These profiles may ultimately be useful in targeting decision support tools and services. In plants, relationships between resistance to herbivorous insect pests and growth are typically controlled by complex interactions between genetically correlated traits. These relationships often result in tradeoffs in phenotypic expression. In this study we used genetical genomics to elucidate genetic relationships between tree growth and resistance to white pine terminal weevil Pissodes strobi Peck.
Genetical genomics uses genetic perturbations caused by allelic segregation in pedigrees to co-locate quantitative trait loci QTLs for gene expression and quantitative traits. Bark tissue of apical leaders from trees was assayed for gene expression using a For a composite resistance phenotype of six attack and oviposition traits, positional candidate genes were identified. These results will enable future work on functional genetic studies of insect resistance in spruce, and provide valuable information about candidate genes for genetic improvement of spruce. An important part of the coordinated care by experienced health care teams for all Pompe disease patients, whether diagnosed through newborn screening NBS , clinical diagnosis, or prenatal diagnosis, is genetic counseling.
Genetic counseling helps families better understand medical recommendations and options presented by the patient's health care team so they can make informed decisions. In addition to providing important information about the inheritance and genetic risks , genetic counseling also provides information about Pompe disease and available treatments and resources and should be offered to families with an affected child and all adults diagnosed with Pompe disease. Although the need for genetic counseling after a positive newborn screen for Pompe disease is recognized, the role that genetic counseling plays for both families of affected patients and health care teams is not fully understood.
Consistent best genetic counseling practices also are lacking. It is intended to help guide genetic counseling efforts and provide a clear understanding of the role for families or carriers of Pompe disease identified through NBS; explain special considerations eg, diagnosis of late-onset Pompe disease before the appearance of symptoms and the impact and implications associated with a diagnosis eg, determination of genetic risk and carrier status and preconception counseling ; and provide health care teams caring for patients with a framework for a standardized approach to genetic counseling for patients and at- risk family members.
Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort. Single-nucleotide polymorphisms SNPs associated with melanoma have been identified though genome-wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk.
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We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women. Genetic risk scores were calculated using 21 genome-wide association study-significant SNPs. Their combined effect on melanoma development was evaluated in 19, postmenopausal white women in the clinical trial and observational study arms of the Women's Health Initiative dataset. Compared to the tertile of weighted genetic risk score with the lowest genetic risk , the women in the tertile with the highest genetic risk were 1.
The incremental change in c-index from adding genetic risk scores to age were 0. Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Women's Health Initiative cohort. Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available. Published by Elsevier Inc. Quantifying introgression risk with realistic population genetics. Introgression is the permanent incorporation of genes from the genome of one population into another.
This can have severe consequences, such as extinction of endemic species, or the spread of transgenes. Quantification of the risk of introgression is an important component of genetically modified crop regulation. Most theoretical introgression studies aimed at such quantification disregard one or more of the most important factors concerning introgression: In addition, the use of linkage as a risk mitigation strategy has not been studied properly yet with genetic introgression models. Current genetic introgression studies fail to take repeated invasions and demographic stochasticity into account properly, and use incorrect measures of introgression risk that can be manipulated by arbitrary choices.
In this study, we present proper methods for risk quantification that overcome these difficulties. We generalize a probabilistic risk measure, the so-called hazard rate of introgression, for application to introgression models with complex genetics and small natural population sizes. We illustrate the method by studying the effects of linkage and recombination on transgene introgression risk at different population sizes. Extreme tolerance to highly toxic dioxin-like contaminants DLCs has evolved independently and contemporaneously in at least four populations of Atlantic killifish Fundulus heteroclitus.
We hypothesized that comparisons among tolerant populations and in contrast to their sensitive neighboring killifish might reveal genetic loci associated with DLC tolerance. Since the aryl hydrocarbon receptor AHR pathway partly or fully mediates DLC toxicity in vertebrates, we identified single nucleotide polymorphisms SNPs from 43 genes associated with the AHR to serve as targeted markers. Wild fish from the four highly tolerant killifish populations and four nearby sensitive populations were genotyped using 59 SNP markers. Consistent with other killifish population genetic analyses, our results revealed strong genetic differentiation among populations, consistent with isolation by distance models.
Pairwise comparisons of nearby tolerant and sensitive populations revealed differentiation among these loci: By grouping tolerant versus sensitive populations, we also identified cytochrome P 1A and the AHR2 loci as under selection, lend. Unconventional PS sequence identified in genetically modified maize. In this research we report the finding of an alternative PS sequence and its incidence in GM maize marketed in Jordan. Occupational and genetic risk factors for osteoarthritis: Although published studies have described several risk factors for OA, very few studies have investigated the occupational and genetic factors that contribute to this debilitating condition.
Other factors include kneeling and regular stair climbing, crawling, bending and whole body vibration, and repetitive movements.
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Numerous studies have also shown the influence of genetic variability in the pathogenesis of OA. Genetic variants of several groups of genes e. Although genetic association studies performed to date identified a number of risk variants, some of these associations have not been consistently replicated across different studies and populations.
Therefore, more research is needed. Will health insurance cover the costs of genetic testing? What are the benefits of genetic testing? What are the risks and limitations of genetic testing? Characterizing the genetic influences on risk aversion. Risk aversion has long been cited as an important factor in retirement decisions, investment behavior, and health. Some of the heterogeneity in individual risk tolerance is well understood, reflecting age gradients, wealth gradients, and similar effects, but much remains unexplained. This study explores genetic contributions to heterogeneity in risk aversion among older Americans.
Using over 2 million genetic markers per individual from the U. Health and Retirement Study, I report results from a genome-wide association study GWAS on risk preferences using a sample of 10, adults. These results suggest that risk aversion is a complex trait that is highly polygenic. The analysis leads to upper bounds on the number of genetic effects that could exceed certain thresholds of significance and still remain undetected at the current sample size. The findings suggest that the known heritability in risk aversion is likely to be driven by large numbers of genetic variants, each with a small effect size.
Genetic Susceptibility to Vitiligo: Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies.
Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study GWAS. More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified , indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo.
In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo.
Risk factors identified for certain lymphoma subtypes. In a large international collaborative analysis of risk factors for non-Hodgkin lymphoma NHL , scientists were able to quantify risk associated with medical history, lifestyle factors, family history of blood or lymph-borne cancers, and occupation for Understanding associations between genotypes and complex traits is a fundamental problem in human genetics.
A major open problem in mapping phenotypes is that of identifying a set of interacting genetic variants, which might contribute to complex traits. Logic regression LR is a powerful multivariant association tool.
Several LR-based approaches have been successfully applied to different datasets. However, these approaches are not adequate with regard to accuracy and efficiency. In this paper, we propose a new LR-based approach, called fish-swarm logic regression FSLR , which improves the logic regression process by incorporating swarm optimization.
In our approach, a school of fish agents are conducted in parallel. Each fish agent holds a regression model, while the school searches for better models through various preset behaviors. A swarm algorithm improves the accuracy and the efficiency by speeding up the convergence and preventing it from dropping into local optimums.
We apply our approach on a real screening dataset and a series of simulation scenarios. Compared to three existing LR-based approaches, our approach outperforms them by having lower type I and type II error rates, being able to identify more preset causal sites, and performing at faster speeds.
Genetic determinants of financial risk taking. Individuals vary in their willingness to take financial risks. Here we show that variants of two genes that regulate dopamine and serotonin neurotransmission and have been previously linked to emotional behavior, anxiety and addiction 5-HTTLPR and DRD4 are significant determinants of risk taking in investment decisions.
These findings contribute to the emerging literature on the genetic determinants of economic behavior. Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.
Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive.
We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels P genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes.
We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score.
Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary. Genetic testing and your cancer risk. Genetically identified spinal interneurons integrating tactile afferents for motor control. Our movements are shaped by our perception of the world as communicated by our senses. Perception of sensory information has been largely attributed to cortical activity. However, a prior level of sensory processing occurs in the spinal cord.
Indeed, sensory inputs directly project to many spinal circuits, some of which communicate with motor circuits within the spinal cord. Therefore, the processing of sensory information for the purpose of ensuring proper movements is distributed between spinal and supraspinal circuits.
The mechanisms underlying the integration of sensory information for motor control at the level of the spinal cord have yet to be fully described. Recent research has led to the characterization of spinal neuron populations that share common molecular identities. Identification of molecular markers that define specific populations of spinal neurons is a prerequisite to the application of genetic techniques devised to both delineate the function of these spinal neurons and their connectivity.
This strategy has been used in the study of spinal neurons that receive tactile inputs from sensory neurons innervating the skin. As a result, the circuits that include these spinal neurons have been revealed to play important roles in specific aspects of motor function. We describe these genetically identified spinal neurons that integrate tactile information and the contribution of these studies to our understanding of how tactile information shapes motor output.
Furthermore, we describe future opportunities that these circuits present for shedding light on the neural mechanisms of tactile processing. Background Genetics plays an important role in venous thromboembolism VTE. To this end, we have designed a new genetic risk score called Thrombo inCode TiC. TiC should improve prevention, diagnosis, and treatment of VTE.
Multilocus genetic risk scores for venous thromboembolism risk assessment. Genetics plays an important role in venous thromboembolism VTE. We hypothesized that primary VTE risk assessment can be improved by using genetic risk scores with more genetic markers than just FVL-rs and prothrombin gene PT-rs This evaluation was performed using 2 age- and sex-matched case-control populations: TiC was compared with other literature-based genetic risk scores.
We conclude that TiC greatly improves prediction of VTE risk compared with other genetic risk scores. Published on behalf of the American Heart Association, Inc. Increased height is a known independent risk factor for atrial fibrillation AF. However, whether genetic determinants of height influence risk is uncertain. After a median follow-up period of Importantly, for all models, the inclusion of actual height completely attenuated the genetic height effect. Finally, we identified 1 nonsynonymous SNP rs that was independently associated with AF and may warrant future study.
In conclusion, we found that genetic determinants of height appear to increase the risk of AF, primarily via height itself. This approach of examining SNPs associated with an intermediate phenotype should be considered as a method for identifying novel genetic targets.
Genetic Risk Variants for Social Anxiety. Social anxiety is a neurobehavioral trait characterized by fear and reticence in social situations. Twin studies have shown that social anxiety has a heritable basis, shared with neuroticism and extraversion, but genetic studies have yet to demonstrate robust risk variants. One meta-analytically genomewide significant locus was seen in each of EUR rs, Chr 6: This first GWAS of social anxiety confirms a genetic basis for social anxiety, shared with extraversion but possibly less so with neuroticism.
Prefrontal gray matter volume mediates genetic risks for obesity. Genetic and neuroimaging research has identified neurobiological correlates of obesity. However, evidence for an integrated model of genetic risk and brain structural alterations in the pathophysiology of obesity is still absent. Higher BMI and higher polygenic risk for obesity were significantly associated with medial prefrontal gray matter decrease, and prefrontal gray matter was further shown to significantly mediate the effect of polygenic risk for obesity on BMI in both samples.
Building on this, the successful individualized prediction of BMI by means of multivariate pattern classification algorithms trained on whole-brain imaging data and external validations in the second cohort points to potential clinical applications of this imaging trait marker.
Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging. An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging. Identifying the specific genes that contribute to cognitive aging may aid in early diagnosis of at- risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms.
Challenges to identifying these specific genes in human studies include complex genetics , difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we identify Hp1bp3 as a novel modulator of cognitive aging using a genetically diverse population of mice and confirm that HP1BP3 protein levels are significantly reduced in the hippocampi of cognitively impaired elderly humans relative to cognitively intact controls.
Deletion of functional Hp1bp3 in mice recapitulates memory deficits characteristic of aged impaired mice and humans, further supporting the idea that Hp1bp3 and associated molecular networks are modulators of cognitive aging. Overall, our results suggest Hp1bp3 may serve as a potential target against cognitive aging and demonstrate the utility of genetically diverse animal models for the study of complex human disease.
Genetic variants in the pharmacokinetic PK mechanism are the main underlying factors affecting the antiplatelet response to clopidogrel. These new variants dramatically improved the predictability of PRU variability to The associations between these loci and PK parameters of clopidogrel and H4 were observed in additional patients, and its function on the activation of clopidogrel was validated in liver S9 fractions P identified to exert a marginal risk effect for major adverse cardiac events in an independent cohort.
In conclusion, new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment. Clients' interpretation of risks provided in genetic counseling. Uncertainty about normalcy of the next child increased as numeric risk increased, and few clients were willing to indicate that the child would probably or definitely be affected regardless of the numeric risk. Characteristics associated with clients' "pessimistic" interpretations of risk , identified by stepwise linear regression, included increased numeric risk , discussion in depth during the counseling session of whether they would have a child, have a living affected child, discussion of the effects of an affected child on relationships with client's other children, and seriousness of the disorder in question causes intellectual impairment.
Client interpretations are discussed in terms of recent developments in cognitive theory, including heuristics that influence judgments about risks , and implications for genetic counseling. Use of toxicogenomics for identifying genetic markers of pulmonary oedema. This study was undertaken primarily to identify genetic markers of oedema and inflammation. Mild pulmonary injury was induced following the instillation of the oedema-producing agent, bleomycin 0. To obtain pertinent results from these data, it was necessary to develop a simple, effective method for bioinformatic analysis of altered gene expression.
Of these genes, 26 were down-regulated whilst only five were up-regulated. Two distinct clusters were identified , with 17 genes classified as encoding hormone receptors, and nine as encoding ion channels. Both these clusters were consistently down-regulated. In conclusion, this study has developed a suitable macroarray analysis procedure and provides the basis for a better understanding of the gene expression changes occurring during the early phase of drug-induced pulmonary oedema. Concerns and coping during cancer genetic risk assessment. To gain an 'in-depth' understanding of patients' concerns and their related coping strategies during the genetic risk assessment process.
Participants were the 'usual care' arm of a trial of a coping intervention targeted at men and women undergoing assessment of genetic risk for familial cancer. Participants completed questionnaires measuring the degree to which they experienced up to 11 concerns and which of 8 coping strategies they used to respond to each of them at entry into the programme and 1 month subsequently before they received their risk information.
A majority of participants were at least 'quite worried' about all the identified concerns, although the levels of concern fell over the waiting period. Participants used several strategies in response to their varying concerns - although a primary coping strategy for each concern was identifiable.
The emotion-focused strategies of acceptance and positive appraisal were generally used in response to concerns they could not change, and seeking social support was used primarily to gain information, but not emotional support from their family. Cluster analysis identified three unique clusters of coping responses. Genetic risk assessment comprises a number of different stressors each of which is coped with using different strategies.
Identifying the effects of maternal risk factors during pregnancy on infant and child health is an area of tremendous research interest. However, of interest to policy makers is unraveling the causal effects of prenatal risk factors, not their associations with child health, which may be confounded by several unobserved factors. In this paper, we evaluate the utility of genetic variants in three genes that have unequivocal evidence of being related to three major risk factors — CHRNA3 for smoking, ADH1B for alcohol use, and FTO for obesity — as instrumental variables for identifying the causal effects of such factors during pregnancy.
Using two independent datasets, we find that these variants are overall predictive of the risk factors and are not systematically related to observed confounders, suggesting that they may be useful instruments. We also find some suggestive evidence that genetic effects are stronger during than before pregnancy.
We provide an empirical example illustrating the use of these genetic variants as instruments to evaluate the effects of risk factors on birth weight. Finally, we offer suggestions for researchers contemplating the use of these variants as instruments. Before failure of these functions occurs, there is a series of clinical signs that serve as a warning.
Genetic lineage tracing identifies in situ Kit-expressing cardiomyocytes. Cardiac cells marked by c-Kit or Kit, dubbed cardiac stem cells CSCs , are in clinical trials to investigate their ability to stimulate cardiac regeneration and repair. These studies were initially motivated by the purported cardiogenic activity of these cells.
Recent lineage tracing studies using Kit promoter to drive expression of the inducible Cre recombinase showed that these CSCs had highly limited cardiogenic activity, inadequate to support efficient cardiac repair. Here we reassess the lineage tracing data by investigating the identity of cells immediately after Cre labeling. Our instant lineage tracing approach identifies Kit-expressing cardiomyocytes, which are labeled immediately after tamoxifen induction. In combination with long-term lineage tracing experiments, these data reveal that the large majority of long-term labeled cardiomyocytes are pre-existing Kit-expressing cardiomyocytes rather than cardiomyocytes formed de novo from CSCs.
The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers NSCLCs by, for instance, mutations in the negative regulator KEAP1. While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities.
We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain, and we demonstrate that these compounds disrupt NR0B1 complexes and impair the anchorage-independent growth of KEAP1-mutant cancer cells. Genetic factors underlying susceptibility to rheumatoid arthritis RA in Arab populations are largely unknown.
This genome-wide association study GWAS was undertaken to explore the generalizability of previously reported RA loci to Arab subjects and to discover new Arab-specific genetic loci. In addition, replication of 15 signals was attempted in RA cases and healthy controls. In addition, 2 novel associations specific to Arab populations were found at the 5q13 and 17p13 loci. Moreover, this study identified 2 novel RA risk loci in Arabs, offering further population-specific insights into the. Preeclampsia is a hypertensive complication of pregnancy characterized by novel onset of hypertension after 20 weeks gestation, accompanied by proteinuria.
Epidemiological evidence suggests that genetic susceptibility exists for preeclampsia; however, whether preeclampsia is the result of underlying genetic risk for essential hypertension has yet to be investigated. Based on the hypertensive state that is characteristic of preeclampsia, we aimed to determine if established genetic risk scores GRSs for hypertension and blood pressure are associated with preeclampsia. Subjects consisted of preeclamptic cases and normotensive pregnant controls, all of Iowa residence.
Missing genotypes were imputed using MaCH and Minimac software. Regression analyses were performed to determine the association between GRS and risk of preeclampsia. These analyses were replicated in an independent US population of cases and 1, controls of European ancestry. The results of the replication analysis also yielded nonsignificant associations. GRSs for hypertension and blood pressure are not associated with preeclampsia, suggesting that an underlying predisposition to essential hypertension is not on the causal pathway of preeclampsia.
For Permissions, please email: Converging Evidence across Multiple Methods. Identifying how genetic risk interacts with experience to predict psychopathology is an important step toward understanding the etiology of mental health problems. Few studies have examined genetic risk by experience interaction GxE in the development of childhood psychopathology. We used both co-twin and parent mental….
Identifying future research needs in landscape genetics: Where to from here? Waits; Aurelie Coulon; J. Arntzen; Rolf Holderegger; Helene H. Landscape genetics is an emerging interdisciplinary field that combines methods and concepts from population genetics , landscape ecology, and spatial statistics. The interest in landscape genetics is steadily increasing, and the field is evolving rapidly. We here outline four major challenges for future landscape genetic research that were identified during an Cerivastatin, Genetic Variants, and the Risk of Rhabdomyolysis. Objective The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis.
The bimodal response--rhabdomyolysis in a small proportion of users-- points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis. Methods The study had two components: Validation relied on functional studies. ValAla was associated with the risk of rhabdomyolysis OR: An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis OR: Conclusion We identified modest genetic risk factors for an extreme response to cerivastatin.
Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin. Oncological Genetic Counselling CGO allows the identification of a genetic component that increases the risk of developing a cancer. Individuals' psychological reactions are influenced by both the content of the received information and the subjective perception of their own risk of becoming ill or being a carrier of a genetic mutation.
The aim of the study was to examine the relation between their cancer risk perception and the genetic risk during CGO before receiving genetic test results, considering the influence of some psychological variables, in particular distress, anxiety and depression. Participants completed the following tools during a psychological interview: The data seem to confirm our hypothesis. Positive and significant correlations were found between the observed variables. Moreover, genetic risk perception determined an increase in depressive symptomatology and cancer risk perception led to an increase in anxious symptomatology, specifically in participants during cancer treatment.
The present results suggest the importance of assessing genetic and cancer risk perception in individuals who undergo CGO, to identify those who are at risk of a decrease in psychological well-being and of developing greater psychological distress.
Ghent University Academic Bibliography
Background Cardiovascular disease CVD incidence, complications and burden differ markedly between women and men. Although there is variation in the distribution of lifestyle factors between the genders, they do not fully explain the differences in CVD incidence and suggest the existence of gender-specific genetic risk factors. In one family a mutation that was present only in the affected individuals was found, and in 4 other families, previously reported mutations were found 1, 2.
Our findings suggest that there is no correlation with age, but with mechanical factors. No additional obvious genotype-phenotype correlation was observed, even when comparing different types of mutations. Rather, identical genotypes presented a very broad interfamilial and intrafamilial variability of phenotypes. Glioblastomas high-grade astrocytomas are highly aggressive brain tumors with poor prognosis and limited treatment options. In the present studies, we have defined the role of fetuin-A, a liver-derived multifunctional serum protein, in the growth of an established glioblastoma cell line, LN We hereby demonstrate that these cells synthesize ectopic fetuin-A which supports their growth in culture in the absence of serum.
We have demonstrated that a panel of tissue microarray TMA of glioblastomas also express ectopic fetuin-A. Knocking down fetuin-A using shRNA approach in LN, significantly reduced their in vitro growth as well as growth and invasion in vivo. Treatment of LN cells with asialofetuin ASF , attenuated their uptake of labeled fetuin-A, and induced senescence in them.
Uptake of labeled exosomes was attenuated in fetuin-A knockdown subclones A and D. Taken together, the studies demonstrate the impact of fetuin-A as significant node of growth, motility, and invasion signaling in glioblastomas that can be targeted for therapy. Thiopurines are a standard treatment for childhood leukemia, but like all chemotherapeutics, their use is limited by inherent or acquired resistance in patients.
Recently, the nucleoside diphosphate hydrolase NUDT15 has received attention on the basis of its ability to hydrolyze the thiopurine effector metabolites 6-thio-deoxyGTP 6-thio-dGTP and 6-thio-GTP, thereby limiting the efficacy of thiopurines. In particular, increasing evidence suggests an association between the NUDT15 missense variant, RC, and thiopurine sensitivity.
We found that NUDT15 RC mutation did not affect enzymatic activity but instead negatively influenced protein stability, likely due to a loss of supportive intramolecular bonds that caused rapid proteasomal degradation in cells. Mechanistic investigations in cells indicated that NUDT15 ablation potentiated induction of the DNA damage checkpoint and cancer cell death by 6-thioguanine. Taken together, our results defined how NUDT15 limits thiopurine efficacy and how genetic ablation via the RC missense mutation confers sensitivity to thiopurine treatment in patients.
Cancer Res; 76 18 ; It is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura MA and migraine without aura MO experience distinct disorders or whether their migraine subtypes are genetically related. Using a novel gene-based statistical approach, we aimed to identify individual genes and pathways associated both with MA and MO.
Gene-based tests were performed using genome-wide association summary statistic results from the most recent International Headache Genetics Consortium study comparing MA cases with 34, controls and MO cases with 40, controls. After accounting for non-independence of gene-based test results, we examined the significance of the proportion of shared genes associated with MA and MO. We found a significant overlap in genes associated with MA and MO.
Combining results across MA and MO, six genes produced genome-wide significant gene-based p values. The genes overlapping in both migraine types were enriched for functions related to inflammation, the cardiovascular system and connective tissue. Our results provide novel insight into the likely genes and biological mechanisms that underlie both MA and MO, and when combined with previous data, highlight the neuropeptide FF-amide peptide encoding gene NPFF as a novel candidate risk gene for both types of migraine.
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However, the role of its downstream signaling molecule, the low-density lipoprotein receptor-related protein 8 LRP8 in these illnesses is still unclear. Further exploratory analysis revealed that LRP8 was preferentially expressed in fetal brain tissues. Collectively, we confirmed that LRP8 is a risk gene for psychosis, and our results provide useful information toward a better understanding of genetic mechanism involving LRP8 underlying risk of complex psychiatric disorders.
Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association GWA studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59, affected subjects and , controls from 22 GWA studies.
In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies. Mutations in polycystin-1 and transient receptor potential polycystin 2 TRPP2 account for almost all clinically identified cases of autosomal dominant polycystic kidney disease ADPKD , one of the most common human genetic diseases.
The activation mechanism of TRPP2 is unknown, which significantly limits the study of its function and regulation. We also found that D, a negatively charged amino acid in the pore, is crucial for channel permeability. The results indicate that, compared with wild type WT , GOF TRPP2 more efficiently rescued morphological abnormalities, including curly tail and cyst formation in the pronephric kidney, caused by down-regulation of endogenous TRPP2 expression.
Osteopontin OPN is a multifunctional protein involved in several inflammatory processes and pathogeneses including obesity-related disorders and cancer. OPN binds to a variety of integrin receptors and CD44 resulting in a proinflammatory stimulus. Therefore, OPN constitutes a novel interesting target to develop new therapeutic strategies, which counteract OPN's proinflammatory properties.
We established a humanized SPP1 hSPP1 mouse model and evaluated its suitability as a model for obesity and insulin resistance. Unchallenged hSPP1 animals did not significantly differ in body weight and gross behavioral properties compared to wild-type WT animals. High-fat diet-challenged hSPP1 similarly developed obesity and inflammation, whereas insulin resistance was markedly changed. The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres.
Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families. Next-generation sequencing techniques were used to screen melanoma families with unknown genetic etiology and control cohorts for mutations in shelterin complex encoding genes: Maximum likelihood and LOD [logarithm base 10 of odds] analyses were used.
RX, respectively and point mutations that cosegregated with melanoma. Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility. Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase ITK.
Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2. The cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas PTCLs. As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin IL , were observed to promote alternative macrophage polarization.
Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. Therefore, its role in the T-cell lymphomas was examined. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas. De Las Rivas J. Just as reference genome sequences revolutionized human genetics, reference maps of interactome networks will be critical to fully understand genotype-phenotype relationships.
Here, we describe a systematic map of? At equal quality, this map is? While currently available information is highly biased and only covers a relatively small portion of the proteome, our systematic map appears strikingly more homogeneous, revealing a "broader" human interactome network than currently appreciated.
The map also uncovers significant interconnectivity between known and candidate cancer gene products, providing unbiased evidence for an expanded functional cancer landscape, while demonstrating how high-quality interactome models will help "connect the dots" of the genomic revolution. A mutation update on the nebulin gene NEB is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, exons containing gene.
Recessive pathogenic variants in NEB are the major cause of nemaline myopathy NM , one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in families, families with NM, and 16 families with NM-related myopathies.
Eighty-eight families are presented here for the first time. We summarize 86 previously published and unpublished variants identified in NEB. This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype-phenotype correlations in NEB-associated disease.
Van den Bergh P. Nemaline myopathy NM is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations nemaline bodies in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing WES and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM.
LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle.
We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis.
Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U cells cultured with human dermal endothelial cells. All nine patients carried recessively inherited mutations in CECR1 cat eye syndrome chromosome region, candidate 1 , encoding adenosine deaminase 2 ADA2 , that were predicted to be deleterious; these mutations were rare or absent in healthy controls.
Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia - phenotypes that were prevented by coinjection with nonmutated but not with mutated human CECR1.
Monocytes from patients induced damage in cocultured endothelial-cell layers. Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. InterAct Consortium van Duijn C. Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts total up to 48, subjects.
There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing melanoma cases from pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes.
We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene POT1 , with a proportion of family members presenting with an early age of onset and multiple primary tumors. Materials and Methods A total of males and females F2 progeny derived from the inbred COP and DA strains of rats were phenotyped for femoral neck volumetric BMD vBMD , cross-sectional area, polar moment of inertia Ip , neck width, ultimate force, and energy to break.
A whole genome screen was performed using 93 microsatellite markers with an average intermarker distance of 20 cM. These maps were used for genome-wide linkage analyses to detect sex-independent and sex-specific QTLs. Results Significant evidence of linkage p identified in this study are homologous to human chromosomal regions previously linked to. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Waist-hip ratio WHR is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity.
WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index comprising up to 77, participants , following up 16 loci in an additional 29 studies comprising up to , subjects. These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to , individuals of East Asian, European and South Asian ancestry. The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified , DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. Our results provide new evidence for the role of DNA methylation in blood pressure regulation. Application of novel polymorphic microsatellite loci identified in the Korean Pacific Abalone Haliotis diversicolor supertexta Haliotidae in the genetic characterization of wild and released populations.
The small abalone, Haliotis diversicolor supertexta, of the family Haliotidae, is one of the most important species of marine shellfish in eastern Asia. Over the past few decades, this species has drastically declined in Korea. Thus, hatchery-bred seeds have been released into natural coastal areas to compensate for the reduced fishery resources. However, information on the genetic background of the small abalone is scarce. In this study, 20 polymorphic microsatellite DNA markers were identified using next-generation sequencing techniques and used to compare allelic variation between wild and released abalone populations in Korea.
Using high-throughput genomic sequencing, a total of 2. Among the 99 loci screened, 28 amplified successfully, and 20 were polymorphic. When comparing allelic variation between wild and released abalone populations, a total of different alleles were observed, with These differences are likely a result of hatchery selection and inbreeding.
Additionally, all the primer pair sets were effectively amplified in another congeneric species, H. These microsatellite loci may be valuable for future aquaculture and population genetic studies aimed at. GWAS of human bitter taste perception identifies new loci and reveals additional complexity of bitter taste genetics. Human perception of bitterness displays pronounced interindividual variation.
This phenotypic variation is mirrored by equally pronounced genetic variation in the family of bitter taste receptor genes. Correction for general taste-sensitivity allowed us to identify a SNP in the cluster of bitter taste receptors on chr12 This association overlaps with—but is statistically distinct from—the previously identified SNP rs influencing the perception of quinine bitterness that falls in the same bitter taste cluster. Our study, thus, furthers our understanding of the complex genetic architecture of bitter taste perception.
This association overlaps with-but is statistically distinct from-the previously identified SNP rs influencing the perception of quinine bitterness that falls in the same bitter taste cluster. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram ECG.
Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. RESULTS We identified 52 genomic loci , of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart.
Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. Genome-wide association studies identified multiple genetic loci for body size at four growth stages in Chinese Holstein cattle. The growth and maturity of cattle body size affect not only feed efficiency, but also productivity and longevity. Dissecting the genetic architecture of body size is critical for cattle breeding to improve both efficiency and productivity.
The volume and weight of body size are indicated by several measurements. They are widely used as predictors of body weight BW. Few association studies have been conducted for HG and HH in cattle focusing on single growth stage. In this study, we extended the Genome-wide association studies to a full spectrum of four growth stages 6-, , , and months after birth in Chinese Holstein heifers. We found 66 candidate genes located nearby the associated SNPs, including nine genes that were known as highly related to development and skeletal and muscular growth.
In addition, biological function analysis was performed by Ingenuity Pathway Analysis and an interaction network related to development was obtained, which contained 16 genes out of the 66 candidates. The set of putative genes provided valuable resources and can help elucidate the genomic architecture and mechanisms underlying growth traits in dairy cattle.
Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia. Mood instability is a core clinical feature of affective and psychotic disorders. In keeping with the Research Domain Criteria approach, it may be a useful construct for identifying biology that cuts across psychiatric categories. We aimed to investigate the biological validity of a simple measure of mood instability and evaluate its genetic relationship with several psychiatric disorders, including major depressive disorder MDD , bipolar disorder BD , schizophrenia, attention deficit hyperactivity disorder ADHD , anxiety disorder and post-traumatic stress disorder PTSD.
Strengths of this study include the very large sample size, but our measure of mood instability may be limited by the use of a single question. Overall, this work suggests a polygenic basis for mood instability. This simple measure can be obtained in very large samples; our findings suggest that doing so may offer the opportunity to illuminate the fundamental biology of mood regulation. Identifying causal variants at loci with multiple signals of association.
Although genome-wide association studies have successfully identified thousands of risk loci for complex traits, only a handful of the biologically causal variants, responsible for association at these loci , have been successfully identified. Current statistical methods for identifying causal variants at risk loci either use the strength of the association signal in an iterative conditioning framework or estimate probabilities for variants to be causal. A main drawback of existing methods is that they rely on the simplifying assumption of a single causal variant at each risk locus, which is typically invalid at many risk loci.
In this work, we propose a new statistical framework that allows for the possibility of an arbitrary number of causal variants when estimating the posterior probability of a variant being causal. A direct benefit of our approach is that we predict a set of variants for each locus that under reasonable assumptions will contain all of the true causal variants with a high confidence level e. We validate our approach using empirical data from an expression QTL study of CHI3L2 to identify new causal variants that affect gene expression at this locus.
Novel genetic loci associated with hippocampal volume. The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study GWAS of 33, individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel.
A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. Raphael; Glahn, David C. Bruce; Potkin, Steven G.
William; Wojcicki, Anne; Eriksson, Nicholas. Although the causes of Parkinson's disease PD are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study GWAS of PD based on a single collection of individuals to date 3, cases and 29, controls.
Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.
Genome-wide association studies identify 25 genetic loci associated with resistance to Bacterial Cold Water Disease in rainbow trout. Bacterial cold water disease BCWD causes significant mortality and economic losses in salmonids aquaculture. However, the recent availability of a high density SNP array and Cytokinesis in plants involves the formation of unique cellular structures such as the phragmoplast and the cell plate, both of which are required to divide the cell after nuclear division. In order to isolate genes that are involved in de novo cell wall formation, we performed a large-scale, microscope-based screen for Arabidopsis mutants that severely impair cytokinesis in the embryo.
We recovered 35 mutations that form abnormally enlarged cells with multiple, often polyploid nuclei and incomplete cell walls. These mutants represent seven genes, four of which have previously been implicated in phragmoplast or cell plate function. No mutations that completely abolish the formation of cross walls in diploid cells were found. Lastly, our results support the idea that cytokinesis in the diploid and haploid generations involve similar mechanisms. Abstract Genome-wide association studies of birth weight have focused on fetal genetics , whereas relatively little is known about the role of maternal genetic variation.
We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8. We used structural equation modelling SEM and analyses of mother—child pairs to quantify the separate maternal and fetal genetic effects. The identified associations indicate that genetic effects on maternal glucose, cytochrome P activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth.
Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights. Genome-wide association studies of birth weight have focused on fetal genetics , whereas relatively little is known about the role of maternal genetic variation. We used structural equation modelling SEM and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Published by Oxford University Press.
Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q Genetic generalized epilepsies GGEs have a lifetime prevalence of 0. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: Meta-analysis of three genome-wide linkage datasets was carried out in GGE-multiplex families of European ancestry including relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising families with predominantly genetic absence epilepsies GAEs and families with an aggregation of juvenile myoclonic epilepsy JME.
To map shared and seizure type-related susceptibility loci , both nonparametric loci NPL and parametric linkage analyses were performed for a broad trait model GGEs in the entire set of GGE-multiplex families and a narrow trait model typical absence or myoclonic seizures in the subgroups of JME and GAE families. For the entire set of GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups.
A genome-wide significant nonparametric logarithm of odds score of 3. Significant parametric linkage to 13q Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.
We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies 23, asthma cases, , controls of individuals from ethnically diverse populations. We identified five new asthma loci , found two new associations at two known asthma loci , established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci , especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
Two genetic loci associated with ankle injury. Ankle injuries, including sprains, strains and other joint derangements and instability, are common, especially for athletes involved in indoor court or jumping sports. Identifying genetic loci associated with these ankle injuries could shed light on their etiologies. A genome-wide association screen was performed using publicly available data from the Research Program in Genes, Environment and Health RPGEH including 1, cases of ankle injury and 97, controls.
The ACTN3 RX mutation was previously reported to show an association with acute ankle sprains, but did not show an association in this cohort. This study is the first genome-wide screen for ankle injury that yields insights regarding the genetic etiology of ankle injuries and provides DNA markers with the potential to inform athletes about their genetic risk for ankle injury. Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: Multiple prostate cancer PCa risk-related loci have been discovered by genome-wide association studies GWAS based on case-control designs.
However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer HPC. The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1, hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics , with a total of 5, affected men.
The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 regions 1, 2 and 3 , 10q11, 11q13, 17q12 region 1 , 17q24 and Xp Lilly; Isaacs, William B. Multiple prostate cancer PCa risk-related loci have been discovered by genome-wide association studies GWAS based on case—control designs. In subgroup analyses, three loci , at 8q24 regions 1 and 2 plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 region 2 , 11q13, 17q12 region 1 , 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less.
Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Genetic loci for Alzheimer's disease AD have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Published by Elsevier Inc. On a systematic level, we show that the association signals within this high-density dataset are enriched in functionally-relevant genomic regions that are active in both human neural crest cells hNCC and mouse embryonic craniofacial tissue.
This enrichment is also detectable in hNCC regions primed for later activity. For each of these, we identify credible SNPs using a Bayesian refinement approach, with two loci harbouring only one probable causal variant. Association analysis identifies 65 new breast cancer risk loci. Shane; Park, Sue K. Breast cancer risk is influenced by rare coding variants in susceptibility genes such as BRCA1 and many common, mainly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown.
We report results from a genome-wide association study GWAS of breast cancer in , cases and , controls of European ancestry and 14, cases and 13, controls of East Asian ancestry1. We identified 65 new loci associated with overall breast cancer at p loci fall in distal regulatory elements, and by integrating in-silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all SNPs in regulatory features was fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites.
These results provide further insight into genetic susceptibility to breast cancer and will improve the utility of genetic risk scores for individualized screening and prevention. Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. Here we report the results of a genome-wide association study of breast cancer in , cases and , controls of European ancestry and 14, cases and 13, controls of East Asian ancestry.
We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention. Blood pressure loci identified with a gene-centric array.
Raised blood pressure BP is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci , we used a bespoke gene-centric array to genotype an independent discovery sample of 25, individuals that combined hypertensive case-control and general population samples. The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples.
These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. In this study, 1, systemic sclerosis SSc cases and 3, controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen HLA region were imputed and tested.
These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4, SSc cases and 5, controls was carried out for several selected non-HLA variants, reaching a total of 5, cases and 9, controls of European ancestry. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.
Loci associated with skin pigmentation identified in African populations. Despite the wide range of skin pigmentation in humans, little is known about its genetic basis in global populations. Genetic evidence indicates that the light pigmentation variant at SLC24A5 was introduced into East Africa by gene flow from non-Africans. At all other loci , variants associated with dark pigmentation in Africans are identical by descent in southern Asian and Australo-Melanesian populations. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.
Chronic obstructive pulmonary disease COPD is a leading cause of mortality worldwide. We performed a genetic association study in 15, cases and 47, controls, with replication of select top results P identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.
Several genome-wide significant associations were detected at known and new loci for blackleg resistance. We further validated statistically significant associations in four genetic mapping populations, demonstrating that GWAS marker loci are indeed associated with resistance to L. One of the novel loci identified for the first time, Rlm12, conveys adult plant resistance in canola. This study reports a genome-wide association study based on 18, polymorphic SNPs to identify loci associated with qualitative and quantitative resistance to L.
Genomic regions delimited with significant SNP markers, that are associated with resistance evaluated using 12 single spore isolates and pathotypes from four canola stubble were identified. In addition, we validated statistically significant associations on A01, A07, and A10 in four genetic mapping populations, demonstrating that GWAS marker loci are indeed associated with resistance to L.
One of the novel loci identified for the first time, Rlm12, conveys adult plant resistance and mapped within We showed that resistance loci are located in the vicinity of R genes of Arabidopsis thaliana and Brassica napus on the sequenced genome of B. Significantly associated SNP markers provide a valuable tool to enrich germplasm for favorable alleles in order to improve the level of resistance to L.
High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis.
Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies GWAS array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies.
To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of Korean and 45, European case-control samples. Further, we refined the number of single nucleotide polymorphisms SNPs that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs.
This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases. For permission to use where not already granted under a licence please go to http: Objective A highly polygenic etiology and high degree of allele-sharing between ancestries have been well-elucidated in genetic studies of rheumatoid arthritis.
Methods We analyzed Korean rheumatoid arthritis case-control samples using the Immunochip and GWAS array to search for new risk alleles of rheumatoid arthritis with anti-citrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data, for a total sample size of 9, Korean and 45, European case-control samples.
Further, we refined the number of SNPs that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusion This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. Genome-wide analysis identifies 12 loci influencing human reproductive behavior. Roy; Timpson, Nicholas J. The genetic architecture of human reproductive behavior — age at first birth AFB and number of children ever born NEB — has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders.
However, very few genetic loci have been identified and the underlying mechanisms of AFB and NEB are poorly understood. We report the largest genome-wide association study to date of both sexes including , individuals for AFB and , for NEB. These loci harbor genes that are likely to play a role — either directly or by affecting non-local gene expression — in human reproduction and infertility, thereby increasing our understanding of these complex traits.
The genetic architecture of human reproductive behavior-age at first birth AFB and number of children ever born NEB -has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified , and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including , individuals for AFB and , individuals for NEB.
These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits. Identification of multiple genetic susceptibility loci in Takayasu arteritis. Takayasu arteritis is a rare inflammatory disease of large arteries.
Additional genetic variants and the classical HLA alleles were imputed and analyzed. Genetic analysis of eight loci tightly linked to neurofibromatosis 1. The genetic locus for neurofibromatosis 1 NF1 has recently been mapped to the pericentromeric region of chromosome Thirty-eight recombination events in the pericentromeric region were identified , eight involving crossovers between NF1 and loci on either chromosomal arm. In this region female recombination rates were significantly higher than those of males.
These data were part of a joint study aimed at the localization of both NF1 and tightly linked pericentromeric markers for chromosome Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus. Systemic lupus erythematosus SLE is a common systemic autoimmune disease with a complex genetic inheritance. We genotyped a cohort of patients with SLE cases and healthy controls from Spain and performed imputation using the Genomes reference data.
We tested for association using logistic regression with correction for the principal components of variation. Meta-analysis of the association results was subsequently performed on 7,, variants using genetic data from a large cohort of patients with SLE and controls of Northern European ancestry. Genetic association was also tested at the pathway level after removing the effect of known risk loci using PASCAL software.
Coronary artery disease CAD is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD. To expand the number of genome-wide significant loci , catalog functional insights, and enhance our understanding of the genetic architecture of CAD. This led to the identification of 21 additional novel loci reaching genome-wide significance P loci P loci , candidate causal genes were prioritized, many without an obvious connection to CAD.
Fine mapping of the CAD loci generated lists of credible sets of single causal variants and genes for functional follow-up. Genetic risk variants of CAD were linked to development of atrial fibrillation, heart failure, and death. We identified 64 novel genetic risk loci for CAD and performed fine mapping of all risk loci to obtain a credible set of causal variants. The large expansion of reconstituted gene sets argues in favor of an expanded omnigenic model view.
Seven newly identified loci for autoimmune thyroid disease. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism SNP array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across distinct susceptibility loci associated with one or more immune-mediated diseases. We found evidence for seven new AITD risk loci P Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.
A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 children from 20 studies in the discovery phase and 11 children from 13 studies in the replication phase. We identified three novel loci: Per additional risk allele, body mass index increased 0. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.
This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. For Permissions, please email: Meta-analysis of , individuals identifies 38 susceptibility loci for migraine.