Hotspots of Large Rare Deletions in the Human Genome

Background: We have examined the genomic distribution of large rare autosomal deletions in a sample of 440 parentparent-child trios from the Quebec founder population (QFP) which was recruited for a study of Attention Deficit Hyperactivity Disorder. Methodology/Principal Findings: DNA isolated from blood was genotyped on Illumina Hap300 arrays. PennCNV combined with visual evaluation of images generated by the Beadstudio program was used to determine deletion boundary definition of sufficient precision to discern independent events, with near-perfect concordance between parent and child in about 98 % of the 399 events detected in the offspring; the remaining 7 deletions were considered de novo. We defined several genomic regions of very high deletion frequency (‘hotspots’), usually of 0.4–0.6 Mb in length where independent rare deletions were found at frequencies of up to 100 fold higher than the average for the genome as a whole. Five of the 7 de novo deletions were in these hotspots. The same hotspots were also observed in three other studies on members of the QFP, those with schizophrenia, with endometriosis and those from a longevity cohort. Conclusions/Significance: Nine of the 13 hotspots carry one gene (7 of which are very long), while the rest contain no known genes. All nine genes have been implicated in disease. The patterns of exon deletions support the proposed roles for some of these genes in human disease, such as NRXN1 and PARKIN, and suggest limited roles or no role at all, for others

The role of GRIP1 and ephrin B3 in blood pressure control and vascular smooth muscle cell contractility

This work was supported by grants from the Canadian Institutes of Health Research to J.W. (MOP57697, MOP69089 and MOP 123389), H.L. (MOP97829), and G.C. (CMI72323). It was also financed by grants from the Natural Sciences and Engineering Research Council of Canada (203906-2012), and the J.-Louis Levesque Foundation to J.W. This study was also made possible by a group grant from the National Sciences Foundation of China (#81361120264) to J.S., S.H. T.W. and J.W. The funders provided support in the form of salaries for authors [Y.W.; Z.W.; H.L.; J.P.; J.R.], and experimental costs, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the “author contributions”. The authors thank Regeneron Pharmaceuticals for generously providing Efnb3 KO mice. The authors thank all the authors of the International Consortium for Blood Pressure Genome-Wide Association Studies for allow us to mine the study dataset

A síndrome respiratória aguda grave e a importância da imunização contra h1n1/ Serious acute respiratory syndrome and the importance of h1n1 immunization

As doenças respiratórias agudas são responsáveis por grande parte das internações nos países de alta renda, sendo a maioria das infecções (80%) de etiologia viral. A influenza é uma infecção respiratória aguda, causada pelos vírus A, B, C e D. O  vírus A está associado a epidemias e pandemias. É um vírus de comportamento sazonal e tem aumento no número de casos entre as estações climáticas mais frias, podendo haver anos com menor ou maior circulação do vírus. Análise crítica, composta de 3 artigos, advindos da base de dados LILACS, de 2015 a 2019, sem restrição de faixa etária, com foco nos grupos prioritários. Foi evidenciado que a influenza A (H1N1) está diretamente relacionado à hospitalização por infecções do trato respiratório. Torna-se evidente a necessidade da atenção à saúde dos grupos prioritários para a imunização, visando promover a sensibilização dos indivíduos e familiares para a adesão à campanha de imunização

TGFBI ( IG-H3) is a diabetes-risk gene based on mouse and human genetic studies

Transforming growth factor beta-induced (TGFBI/βIG-H3), also known as βig-H3, is a protein inducible by TGFβ1 and secreted by many cell types. It binds to collagen, forms part of the extracellular matrix and interacts with integrins on the cell surface. Recombinant TGFBI and transgenic TGFBI overexpression can promote both islet survival and function. In this study, we generated TGFBI KO mice and further assessed TGFBI function and signaling pathways in islets. Islets from KO mice were of normal size and quantity, and these animals were normoglycemic. However, KO islet survival and function was compromised in vitro. In vivo, KO donor islets became inferior to wild-type donor islets in achieving normoglycemia when transplanted into KO diabetic recipients. TGFBI KO mice were more prone to straptozotocin-induced diabetes than the wild-type counterpart. Phosphoprotein array analysis established that AKT1S1, a molecule linking the AKT and mTORC1 signaling pathways, was modulated by TGFBI in islets. Phosphorylation of four molecules in the AKT and mTORC1 signaling pathway, i.e. AKT, AKT1S1, RPS6 and EIF4EBP1, was upregulated in islets upon TGFBI stimulation. Suppression of AKT activity by a chemical inhibitor, or knockdown of AKT1S1, RPS6 and EIF4EBP1 expression by small interfering RNA, modulated islet survival, proving the relevance of these molecules in TGFBI-triggered signaling. Human genetic studies revealed that in the TGFBI gene and its vicinity, three single-nucleotide polymorphisms were significantly associated with type 1 diabetes risks, and one with type 2 diabetes risks. Our study suggests that TGFBI is a potential risk gene for human diabetes

LINGO1 Variants in the French-Canadian Population

Essential tremor (ET) is a complex genetic disorder for which no causative gene has been found. Recently, a genome-wide association study reported that two variants in the LINGO1 locus were associated to this disease. The aim of the present study was to test if this specific association could be replicated using a French-Canadian cohort of 259 ET patients and 479 ethnically matched controls. Our genotyping results lead us to conclude that no association exists between the key variant rs9652490 and ET (Pcorr = 1.00)

An Investigation of Genome-Wide Studies Reported Susceptibility Loci for Ulcerative Colitis Shows Limited Replication in North Indians

Genome-Wide Association studies (GWAS) of both Crohn's Disease (CD) and Ulcerative Colitis (UC) have unearthed over 40 risk conferring variants. Recently, a meta-analysis on UC revealed several loci, most of which were either previously associated with UC or CD susceptibility in populations of European origin. In this study, we attempted to replicate these findings in an ethnically distinct north Indian UC cohort. 648 UC cases and 850 controls were genotyped using Infinium Human 660W-quad. Out of 59 meta-analysis index SNPs, six were not in the SNP array used in the study. Of the remaining 53 SNPs, four were found monomorphic. Association (p<0.05) at 25 SNPs was observed, of which 15 were CD specific. Only five SNPs namely rs2395185 (HLA-DRA), rs3024505 (IL10), rs6426833 (RNF186), rs3763313 (BTNL2) and rs2066843 (NOD2) retained significance after Bonferroni correction. These results (i) reveal limited replication of Caucasian based meta-analysis results; (ii) reiterate overlapping molecular mechanism(s) in UC and CD; (iii) indicate differences in genetic architecture between populations; and (iv) suggest that resources such as HapMap need to be extended to cover diverse ethnic populations. They also suggest a systematic GWAS in this terrain may be insightful for identifying population specific IBD risk conferring loci and thus enable cross-ethnicity fine mapping of disease loci

Casos de dengue em Fortaleza: um estudo epidemiológico documental/ Dengue cases in Fortaleza: a documentary epidemiological study

A dengue é uma doença febril aguda sistêmica de origem viral, transmitida pelo mosquito Aedes aegypti, o qual está presente em todas as regiões do Brasil, e o estado do Ceará apresentou períodos endêmicos e epidêmicos ao longo dos anos. Teve-se como objetivo verificar os casos de dengue confirmados no município de Fortaleza-Ceará. Estudo epidemiológico, documental, de natureza quantitativa dos casos de dengue confirmados em Fortaleza, no período de 2014 a 2017. Os dados foram obtidos por meio do Sistema de Monitoramento Diário de Agravos (SIMDA), organizados em tabelas e gráficos no programa Excel. A capital do estado, Fortaleza, é a responsável pelo maior número de casos. Os resultados mostraram que no período do estudo Fortaleza apresentou um total de (67.357) casos de dengue confirmados, sendo o ano de 2015 o responsável pelo maior quantitativo com 26.816 casos, seguido do ano de 2016 (21.853), 2017 (13.561) e 2014 (5.127). No período do estudo, a Secretária Regional VI teve o maior número de casos confirmados (22.185). O mês que mais se destacou foi maio com uma média anual de 4.772 casos. A faixa etária mais acometida foi de 19 a 59 anos (43.041). O estabelecimento de saúde com o maior número de casos foram as Unidades de Pronto Atendimento com (37.017). Torna-se evidente que Fortaleza apresentou um número elevado de casos confirmados de dengue ao longo dos anos, sendo necessário a construção de ações eficazes de combate ao vetor da doença.

Evolutionary Dynamics of Co-Segregating Gene Clusters Associated with Complex Diseases

BACKGROUND: The distribution of human disease-associated mutations is not random across the human genome. Despite the fact that natural selection continually removes disease-associated mutations, an enrichment of these variants can be observed in regions of low recombination. There are a number of mechanisms by which such a clustering could occur, including genetic perturbations or demographic effects within different populations. Recent genome-wide association studies (GWAS) suggest that single nucleotide polymorphisms (SNPs) associated with complex disease traits are not randomly distributed throughout the genome, but tend to cluster in regions of low recombination. PRINCIPAL FINDINGS: Here we investigated whether deleterious mutations have accumulated in regions of low recombination due to the impact of recent positive selection and genetic hitchhiking. Using publicly available data on common complex diseases and population demography, we observed an enrichment of hitchhiked disease associations in conserved gene clusters subject to selection pressure. Evolutionary analysis revealed that these conserved gene clusters arose by multiple concerted rearrangements events across the vertebrate lineage. We observed distinct clustering of disease-associated SNPs in evolutionary rearranged regions of low recombination and high gene density, which harbor genes involved in immunity, that is, the interleukin cluster on 5q31 or RhoA on 3p21. CONCLUSIONS: Our results suggest that multiple lineage specific rearrangements led to a physical clustering of functionally related and linked genes exhibiting an enrichment of susceptibility loci for complex traits. This implies that besides recent evolutionary adaptations other evolutionary dynamics have played a role in the formation of linked gene clusters associated with complex disease traits

Assessing batch effects of genotype calling algorithm BRLMM for the Affymetrix GeneChip Human Mapping 500 K array set using 270 HapMap samples

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies (GWAS) aim to identify genetic variants (usually single nucleotide polymorphisms [SNPs]) across the entire human genome that are associated with phenotypic traits such as disease status and drug response. Highly accurate and reproducible genotype calling are paramount since errors introduced by calling algorithms can lead to inflation of false associations between genotype and phenotype. Most genotype calling algorithms currently used for GWAS are based on multiple arrays. Because hundreds of gigabytes (GB) of raw data are generated from a GWAS, the samples are typically partitioned into batches containing subsets of the entire dataset for genotype calling. High call rates and accuracies have been achieved. However, the effects of batch size (i.e., number of chips analyzed together) and of batch composition (i.e., the choice of chips in a batch) on call rate and accuracy as well as the propagation of the effects into significantly associated SNPs identified have not been investigated. In this paper, we analyzed both the batch size and batch composition for effects on the genotype calling algorithm BRLMM using raw data of 270 HapMap samples analyzed with the Affymetrix Human Mapping 500 K array set.</p> <p>Results</p> <p>Using data from 270 HapMap samples interrogated with the Affymetrix Human Mapping 500 K array set, three different batch sizes and three different batch compositions were used for genotyping using the BRLMM algorithm. Comparative analysis of the calling results and the corresponding lists of significant SNPs identified through association analysis revealed that both batch size and composition affected genotype calling results and significantly associated SNPs. Batch size and batch composition effects were more severe on samples and SNPs with lower call rates than ones with higher call rates, and on heterozygous genotype calls compared to homozygous genotype calls.</p> <p>Conclusion</p> <p>Batch size and composition affect the genotype calling results in GWAS using BRLMM. The larger the differences in batch sizes, the larger the effect. The more homogenous the samples in the batches, the more consistent the genotype calls. The inconsistency propagates to the lists of significantly associated SNPs identified in downstream association analysis. Thus, uniform and large batch sizes should be used to make genotype calls for GWAS. In addition, samples of high homogeneity should be placed into the same batch.</p