FRA2A is a CGG repeat expansion associated with silencing of AFF3

Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship

Identification of rare de novo epigenetic variations in congenital disorders

Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance.The authors are grateful to the patients and families who participated in this study and to the collaborators who supported patient recruitment. This work was supported by NIH grant HG006696 and research grant 6-FY13-92 from the March of Dimes to A.J.S., grant HL098123 to B.D.G. and A.J.S., Gulbenkian Programme for Advanced Medical Education and the Portuguese Foundation for Science and Technology (SFRH/BDINT/51549/ 2011, PIC/IC/83026/2007, PIC/IC/83013/2007, SFRH/BD/90167/2012, Portugal) to P.M., F.L., and M.B., by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013) to P.M., a Beatriu de Pinos Postdoctoral Fellowship to R.S.J. (2011BP-A00515), and a Seaver Foundation fellowship to S.D.R. The views expressed are those of the authors and do not necessarily reflect those of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.The authors are grateful to the patients and families who participated in this study and to the collaborators who supported patient recruitment. This work was supported by NIH grant HG006696 and research grant 6-FY13-92 from the March of Dimes to A.J.S., grant HL098123 to B.D.G. and A.J.S., Gulbenkian Programme for Advanced Medical Education and the Portuguese Foundation for Science and Technology (SFRH/BDINT/51549/ 2011, PIC/IC/83026/2007, PIC/IC/83013/2007, SFRH/BD/90167/2012, Portugal) to P.M., F.L., and M.B., by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013) to P.M., a Beatriu de Pinos Postdoctoral Fellowship to R.S.J. (2011BP-A00515), and a Seaver Foundation fellowship to S.D.R. The views expressed are those of the authors and do not necessarily reflect those of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai

FCGR polymorphisms in the treatment of rheumatoid arthritis with Fc-containing TNF inhibitors

[EN] Objectives: Reproducible association of a functional polymorphism in FCGR2A with response to a TNF inhibitor (TNFi) in patients with rheumatoid arthritis (RA) led us to explore other Fc?R functional polymorphisms. Methods: Functional polymorphisms FCGR3A F158V, FCGR2B I223T and promoter VNTR in FCGRT were analyzed in up to 429 patients with RA. Response to TNFi was recorded during standard care at 3, 6 and 12 months of follow-up. Fixed effects meta-analysis of studies addressing FCGR3A F158V polymorphism, which is the most studied of these polymorphisms, was conducted with inverse variance weighting. Results: None of the functional polymorphisms were associated with change in DAS28. Meta-analysis of the seven studies (899 patients) with available data addressing association of FCGR3A F158V with response to TNFi in RA showed no association (OR: 1.11, 95% CI: 0.8-1.5; p = 0.5). Conclusion: None of the three functional polymorphisms in Fc?R genes showed association with response to TNFi in patients with RA. These negative results were obtained in spite of the larger size of this study relative to previous studies addressing the same polymorphisms. In addition, meta-analysis of FCGR3A F158V was also negative against the results provided by previous studies

Wide-Geographic and Long-Term Analysis of the Role of Pathogens in the Decline of Pinna nobilis to Critically Endangered Species

A mass mortality event (MME) affecting the fan mussel Pinna nobilis was first detected in Spain in autumn 2016 and spread north- and eastward through the Mediterranean Sea. Various pathogens have been blamed for contributing to the MME, with emphasis in Haplosporidium pinnae, Mycobacterium sp. and Vibrio spp. In this study, samples from 762 fan mussels (necropsies from 263 individuals, mantle biopsies from 499) of various health conditions, with wide geographic and age range, taken before and during the MME spread from various environments along Mediterranean Sea, were used to assess the role of pathogens in the MME. The number of samples processed by both histological and molecular methods was 83. The most important factor playing a main role on the onset of the mass mortality of P. nobilis throughout the Mediterranean Sea was the infection by H. pinnae. It was the only non-detected pathogen before the MME while, during MME spreading, its prevalence was higher in sick and dead individuals than in asymptomatic ones, in MME-affected areas than in non-affected sites, and it was not associated with host size, infecting both juveniles and adults. Conversely, infection with mycobacteria was independent from the period (before or during MME), from the affection of the area by MME and from the host health condition, and it was associated with host size. Gram (-) bacteria neither appeared associated with MME.En prens

Genome-Wide association study (GWAS) for growth rate and age at sexual maturation in atlantic salmon (Salmo salar)

Early sexual maturation is considered a serious drawback for Atlantic salmon aquaculture as it retards growth, increases production times and affects flesh quality. Although both growth and sexual maturation are thought to be complex processes controlled by several genetic and environmental factors, selection for these traits has been continuously accomplished since the beginning of Atlantic salmon selective breeding programs. In this genome-wide association study (GWAS) we used a 6.5K single-nucleotide polymorphism (SNP) array to genotype ∼480 individuals from the Cermaq Canada broodstock program and search for SNPs associated with growth and age at sexual maturation. Using a mixed model approach we identified markers showing a significant association with growth, grilsing (early sexual maturation) and late sexual maturation. The most significant associations were found for grilsing, with markers located in Ssa10, Ssa02, Ssa13, Ssa25 and Ssa12, and for late maturation with markers located in Ssa28, Ssa01 and Ssa21. A lower level of association was detected with growth on Ssa13. Candidate genes, which were linked to these genetic markers, were identified and some of them show a direct relationship with developmental processes, especially for those in association with sexual maturation. However, the relatively low power to detect genetic markers associated with growth (days to 5 kg) in this GWAS indicates the need to use a higher density SNP array in order to overcome the low levels of linkage disequilibrium observed in Atlantic salmon before the information can be incorporated into a selective breeding program

Meta-analysis of gene expression data in adipose tissue reveals new obesity associated genes

High-throughput transcriptomic and proteomic data like microarray data are deposited in public databases such as Gene Expression Omnibus (GEO). Omics data integration and processing from different and independent studies is achieved by using efficient and effective computational tools through meta-analysis. Meta-analysis is a statistical powerful tool combining data from numerous studies, minimizes bias and increases statistical power by increasing sample size compared to individual studies. Therefore, we performed a meta-analysis of gene expression data in adipose tissue to identify genes that are differentially expressed between obese and non-obese subjects as well as to detect gene expression signatures, pathways and networks associated with obesity. We identified 821 differentially expressed genes (DEGs) in adipose tissue of obese subjects compared to non-obese. A protein–protein interactions (PPIs) network was reconstructed consisting of 168 proteins. Functional enrichment analysis in the network revealed proteins involved in RNA and energy metabolism. The KEGG pathway analysis revealed 15 enriched pathway terms. Furthermore, multiple testing correction methods identified five statistically significant obesity associated genes (NDUFA12, SFI1, SSB, FAR2 and LACE1) that require further investigation. © 2022 Elsevier B.V

Association analysis of FTO gene polymorphisms with obesity in Greek adults

Nowadays, obesity is the greatest scourge worldwide, particularly for the developed countries and is a huge burden for the public health. Over the past decade, GWAS have revealed a number of genes associated with obesity. The fat mass and obesity associated (FTO) gene was the first one associated with obesity in a significant number of populations and recent meta-analysis studies confirm this association. FTO is a N-methyladenosine demethylase and in addition to the genetic association, its biological role in the regulation of body weight has been documented. Due to lack of replication regarding FTO association with obesity in the Greek adult population, we analyzed three SNPs, i.e. rs9939609, rs9930506 and rs3751812 in a cohort of 203 adults, comprising of 95 obese, 58 overweight and 50 control individuals. Analysis has shown a significant association for FTO (rs9930506; A/G) ‘G’ allele with obesity and a difference by 3.2 BMI units between the two homozygotes (AA versus GG). This association, which was detected for the first time in this population, suggests that FTO rs9930506 is a predisposition marker to obesity in the Greek adults, but the results should be taken cautiously due to the limitation of the relatively small sample size of the subjects. © 2017 Elsevier B.V

Early experiences and attachment relationships of Greek infants raised in residential group care

FSW - Gezinsopvoeding - Ou

Association Between Polymorphisms in MTHFR and APOA5 and Metabolic Syndrome in the Greek Population

Impaired energy homeostasis and low-grade inflammation have been related to components of the metabolic syndrome (MetS) such as dyslipidemia, obesity, and insulin resistance. Single-nucleotide polymorphisms in the genes encoding for IL-6 (g.-634G>C; c.174G>C), TNF alpha (g.-308G>A), methylenetetrahydrofolate reductase (MTHFR) (c.677C>T), APOC3 (c.3175C>G), and APOA5 (g.-1131T>C) have been implicated in the processes of inflammation and energy intake that take place in the development of MetS manifestations. The aim of this study was to investigate the association between these polymorphisms and MetS, as defined by the National Cholesterol Education Program-Adult treatment Panel III criteria, in the Greek population. Overall, 30 unrelated subjects who met the criteria of MetS and 60 matched control subjects from central Greece were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. There was a significant association between both MTHFR c.677C>T (odds ratio: 4.02; confidence interval: 1.496-10.777; p = 0.003) and APOA5 g.-1131T>C (odds ratio: 3.514; confidence interval: 1.065-11.585; p = 0.035) and MetS. Analysis of constructed haplotypes showed a highly significant association between 677C-1131T-3175C haplotype and MetS (p<0.0001). Carriers of both MTHFR c.677T and APOA5 g.-1131C were associated with increased triglyceride levels (p = 0.001 and p = 0.003, respectively), compared with noncarriers. These results support a role for MTHFR and APOA5 as risk factors for MetS and suggest their further validation in larger independent populations