Potential Genetic Variants Research Articles

Lack of association of metastasis-associated lung adenocarcinoma transcript 1 variants with melanoma skin cancer risk.

The long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in melanoma. Polymorphisms in MALAT1 may play a vital role in the progress of melanoma by its regulative function. However, potential genetic variants in MALAT1 affecting the risk of melanoma onset have not been explored. In this study, two single nucleotide polymorphisms (rs3200401 and rs619586) in MALAT1 were selected for genotyping of 334 melanoma patients and 291 cancer-free controls in an Italian population. The results showed that MALAT1 rs3200401 and rs619586 were not associated with melanoma risk. A further breakdown analysis by sex stratification also indicated a lack of association between these polymorphisms and melanoma. In addition, we tested 450 bp of the proximal 5´ flanking region of the gene for the presence of polymorphisms that could be associated with melanoma risk and found no variants in 96 melanoma patients. In conclusion, our results suggest that there is no contribution of MALAT1 rs3200401 and rs619586 polymorphisms or polymorphisms in the core promoter that could be associated with the risk of melanoma skin cancer in this specific study setting. Further validation will be required in larger studies involving different settings/larger populations in order to reach conclusive results.

GENOME-WIDE LINKAGE ANALYSIS IDENTIFIES A NOVEL LOCUS FOR LONGITUDINAL GAIT SPEED CHANGE WITH AGING

Gait speed is an indicator of health and function with aging. The potential genetic contributions to gait speed and its decline with aging are not well characterized. We sought to better quantify the genetic contributions to and identify potential genes and genetic variants underlying change in gait speed among older adults. To accomplish these aims, we used data from 2379 individuals belonging to 509 families in the Long Life Family Study (mean age 64 ± 12, range 30–110 years; 45% men). Gait-speed was measured over 4 meters at baseline and after an average of 7±1.1 years. Quantitative trait linkage analyses were completed using pedigree-based maximum-likelihood methods with logarithm of the odds (LOD) scores > 3.3 indicating genome-wide significance. We also performed linkage analysis in the top 10% of families contributing to LOD scores to allow for heterogeneity among families (HLOD). Data were adjusted for age, sex, height and field center. At baseline, 26.9% of individuals had “low” gait-speed <1.0 m/s (mean: 1.1±0.2 m/s) and gait speed declined at a rate of -0.02±0.03 m/s per year (p<0.0001). Baseline and change in gait-speed were significantly heritable (h2 = 0.24-0.32, p<0.05). We did not find significant evidence for linkage for baseline gait speed; however, we identified a potentially novel locus for change in gait speed on chromosome 16p (LOD 4.2). A subset of 21 families contributed to this linkage peak (HLOD = 6.83). Sequence analysis of the chromosome 16 region may yield new insight on the biology of age-related mobility decline.

Suggestive evidence of protective haplotype within TGF-B1 gene region in breast density utilizing fine mapping analysis

Introduction and aimIncreased mammographic density is a strong and independent attribute factor for breast carcinoma. The density is associated with epithelial cell proliferation and stromal fibrosis development that is regulated by Transforming Growth Factor-Beta 1 (TGF-β1). This study was aimed to fine map the TGF-β1 gene cluster in predicting the role of predisposing haplotypes in breast density development using tagging SNPs. Materials and methodsGenotyping was conducted for three tagging TGF-β1 SNPs assigned as rs1800469, rs1800470 and rs4803455 in a total of 50 consented female participants as case group which involved BI-RADS 3 and 4, while the control group (n = 50) consisted of BI-RADS 1 and 2 who underwent a mammography check-up at The Department of Radiology, Hospital Sultanah Nur Zahirah of Kuala Terengganu. A series of bioinformatics analysis including individual SNP-based association analysis, haplotype-based association analysis and fine mapping analysis was conducted spanning the gene region of 20 kb utilizing Chinese Hans Beijing (CHB) and Japanese (JPT) representing the Asian dataset from the HapMap database. ResultsThe study demonstrated two tagging SNPs of TGF-β1 yielded a significant association (rs1800469, p-value = .034; rs1800470, p-value = .004). However, rs4803455 did not show a significant association with p value of 0.053. We further revealed the susceptible haplotype that was assigned as haplotype GGA with significant P value 0.003 indicated by odd ratio of 3.349 (1.482–7.568). A potential protective haplotype was observed in haplotype AGC with odd ratio 0.585 (0.316–1.080) even though with less significant (p = .085). The fine map revealed four targeted SNPs in which consist of rs12461895, rs10416269, rs7408955 and rs1549934 from Block 2 and five potential SNPs from Block 4 assigned as rs4803457, rs2317130, rs1166933, rs1982072, rs11670143 as another potential genetic variant that might contribute to breast density. DiscussionThis fine map study suggests the potential protective haplotype and genetic variants of TGF-β1 in predisposing to breast density development which is worth to be genotyped and further investigated.

A Novel Splice-Site Variation in COL5A1 Causes Keratoconus in an Indian Family.

Objective This study aims to clarify the association between keratoconus (KC) and potential pathogenic genetic variants in a three-generation South Indian family. Methods In the present study, a three-generation KC family, which comprised 10 affected patients and nine unaffected individuals, was recruited. The family history and necessary ophthalmological exams, such as visual acuity and slit-lamp, were performed for all participants. Genomic DNA was extracted from peripheral blood leukocytes, and whole exome sequencing (WES) was performed using the genomic DNA of the proband (III:4) and two other family members (III:2, III:3). The acceptor-splice-site mutation was validated and verified using polymerase chain reaction (PCR) and Sanger sequencing. Gene functions and pathways associated with the identified mutations were subjected to in silico analysis. Results A novel COL5A1 acceptor-splice-site mutation IVS50-4C > G was found in the 10 affected individuals in the three-generation KC family, but this was not found in any of the unaffected family members or unrelated healthy individuals. Gene functional analysis using the SpliceMan and ExonScan software predicted that the splice-site mutation was potentially associated with KC pathogenesis. This mutation might affect the assembly of the collagen triple helix. Conclusion The present study confirmed the association between the COL5A1 gene and KC and identified a novel COL5A1 acceptor-splice-site mutation (IVS50-4C > G) in intron 50, which may affect the splicing of the adjacent exon 50.

PROGRESS IN THE GENETICS OF SUBSTANCE USE DISORDERS – AN UPDATE

Alcohol use disorder (AUD) is a common and chronic psychiatric disorder characterized by harmful drinking patterns that have substantial negative effects on both personal and public health. Despite its prevalence in society, the underlying pathophysiology of AUD is poorly understood. Although substantial evidence supports a genetic component of the disorder, identification of potential genetic susceptibility factors for AUD has been challenging. Efforts to identify universal genetic risk variants for AUD have included twin, linkage, candidate gene, and genome-wide association studies. Evidence indicates several potential genetic risk variants for AUD, which underscores the complexity and heterogeneity of the disorder. The most consistently identified variants were alcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH), the genes of alcohol metabolism. These had protective effects against AUD development. Understanding genetic mechanisms underlying AUD could guide development of targeted pharmacological interventions that would enhance treatment of the disorder.

Genetic Variants of lncRNA MALAT1 Exert Diverse Impacts on the Risk and Clinicopathologic Characteristics of Patients with Hepatocellular Carcinoma.

The long noncoding (lnc)RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), plays a crucial role in the development of hepatocellular carcinoma (HCC). However, potential genetic variants (single nucleotide polymorphisms, SNPs) in MALAT1 that affect the susceptibility and progression of HCC have rarely been explored. Three tagging SNPs, viz., rs3200401 C > T, rs619586 A > G, and rs1194338 C > A, in MALAT1 were genotyped by a TaqMan allelic discrimination assay in 394 HCC patients and 1199 healthy controls. A stratified analysis showed that younger patients (<55 years) with the MALAT1 rs619586 G allele had a decreased risk of HCC under a codominant model (AOR = 0.289, 95% CI: 0.108–0.773, p = 0.013) and dominant model (AOR = 0.286, 95% CI: 0.107–0.765, p = 0.013). Female patients and patients with a smoking habit who carried the CA + AA genotype of rs1194338 had a lower risk of developing vascular invasion (p = 0.049) and a high Child–Pugh grade (B or C) (p = 0.036), respectively. Under the dominant model, smokers with the MALAT1 rs3200401 CT + TT genotype had a higher frequency of hepatitis B virus (HBV) infection (p = 0.034). Moreover, the aspartate aminotransferase was higher in patients with the rs3200401 CT + TT genotype. Furthermore, analyses of clinical datasets revealed that MALAT1 expression level was gradually unregulated during HCC development from normal liver, cirrhotic liver, dysplastic liver to HCC and correlated with poor survival rates in HCC patients, especially in the hepatitis virus-infected population.

Novel mutations of the POLR3A gene caused POLR3-related leukodystrophy in a Chinese family: a case report

BackgroundPOLR3-related leukodystrophy is an autosomal recessive neurodegenerative disorder characterized by onset time ranging from the neonatal period to late childhood, progressive motor decline that manifests as spasticity, ataxia, tremor, and cerebellar symptoms, as well as mild cognitive regression and hypodontia. POLR3-related leukodystrophy belongs to the family of RNA polymerase III-related leukodystrophy, which are caused by biallelic mutations in the POLR3A, POLR3B, POLRC1, or POLR3K genes.Case presentationIn this study, we report a female child with POLR3-related leukodystrophy manifesting as cognitive decline, moderate dysarthria, motor decline, cerebellar syndrome, short stature, dysphagia, hypodontia, and mild delayed myelination by brain imaging. Interestingly, polytrichia and bronchodysplasia were first observed in a POLR3-related leukodystrophy patient. Medical exome sequencing with high coverage depth was employed to identify potential genetic variants in the patient. Novel compound heterozygous mutations of the POLR3A gene, c.1771-6C > G and c.2611del (p.M871Cfs*8), were detected. One of them is an uncommon splice site mutation, and this is the first report of this mutation in a Chinese family. The father was determined to be a heterozygous carrier of the c.2611del (p.M871Cfs*8) mutation and the mother a heterozygous carrier of the c.1771-6C > G mutation.ConclusionThe patient’s newly emerged clinical features and mutations provide useful information for further exploration of genotype-phenotype correlations of POLR3-related leukodystrophy.

Exome sequencing reveals a novel variant in NFX1 causing intracranial aneurysm in a Chinese family

BackgroundGenetic risk factors play an important role in the pathogenesis of familial intracranial aneurysms (FIAs); however, the molecular mechanisms remain largely unknown.ObjectiveTo investigate potential FIA-causing genetic variants by rare variant...

Serum IL-33 Level and IL-33, IL1RL1 Gene Polymorphisms in Asthma and Multiple Sclerosis Patients.

Asthma is a chronic and complex inflammatory disease of the respiratory tract. Also, multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Against this background, IL-33 and IL1RL1 play a critical role in autoimmune and inflammatory disorders. Here, we explored the IL-33 serum level and two potential genetic variants in the IL33 gene and its receptor in Iranian asthma and MS patients. This study consisted of asthma (n=140) and MS patients (n=140), and healthy subjects (n=72). Genotyping was carried out in two genetic polymorphisms, rs1342326 variant of IL-33 and rs10204137SNP variant of IL-33 receptor genes, using High- Resolution Melt Real- Time PCR based method. The level of serum IL-33 was also measured using enzyme-linked immunosorbent assay method. The level of IL33 was significantly higher in asthma and MS patients compared to the control group (P< 0.001- P<0.001).The frequency distribution of the genotype in rs1342326 variant of IL-33 gene in patients with asthma, MS and healthy subjects was not significantly different (P>0.05). The frequency distribution of the genotype in rs10204137 variant of IL-33 gene in MS patients and healthy subjects was significantly different (p = 0.013). Our findings demonstrated that asthma and MS patients had a higher level of IL-33, and IL-33 receptor genetic polymorphism was associated with MS. Further studies in a larger multicenter setting are needed to explore the value of this marker as a risk stratification biomarker.

Genome-Wide Association Study of Cerebral Microbleeds on MRI.

Cerebral microbleeds are the presence of a group of pathological processes affecting the small arteries, arterioles, capillaries, and venules of the brain. Previous studies showed that cerebral microbleeds were associated with higher risk of dementia and stroke. We conducted a genome-wide association study of cerebral microbleeds to identify novel loci associated with the presence and progression of cerebral microbleeds. This study included 454 individuals composed by 176 subjects with cerebral microbleeds and 278 subjects without cerebral microbleeds in a non-Hispanic/Latino white population. Association of genetic variants with the presence and progression of cerebral microbleeds was assessed by logistic regression model. Potential genetic risk variants Apolipoprotein E (ApoE) polymorphisms were independently genotyped and checked the association with the presence and progression of cerebral microbleeds. No single-nucleotide polymorphisms (SNPs) associated with the presence or progression of cerebral microbleeds were identified at genome-wide significant level (P< 1 × 10-8). A total of 19 SNPs were associated with the presence of microbleeds at suggestive level (P< 1 × 10-5). One SNP was associated with lower progression risk for cerebral microbleeds with suggestive evidence (P< 1 × 10-5). ApoE ε4ε4 was independently associated with the presence and progression of cerebral microbleeds (odds ratio = 2.54, 95% confidence interval 1.08-6.00 and odds ratio = 5.1, 95% confidence interval 1.36-19.16). We highlighted 19 novel SNPs associated with the presence of cerebral microbleeds and one novel SNP associated with the progression of cerebral microbleeds for the first time. ApoE ε4ε4 was confirmed independently associated with the presence and progression of cerebral microbleeds.

Rs4143815-PDL1, a New Potential Immunogenetic Biomarker of Biochemical Recurrence in Locally Advanced Prostate Cancer after Radiotherapy.

Up to 30–50% of patients with locally advanced prostate cancer (PCa) undergoing radiotherapy (RT) experience biochemical recurrence (BCR). The immune system affects the RT response. Immunogenetics could define new biomarkers for personalization of PCa patients’ treatment. The aim of this study is to define the immunogenetic biomarkers of 10 year BCR (primary aim), 10 year overall survival (OS) and 5 year BCR (secondary aims). In this mono-institutional retrospective study, 549 Caucasian patients (a discovery set n = 418; a replication set n = 131) were affected by locally advanced PCa and homogeneously treated with RT. In the training set, associations were made between 447 SNPs in 77 genes of the immune system; and 10 year BCR and 10 year OS were tested through a multivariate Cox proportional hazard model. Significant SNPs (p-value < 0.05, q-value < 0.15) were analyzed in the replication set. Replicated SNPs were tested for 5 year BCR in both sets of patients. A polymorphism in the PDL1 gene (rs4143815) was the unique potential genetic variant of 10 year BCR (training set: p = 0.003, HR (95% CI) = 0.58 (0.41–0.83); replication set: p = 0.063, HR (95% CI) = 0.52 (0.26–1.04)) that was significantly associated with 5 year BCR (training set: p = 0.009, HR (95% CI) = 0.59 (0.40–0.88); replication set: p = 0.036, HR (95% CI) = 0.39 (0.16–0.94)). No biomarkers of OS were replicated. rs4143815-PDL1 arose as a new immunogenetic biomarker of BCR in PCa, giving new insights into the RT/immune system interaction, which could be potentially useful in new approaches using anti-PDL1 therapies for PCa.

Association between polymorphism in the promoter region of lncRNA GAS5 and the risk of colorectal cancer.

The growth arrest special 5 (GAS5), as a research hotspot of long noncoding RNAs (lncRNAs), has been reported to be associated with colorectal cancer (CRC). However, the association between polymorphisms in GAS5 and the risk of CRC was not clear. In the present study, a case–control study in 1078 CRC patients and 1175 matched healthy controls was performed to evaluate the association between the potential functional genetic variants in GAS5 and the risk of CRC. PCR-TaqMan, qPCR, dual-luciferase assay, electrophoretic mobility shift assay (EMSA), flow cytometry, migration and invasion assays were performed to evaluate the function of polymorphism. Results showed that subjects carrying the rs55829688 CT/TT genotypes had a significantly higher risk of CRC when compared with the CC genotype. Further qPCR assay confirmed that the CRC tissues with rs55829688 CT/TT genotypes had a higher GAS5 mRNA expression level. The dual-luciferase assay, qPCR and EMSA assay revealed that rs55829688 T>C polymorphism could decrease the expression level of GAS5 by impacting the binding ability of the transcription factor Yin Yang-1 (YY1) to the GAS5 promoter region. The expression of apoptosis-related proteins were detected by Western blot. Further, flow cytometry, migration, and invasion experiments showed that GAS5 repressed apoptosis and increased invasion and migration capability of CRC cells. Taken together, our findings provided evidence that the rs55829688 variant in the GAS5 promoter was associated with the risk of CRC and decreased expression of GAS5 by affecting the binding affinity of the transcription factors YY1 to GAS5.

Screening the RFX6-DNA binding domain for potential genetic variants in patients with type 2 diabetes.

BACKGROUNDThe regulatory factor X6 (RFX6), a member of regulatory factor X family, is known to play a key role in the development and differentiation of pancreatic beta cells as well as insulin production and secretion. However, the potential role of RFX6 in type 2 diabetes (T2D) is still unclear.AIMRecent studies have indicated that RFX6 binding to DNA could be disrupted in diabetes. Therefore, in this study we investigated whether genetic mutations are present in the DNA binding domain of RFX6 gene that could abrogate its function in T2D.METHODSA cohort of T2D patients was enrolled in this study, and the gene encoding the DNA binding domain of RFX6 was amplified by polymerase chain reaction and then analysed by direct DNA sequencing.RESULTSThe DNA sequence analysis revealed the absence of any exonic mutation. However, we have identified a new heterozygous single nucleotide polymorphism (IVS6+31 C>T) in the intronic region of DNA binding domain gene that is present in 9.2% and 8.5% of diabetic and control people, respectively (P = 0.97).CONCLUSIONWe report the absence of any significant genetic variant that could affect the function of RFX6-DNA binding domain in T2D.

Identification of Alzheimer's Disease-Related Genes Based on Data Integration Method.

Alzheimer disease (AD) is the fourth major cause of death in the elderly following cancer, heart disease and cerebrovascular disease. Finding candidate causal genes can help in the design of Gene targeted drugs and effectively reduce the risk of the disease. Complex diseases such as AD are usually caused by multiple genes. The Genome-wide association study (GWAS), has identified the potential genetic variants for most diseases. However, because of linkage disequilibrium (LD), it is difficult to identify the causative mutations that directly cause diseases. In this study, we combined expression quantitative trait locus (eQTL) studies with the GWAS, to comprehensively define the genes that cause Alzheimer disease. The method used was the Summary Mendelian randomization (SMR), which is a novel method to integrate summarized data. Two GWAS studies and five eQTL studies were referenced in this paper. We found several candidate SNPs that have a strong relationship with AD. Most of these SNPs overlap in different data sets, providing relatively strong reliability. We also explain the function of the novel AD-related genes we have discovered.

17 - FUMA: FUNCTIONAL MAPPING AND ANNOTATION OF GENETIC ASSOCIATIONS

Background A main challenge in genome-wide association studies (GWAS) is to prioritize genetic variants and identify potential causal mechanisms of human diseases. Although a variety of bioinformatics tools are now available for downstream analyses of GWAS results, a standard, integrative approach is lacking. We developed FUMA: a web-based platform to facilitate functional annotation of GWAS results, prioritization of potential causal genetic variants and genes, and interactive visualization by incorporating 14 biological data repositories and tools. FUMA is available as an online tool at http://fuma.ctglab.nl. Methods FUMA contains two core functions to annotate input summary statistics to prioritize potential causal genetic variants and genes; SNP2GENE and GENE2FUNC. In SNP2GENE, SNPs are annotated with their biological functionality and mapped to genes based on positional and functional information of SNPs. In this process, significantly associated SNPs from GWAS are characterized as genomic risk loci by incorporating the linkage disequilibrium structure. Functionally annotated SNPs are mapped to genes based on functional consequences on genes (positional mapping), expression quantitative trait loci (eQTLs) and chromatin interactions of phenotype relevant tissue types (eQTL and chromatin interaction mappings). By combining these three mapping strategies, FUMA enables to prioritize genes that are highly likely involved in the trait of interest. To obtain insight into putative causal mechanisms, the GENE2FUNC process annotates the prioritized genes in biological context, such as tissue specific gene expression pattern, enrichment of gene sets and direct links to well defined external biological databases such as disease associated genes and drug targets. Results We have applied FUMA to the most recent Body Mass Index (BMI)[1]. We successfully prioritized previously reported genes from the original GWAS study, and also novel candidates by combining positional mapping of deleterious coding SNPs and eQTL mapping. For example, IRX3 was prioritized by eQTLs from FTO locus which is the most significantly associated locus with BMI. Although, FTO is the only gene reported in the original study since the genomic risk locus is located within the FTO gene and not overlapped with any other genes, IRX3 has been recently validated as whose expression is affected by variants in the FTO locus[2]. Thus, by incorporating multiple biological information, we could prioritise genes that are located outside of genomic risk loci. Chromatin interaction mapping identified additional novel candidates, including genes located outside of the risk loci, which showed share biological functions with the previously reported genes. Discussion In summary, FUMA provides an easy-to-use tool to interpret and functionally annotate results from genetic association studies. It allows to quickly gain insight into the directional biological implications of significant genetic associations. FUMA combines information of state-of-the-art biological data sources in a single platform to facilitate the generation of hypotheses for functional follow-up analysis aimed at proving causal relations between genetic variants and diseases.

Blood Donation and Iron Deficiency

In the United States about 40,000 people per day donate blood. Donors are from all racial/ethnic backgrounds and range in age from 16 to over 80 years old. They are allowed to repeatedly donate blood every 56 days, as long as they maintain their hemoglobin above 12.5 g/dL for females or 13.0 g/dL for males. Although each donation removes 200-250 mg of iron from the donor, testing for iron deficiency is not performed. Thus, blood donation can be viewed as a large clinical study to examine the physiological effects of repeated phlebotomy of approximately 10% of an individual's blood volume. In addition, blood donors are altruistic by nature and typically are very willing to participate in research studies. We have utilized this rich clinical population to perform studies on iron metabolism and red blood cell biology in an otherwise healthy population. These include a study of over 750,000 donors to define the demographics of anemia. A study detailing the body's response to blood donation, finding that recovery of iron stores takes over 90 days, if the donor takes daily iron pills following donation, and much longer if they do not. Despite this long time for recovery of iron stores, some donors are capable of repeatedly donating blood every 56 days for several years without experiencing a low hemoglobin deferral. Study of these “superdonors” has identified potential associated genetic variants and behaviors that allow frequent donation without development of anemia. Teenagers are allowed to donate blood in the United States at the same 56 day donation frequency and hemoglobin cut-off values as adults even though they have increased iron requirements for continued growth and neurocognitive development. A study detailing the impact of blood donation on teenager hemoglobin and iron stores has found that they are more susceptible to iron deficiency than adults, and, therefore, should have extra protections to prevent donation-induced iron deficiency. DisclosuresMast:Novo Nordisk: Research Funding.

Spread of the emerging equine-like G3P[8] DS-1-like genetic backbone rotavirus strain in Brazil and identification of potential genetic variants.

In 2013, the equine-like G3P[8] DS-1-like rotavirus (RVA) strain emerged worldwide. In 2016, this strain was reported in northern Brazil. The aims of the study were to conduct a retrospective genetic investigation to identify the possible entry of these atypical strains in Brazil and to describe their distribution across a representative area of the country. From 2013 to 2017, a total of 4226 faecal samples were screened for RVA by ELISA, PAGE, RT-PCR and sequencing. G3P[8] represented 20.9 % (167/800) of all RVA-positive samples, further subdivided as equine-like G3P[8], DS-1-like (11.0 %; 88/800) and Wa-like G3P[8] (9.9 %; 79/800). Six equine-like G3P[8] DS-1-like samples were selected for whole-genome investigation, confirming the backbone I2-R2-C2-M2-A2-N2-T2-E2-H2. During 2013-2014, Wa-like G3P[8] was predominant and no equine-like G3P[8] DS-1-like was detected. Equine-like G3P[8] DS-1-like was first identified in Paraná in March/2015, suggesting that the strain entered Brazil through the Southern region. Equine-like G3P[8] rapidly spread across the area under surveillance and displayed a marked potential to replace Wa-like G3P[8] strains. Brazilian equine-like G3P[8] DS-1-like strains clustered with contemporary equine-like G3P[8] DS-1-like detected worldwide, but exhibited a distinct NSP2 genotype (N2) compared to the previously reported Amazon equine-like G3P[8] DS-1-like strain (N1). Two distinct NSP4 E2 genotype lineages were also identified. Taken together, these data suggest that different variants of equine-like G3P[8] DS-1-like strains might have been introduced into the country at distinct time points, and co-circulated in the period 2015-2017. The global emergence of equine-like G3P[8] DS-1-like strains, predominantly in countries using the Rotarix vaccine, raises the question of whether vaccines may be inducing selective pressures on zoonotic strains.

WISH-R\u2013 a fast and efficient tool for construction of epistatic networks for complex traits and diseases

BackgroundGenetic epistasis is an often-overlooked area in the study of the genomics of complex traits. Genome-wide association studies are a useful tool for revealing potential causal genetic variants, but in this context, epistasis is generally ignored. Data complexity and interpretation issues make it difficult to process and interpret epistasis. As the number of interaction grows exponentially with the number of variants, computational limitation is a bottleneck. Gene Network based strategies have been successful in integrating biological data and identifying relevant hub genes and pathways related to complex traits. In this study, epistatic interactions and network-based analysis are combined in the Weighted Interaction SNP hub (WISH) method and implemented in an efficient and easy to use R package.ResultsThe WISH R package (WISH-R) was developed to calculate epistatic interactions on a genome-wide level based on genomic data. It is easy to use and install, and works on regular genomic data. The package filters data based on linkage disequilibrium and calculates epistatic interaction coefficients between SNP pairs based on a parallelized efficient linear model and generalized linear model implementations. Normalized epistatic coefficients are analyzed in a network framework, alleviating multiple testing issues and integrating biological signal to identify modules and pathways related to complex traits. Functions for visualizing results and testing runtimes are also provided.ConclusionThe WISH-R package is an efficient implementation for analyzing genome-wide epistasis for complex diseases and traits. It includes methods and strategies for analyzing epistasis from initial data filtering until final data interpretation. WISH offers a new way to analyze genomic data by combining epistasis and network based analysis in one method and provides options for visualizations. This alleviates many of the existing hurdles in the analysis of genomic interactions.

Exploring shared genetic bases and causal relationships of schizophrenia and bipolar disorder with 28 cardiovascular and metabolic traits.

Cardiovascular diseases represent a major health issue in patients with schizophrenia (SCZ) and bipolar disorder (BD), but the exact nature of cardiometabolic (CM) abnormalities involved and the underlying mechanisms remain unclear. Psychiatric medications are known risk factors, but it is unclear whether there is a connection between the disorders (SCZ/BD) themselves and CM abnormalities. Using polygenic risk scores and linkage disequilibrium score regression, we investigated the shared genetic bases of SCZ and BD with 28 CM traits. We performed Mendelian randomization (MR) to elucidate causal relationships between the two groups of disorders. The analysis was based on large-scale meta-analyses of genome-wide association studies. We also identified the potential shared genetic variants and inferred the pathways involved. We found tentative polygenic associations of SCZ with glucose metabolism abnormalities, adverse adipokine profiles, increased waist-to-hip ratio and visceral adiposity (false discovery rate or FDR&lt;0.05). However, there was an inverse association with body mass index. For BD, we observed several polygenic associations with favorable CM profiles at FDR&lt;0.05. MR analysis showed that SCZ may be causally linked to raised triglyceride and that lower fasting glucose may be linked to BD. We also identified numerous single nucleotide polymorphisms and pathways shared between SCZ/BD with CM traits, some of which are related to inflammation or the immune system. Our findings suggest that SCZ patients may be genetically predisposed to several CM abnormalities independent of medication side effects. On the other hand, CM abnormalities in BD may be more likely to be secondary. However, the findings require further validation.

Functional Polymorphisms in IRAKs Are Related to Hepatocellular Carcinoma Risk in Chinese Population

Background Interleukin 1 receptor associated kinases (IRAKs) play a central role in TLR signaling pathway. Scarce literature has investigated the association of potential functional genetic variants of IRAKs with Hepatitis B Virus- (HBV-) related hepatocellular carcinoma (HCC). Methods A case-control study with 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers was conducted to evaluate the effects of common missense variants of IRAK family members on HCC. Proliferation assays and real-time polymerase chain reactions were carried out to evaluate the functions. Multivariable adjusted logistic regression was adopted to estimate effect size and identify risk factors. Results Association analysis indicated that rs4251545 A allele of IRAK4 (p.Ala428Thr) was positively associated with HBV-related HCC risk (OR = 1.30, 95% CI: 1.09–1.54, P = 0.003). Functional annotation indicated that rs4251545 reduced its own expression in liver (P = 0.031). Further molecular functional analysis detected that rs4251545 increased the proliferation rate of L02 cells (P < 0.05). Meanwhile, rs4251545 reduced mRNA expressions of IL-6, IL-8, CXCL-1, and CXCL-2 in L02 cells (P < 0.01). Conclusion rs4251545 of IRAK4 (p.Ala428Thr) modified the susceptibility to HBV-related HCC via increased proliferation rate and reduced production of inflammatory cytokines and chemokines. Further well-designed experiments are warranted to validate our findings.