92 Fe 0.01–014 )(PO 4 ) 1.82–2.03 (SO 4 ) 0.14–0.35 (OH) 6 ], whereas the later alteration of the APS minerals results in a compositional shift to endmember florencite [Sr 0.15 Ca 0.11 LREE 0.57 (Al 2.86 Fe 0.02 )(PO 4 ) 1.98 (SO 4 ) 0.15 (OH) 6 ]. Fluids responsible for the alteration of APS to florencite are paragenetically linked to late hydrothermal fluids associated with mafic Mackenzie dikes and do not appear to be related to proximity to uranium mineralization. Both zoned and altered portions of the crystals have bulk compositions that overlap with APS minerals in other areas of the basin suggesting a common genetic origin. However, it is critical to link the paragenetic context to observed compositional changes. An increase in MREE from early to late stages of zoned crystal growth correlates with the greatest concentration of REE found in uraninite from unconformity-related uranium deposits. This could be a link between broader APS growth and uraninite precipitation.

Non-targeted metabolomics combined with genetic analyses identifies bile acid synthesis and phospholipid metabolism as being associated with incident type 2 diabetes.

Identification of novel biomarkers for type 2 diabetes and their genetic determinants could lead to improved understanding of causal pathways and improve risk prediction. In this study, we used data from non-targeted metabolomics performed using liquid chromatography coupled with tandem mass spectrometry in three Swedish cohorts (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1138; Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS], n = 970; TwinGene, n = 1630). Metabolites associated with impaired fasting glucose (IFG) and/or prevalent type 2 diabetes were assessed for associations with incident type 2 diabetes in the three cohorts followed by replication attempts in the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort (n = 855). Assessment of the association of metabolite-regulating genetic variants with type 2 diabetes was done using data from a meta-analysis of genome-wide association studies. Out of 5961 investigated metabolic features, 1120 were associated with prevalent type 2 diabetes and IFG and 70 were annotated to metabolites and replicated in the three cohorts. Fifteen metabolites were associated with incident type 2 diabetes in the four cohorts combined (358 events) following adjustment for age, sex, BMI, waist circumference and fasting glucose. Novel findings included associations of higher values of the bile acid deoxycholic acid and monoacylglyceride 18:2 and lower concentrations of cortisol with type 2 diabetes risk. However, adding metabolites to an existing risk score improved model fit only marginally. A genetic variant within the CYP7A1 locus, encoding the rate-limiting enzyme in bile acid synthesis, was found to be associated with lower concentrations of deoxycholic acid, higher concentrations of LDL-cholesterol and lower type 2 diabetes risk. Variants in or near SGPP1, GCKR and FADS1/2 were associated with diabetes-associated phospholipids and type 2 diabetes. We found evidence that the metabolism of bile acids and phospholipids shares some common genetic origin with type 2 diabetes. Metabolomics data have been deposited in the Metabolights database, with accession numbers MTBLS93 (TwinGene), MTBLS124 (ULSAM) and MTBLS90 (PIVUS).

Network analysis of genes and their association with diseases

A plethora of network-based approaches within the Systems Biology universe have been applied, to date, to investigate the underlying molecular mechanisms of various human diseases. In the present study, we perform a bipartite, topological and clustering graph analysis in order to gain a better understanding of the relationships between human genetic diseases and the relationships between the genes that are implicated in them. For this purpose, disease-disease and gene-gene networks were constructed from combined gene-disease association networks. The latter, were created by collecting and integrating data from three diverse resources, each one with different content covering from rare monogenic disorders to common complex diseases. This data pluralism enabled us to uncover important associations between diseases with unrelated phenotypic manifestations but with common genetic origin. For our analysis, the topological attributes and the functional implications of the individual networks were taken into account and are shortly discussed. We believe that some observations of this study could advance our understanding regarding the etiology of a disease with distinct pathological manifestations, and simultaneously provide the springboard for the development of preventive and therapeutic strategies and its underlying genetic mechanisms.

Detecting shared pathways linked to rheumatoid arthritis with other autoimmune diseases in a in silico analysis

Pathway-based analysis approach has exploded in use during the last several years. It is successful in recognizing additional biological insight of disease and finding groupings of risk genes that represent disease developing processes. Therefore, shared pathways, with pleiotropic effects, are important for understanding similar pathogenesis and indicating the common genetic origin of certain diseases. Here, we present a pathway analysis to reveal the potential disease associations between RA and three potential RA-related autoimmune diseases: psoriasis, diabetes mellitus, type 1 (T1D) and systemic lupus erythematosus (SLE). First, a comprehensive knowledge mining of public databases is performed to discover risk genes associated with RA, T1D, SLE and psoriasis; then by enrichment test of these genes, disease-related risk pathways are detected to recognize the pathways common for RA and three other diseases. Finally, the underlying disease associations are evaluated with the association rules mining method. In total, we identify multiple RA risk pathways with significant pleiotropic effects, the most unsurprising of which are the immunology related pathways. Meanwhile for the first time we highlight the involvement of the viral myocarditis pathway related to cardiovascular disease (CVD) in autoimmune diseases such as RA, psoriasis, T1D and SLE. Further Association rule mining results validate the strong association between RA and T1D and RA and SLE. It is clear that pleiotropy is a common property of pathways associated with disease traits. We provide novel pathway associations among RA and three autoimmune diseases. These results ascertain that there are shared genetic risk profiles that predispose individuals to autoimmune diseases.

Clear cell ovarian cancer and endometriosis: is there a relationship?

IntroductionOvarian clear cell carcinoma is a rare type of ovarian cancer. In recent years, issues of the common genetic origin of endometriosis and ovarian clear cell carcinoma have been raised.Aim of this studyAim of this study was to evaluate the prevalence of this type of cancer, risk factors, prognosis and its potential aetiological association with endometriosis.Material and methodsIn a retrospective study, we analysed histopathological data of patients operated in the First Department of Gynaecology and Obstetrics (MU, Lodz) due to ovarian cancer in 2004-2014. Among the 394 patients operated on for ovarian cancer, clear cell carcinoma was found in 0.02% (9/394). Menstrual history, parity, comorbidities, data from physical examination, operational protocols and histopathological diagnoses were analysed. Follow-up was obtained from 77.8% of patients. Statistical analysis was performed using Microsoft Excel 2013.ResultsThe mean age of patients at diagnosis was 57.6 years; the BMI in the study group was 27.2; the majority of patients were multiparous (77.8%). Clear cell carcinoma was detected mostly at stage Ia (n = 4). The concentration of Ca125 in the study group had an average of 142.75 U/ml and a median of 69.3 U/ml. The coexistence of endometriosis could not be clinically or histologically confirmed amongst our patients. The most common comorbidity in the study group was hypertension.ConclusionsIn our clinical material, ovarian clear cell carcinoma is a rare histopathological specimen with a prognostic value comparable to that of serous ovarian cancer. Due to the rarity of this histopathological subtype, proving a cause-and-effect relationship between it and endometriosis can only be elucidated through statistical studies of the entire population.