563 research outputs found
SĂ©quençage dâexomes dâune cohorte de familles caucasiennes simplex dont les patients sont atteints du syndrome dâinterruption de la tige hypophysaire
Le syndrome dâinterruption de la tige hypophysaire (PSIS) est un dĂ©sordre rare qui affecte la
fonction du systĂšme endocrinien. JusquâĂ nos jours, lâimagerie par la rĂ©sonance magnĂ©tique (IRM)
demeure la mĂ©thode la plus entreprise afin dâĂ©valuer in vivo lâanomalie dâorganogenĂšse de la tige
hypophysaire chez les patients. Lâabsence de la tige caractĂ©rise une dĂ©ficience permanente en
hormone de croissance (GH) pendant que lâĂ©tiologie du syndrome demeure inconnue. PSIS se
dĂ©finit comme lâhypopituitarisme congĂ©nital et il se caractĂ©rise soit par une ectopique post-
hypophysaire, soit par une hypoplasie antéhypophysaire, ou encore par une hypoplasie de la tige
hypophysaire. Notre objectif consiste à déterminer les mutations génétiques partagées entre les
sujets affectĂ©s de lâĂ©tude et qui pourraient expliquer les causes du syndrome. Pour y parvenir, nous
avons analysĂ© les donnĂ©es de sĂ©quençage dâexomes (WES) provenant de sept familles
caucasiennes simplex, une famille dâorigine arabique et cinq autres dont la gĂ©nĂ©alogie est
incomplĂšte. Ces donnĂ©es ont Ă©tĂ© prĂ©cĂ©demment analysĂ©es, pour le mĂȘme but, par dâautres
membres de lâĂ©quipe en utilisant le pipeline bio-informatique standard basĂ© sur lâutilisation du
logiciel GATK. Nous avons préférentiellement opté pour une nouvelle analyse en utilisant deux
différents pipelines bio-informatiques indépendants, pour ensuite comparer conjointement les
rĂ©sultats obtenus. Notre protocole consiste Ă assembler : dâabord, deux pipelines alternatifs de
dĂ©tection de mutations gĂ©nĂ©tiques ponctuelles (SNV). Ils sont composĂ©s dâun logiciel
dâalignement de sĂ©quence (Bowtie2) et deux logiciels dâappel de variantes (Freebayes et
SAMtools). Ensuite, nous avons assemblé trois pipelines de détection de variations du nombre de
copies (CNV) gĂ©nomiques composĂ©s communĂ©ment dâun logiciel dâalignement de sĂ©quence
(BWA) et trois logiciels dâappel de CNV (CoNIFER, fishingCNV, xHmm). Nos rĂ©sultats nous ont
permis dâidentifier des mutations candidates additionnelles qui nâont jamais Ă©tĂ© identifiĂ©es. De
plus, notre méthodologie nous a permis de caractériser certains résultats faux positifs, par
conséquent elle pourra nous aider à améliorer la performance des pipelines de détection de
variations génomiques existantes.Pituitary stalk interruption syndrome (PSIS) is a rare disorder that affects the function of the
endocrine system of the affected individuals. The absence of the pituitary stalk, assessed by MRI,
characterizes patients with permanent growth hormone deficiency while the etiology of the
syndrome remains unknown. PSIS is defined by clinical hypopituitarism together with anatomical
findings including a hypoplastic anterior pituitary, ectopic posterior pituitary and reduced or
hypoplastic pituitary stalk. We aim to find shared variations (SNP, CNV) among affected patients
in coding regions which could explain the origin of the syndrome. We analyzed the exome NGS
data from 8 affected French Canadian trio families, with one additional consanguineous Arabic
trio family and 5 families with incomplete pedigree. These data were previously analyzed, for the
same objective, by other members of the team using a standardize GATK based bioinformatics
pipeline. It was desired to reanalyze the complete data set with two other independent pipelines,
followed by a comparison of the SNP discovery results. In the present aspect of the study, we built
two SNP discovery pipelines, both composed of a different NGS data aligners (Bowtie2) and each
composed a different variant caller (Freebayes, SAMtools), then a CNV discovery pipeline which
is composed of three different CNV callers (CoNIFER, fishingCNV, xHmm). In addition to the
candidate mutations identified in the previous analysis, we identified additional candidate
mutations which had not been detected and never been reported. Furthermore, our method helps
to discover the sources of variation false discovery which could help to improve existing genomic
mutation discovery pipelines
Investigating the contributions of circadian pathway and insomnia risk genes to autism and sleep disturbances
Sleep disturbance is prevalent in youth with Autism Spectrum Disorder (ASD). Researchers have posited that circadian dysfunction may contribute to sleep problems or exacerbate ASD symptomatology. However, there is limited genetic evidence of this. It is also unclear how insomnia risk genes identified through GWAS in general populations are related to ASD and common sleep problems like insomnia traits in ASD. We investigated the contribution of copy number variants (CNVs) encompassing circadian pathway genes and insomnia risk genes to ASD risk as well as sleep disturbances in children with ASD. We studied 5860 ASD probands and 2092 unaffected siblings from the Simons Simplex Collection (SSC) and MSSNG database, as well as 7509 individuals from two unselected populations (IMAGEN and Generation Scotland). Sleep duration and insomnia symptoms were parent reported for SSC probands. We identified 335 and 616 rare CNVs encompassing circadian and insomnia risk genes respectively. Deletions and duplications with circadian genes were overrepresented in ASD probands compared to siblings and unselected controls. For insomnia-risk genes, deletions (not duplications) were associated with ASD in both cohorts. Results remained significant after adjusting for cognitive ability. CNVs containing circadian pathway and insomnia risk genes showed a stronger association with ASD, compared to CNVs containing other genes. Circadian genes did not influence sleep duration or insomnia traits in ASD. Insomnia risk genes intolerant to haploinsufficiency increased risk for insomnia when duplicated. CNVs encompassing circadian and insomnia risk genes increase ASD liability with little to no observable impacts on sleep disturbances
The genetics-BIDS extension: Easing the search for genetic data associated with human brain imaging
Metadata are what makes databases searchable. Without them, researchers would have difficulty finding data with features they are interested in. Brain imaging genetics is at the intersection of two disciplines, each with dedicated dictionaries and ontologies facilitating data search and analysis. Here, we present the genetics Brain Imaging Data Structure extension, consisting of metadata files for human brain imaging data to which they are linked, and describe succinctly the genomic and transcriptomic data associated with them, which may be in different databases. This extension will facilitate identifying micro-scale molecular features that are linked to macro-scale imaging repositories, facilitating data aggregation across studies
Genetic determination of the effect of post-translational modification on the innate immune response to the 19 kDa lipoprotein of Mycobacterium tuberculosis
<p>Abstract</p> <p>Background</p> <p>The 19 kDa lipoprotein of <it>Mycobacterium tuberculosis </it>(MTB) is an important target of the innate immune response. To investigate the effect of post-translation modification of this protein on innate recognition in the context of the whole bacillus, we derived a recombinant <it>M. tuberculosis </it>H37Rv that lacked the 19 kDa gene (Î19) and complemented this strain by reintroduction of the 19 kDa gene into the chromosome as a single copy to produce Î19::19. We also reintroduced the 19 kDa gene in two modified forms that lacked motifs for acylation (Î19::19NA) and <it>O</it>-glycosylation (Î19::19NOG).</p> <p>Results</p> <p>Both acylation and <it>O</it>-glycosylation were necessary for the protein to remain within the cell. IL-1 Beta secretion from human monocytes was significantly reduced by deletion of the 19 kDa gene (p < 0.02). Complementation by the wild type, but not the mutagenised gene reversed this phenotype. The effect of deletion and complementation on IL-12p40 and TNF secretion was less marked with no statistically significant differences between strains. Although deletion of the 19 kDa reduced apoptosis, an effect that could also only be reversed by complementation with the wild type gene, the results were variable between donors and did not achieve statistical significance.</p> <p>Conclusion</p> <p>These results confirm in the context of the whole bacillus an important role for post-translational modification of the 19 kDa on both the cellular location and immune response to this protein.</p
Factors Associated with the Performance of a Blood-Based Interferon-Îł Release Assay in Diagnosing Tuberculosis
Background: Indeterminate results are a recognised limitation of interferon-Îł release assays (IGRA) in the diagnosis of latent tuberculosis (TB) infection (LTBI) and TB disease, especially in children. We investigated whether age and common co-morbidities were associated with IGRA performance in an unselected cohort of resettled refugees. Methods: A retrospective cross-sectional study of refugees presenting for their post-resettlement health assessment during 2006 and 2007. Refugees were investigated for prevalent infectious diseases, including TB, and for common nutritional deficiencies and haematological abnormalities as part of standard clinical screening protocols. Tuberculosis screening was performed by IGRA; QuantiFERON-TB Gold in 2006 and QuantiFERON-TBGold In-Tube in 2007. Results: Complete data were available on 1130 refugees, of whom 573 (51%) were children less than 17 years and 1041 (92%) were from sub-Saharan Africa. All individuals were HIV negative. A definitive IGRA result was obtained in 1004 (89%) refugees, 264 (26%) of which were positive; 256 (97%) had LTBI and 8 (3%) had TB disease. An indeterminate IGRA result was obtained in 126 (11%) refugees (all failed positive mitogen control). In multivariate analysis, younger age (linear OR = 0.93 [95% CI 0.91-0.95],
Genome wide analysis of gene dosage in 24,092 individuals estimates that 10,000 genes modulate cognitive ability
International audienceGenomic copy number variants (CNVs) are routinely identified and reported back to patients with neuropsychiatric disorders, but their quantitative effects on essential traits such as cognitive ability are poorly documented. We have recently shown that the effect size of deletions on cognitive ability can be statistically predicted using measures of intolerance to haploinsufficiency. However, the effect sizes of duplications remain unknown. It is also unknown if the effect of multigenic CNVs are driven by a few genes intolerant to haploinsufficiency or distributed across tolerant genes as well. Here, we identified all CNVsâ>â50 kilobases in 24,092 individuals from unselected and autism cohorts with assessments of general intelligence. Statistical models used measures of intolerance to haploinsufficiency of genes included in CNVs to predict their effect size on intelligence. Intolerant genes decrease general intelligence by 0.8 and 2.6 points of intelligence quotient when duplicated or deleted, respectively. Effect sizes showed no heterogeneity across cohorts. Validation analyses demonstrated that models could predict CNV effect sizes with 78% accuracy. Data on the inheritance of 27,766 CNVs showed that deletions and duplications with the same effect size on intelligence occur de novo at the same frequency. We estimated that around 10,000 intolerant and tolerant genes negatively affect intelligence when deleted, and less than 2% have large effect sizes. Genes encompassed in CNVs were not enriched in any GOterms but gene regulation and brain expression were GOterms overrepresented in the intolerant subgroup. Such pervasive effects on cognition may be related to emergent properties of the genome not restricted to a limited number of biological pathways
Using rare genetic mutations to revisit structural brain asymmetry
Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities
Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability
IntroductionRare copy number variants (CNVs) and polygenic risk for intelligence (PRS-IQ) both confer susceptibility for autism spectrum disorder (ASD) but have opposing effects on cognitive ability. The field has struggled to disentangle the effects of these two classes of genomic variants on cognitive ability from their effects on ASD susceptibility, in part because previous studies did not include controls with cognitive measures. We aim to investigate the impact of these genomic variants on ASD risk while adjusting for their known effects on cognitive ability.MethodsIn a cohort of 8,426 subjects with ASD and 169,804 controls with cognitive assessments, we found that rare coding CNVs and PRS-IQ increased ASD risk, even after adjusting for their effects on cognitive ability.ResultsBottom decile PRS-IQ and CNVs both decreased cognitive ability but had opposing effects on ASD risk. Models combining both classes of variants showed that the effects of rare CNVs and PRS-IQ on ASD risk and cognitive ability were largely additive, further suggesting that susceptibility for ASD is conferred independently from its effects on cognitive ability. Despite imparting mostly additive effects on ASD risk, rare CNVs and PRS-IQ showed opposing effects on core and associated features and developmental history among subjects with ASD.DiscussionOur findings suggest that cognitive ability itself may not be the factor driving the underlying liability for ASD conferred by these two classes of genomic variants. In other words, ASD risk and cognitive ability may be two distinct manifestations of CNVs and PRS-IQ. This study also highlights the challenge of understanding how genetic risk for ASD maps onto its dimensional traits
Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies
There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity
Rare copy number variation in posttraumatic stress disorder
Posttraumatic stress disorder (PTSD) is a heritable (h2â=â24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (betaâ=â0.029, SEâ=â0.005, Pâ=â6.3âĂâ10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (betaâ=â0.0206, SEâ=â0.0056, Pâ=â0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR qâ<â0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further
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