Autism spectrum disorders (ASD) is a complex neurodevelopmental disorder that may significantly impact on the affected individual's life. Common variation (SNPs) could explain about 50% of ASD ...heritability. Despite this fact and the large size of the last GWAS meta-analysis, it is believed that hundreds of risk genes in ASD have yet to be discovered. New tools, such as TWAS (Transcriptome Wide Association Studies) which integrate tissue expression and genetic data, are a great approach to identify new ASD susceptibility genes. The main goal of this study is to use UTMOST with the publicly available summary statistics from the largest ASD GWAS meta-analysis as genetic input. In addition, an in silico biological characterization for the novel associated loci was performed. Our results have shown the association of 4 genes at the brain level (CIPC, PINX1, NKX2-2, and PTPRE) and have highlighted the association of NKX2-2, MANBA, ERI1, and MITF at the gastrointestinal level. The gastrointestinal associations are quite relevant given the well-established but unexplored relationship between ASD and gastrointestinal symptoms. Cross-tissue analysis has shown the association of NKX2-2 and BLK. UTMOST-associated genes together with their in silico biological characterization seems to point to different biological mechanisms underlying ASD etiology. Thus, it would not be restricted to brain tissue and it will involve the participation of other body tissues such as the gastrointestinal.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with increasing prevalence, and a male-to-female ratio of 4:1. Research has been suggesting that discrepancy in prevalence may be due ...to the fact that females camouflage their symptoms. In this study, we aimed to systematically review evidence on the camouflage effect in females with ASD. Following the PRISMA guidelines, we reviewed empirical research published from January 2009 to September 2019 on PubMed, Web of Science, PsychInfo and Scopus databases. Thirteen empirical articles were included in this review. Overall, evidence supports that camouflaging seems to be an adaptive mechanism for females with ASD, despite the negative implications of these behaviours in their daily life.
Developmental periods in early life may be particularly vulnerable to impacts of environmental exposures. Human research on this topic has generally focused on single exposure-health effect ...relationships. The "exposome" concept encompasses the totality of exposures from conception onward, complementing the genome.
The Human Early-Life Exposome (HELIX) project is a new collaborative research project that aims to implement novel exposure assessment and biomarker methods to characterize early-life exposure to multiple environmental factors and associate these with omics biomarkers and child health outcomes, thus characterizing the "early-life exposome." Here we describe the general design of the project.
In six existing birth cohort studies in Europe, HELIX will estimate prenatal and postnatal exposure to a broad range of chemical and physical exposures. Exposure models will be developed for the full cohorts totaling 32,000 mother-child pairs, and biomarkers will be measured in a subset of 1,200 mother-child pairs. Nested repeat-sampling panel studies (n = 150) will collect data on biomarker variability, use smartphones to assess mobility and physical activity, and perform personal exposure monitoring. Omics techniques will determine molecular profiles (metabolome, proteome, transcriptome, epigenome) associated with exposures. Statistical methods for multiple exposures will provide exposure-response estimates for fetal and child growth, obesity, neurodevelopment, and respiratory outcomes. A health impact assessment exercise will evaluate risks and benefits of combined exposures.
HELIX is one of the first attempts to describe the early-life exposome of European populations and unravel its relation to omics markers and health in childhood. As proof of concept, it will form an important first step toward the life-course exposome.
HLA alleles: important pieces to the COVID-19 puzzle Castro-Santos, Patricia; Carracedo, Ángel; Díaz-Peña, Roberto
Trends in immunology,
October 2023, 2023-10-00, 20231001, Letnik:
44, Številka:
10
Journal Article
Recenzirano
Research on human leukocyte antigen (HLA) molecules in coronavirus disease 2019 (COVID-19) raised high expectations but has yielded limited results. Augusto et al.'s recent study in Nature unveils a ...strong association of HLA-B*15:01 with asymptomatic COVID-19, representing an important contribution to genetics in COVID-19.
Research on human leukocyte antigen (HLA) molecules in coronavirus disease 2019 (COVID-19) raised high expectations but has yielded limited results. Augusto et al.'s recent study in Nature unveils a strong association of HLA-B*15:01 with asymptomatic COVID-19, representing an important contribution to genetics in COVID-19.
We present an up-to-date review of STRUCTURE software: one of the most widely used population analysis tools that allows researchers to assess patterns of genetic structure in a set of samples. ...STRUCTURE can identify subsets of the whole sample by detecting allele frequency differences within the data and can assign individuals to those sub-populations based on analysis of likelihoods. The review covers STRUCTURE's most commonly used ancestry and frequency models, plus an overview of the main applications of the software in human genetics including case-control association studies (CCAS), population genetics, and forensic analysis. The review is accompanied by supplementary material providing a step-by-step guide to running STRUCTURE.
With reference to a worked example, we explore the effects of changing the principal analysis parameters on STRUCTURE results when analyzing a uniform set of human genetic data. Use of the supporting software: CLUMPP and distruct is detailed and we provide an overview and worked example of STRAT software, applicable to CCAS.
The guide offers a simplified view of how STRUCTURE, CLUMPP, distruct, and STRAT can be applied to provide researchers with an informed choice of parameter settings and supporting software when analyzing their own genetic data.
Ancestry-informative markers (AIMs) show high allele frequency divergence between different ancestral or geographically distant populations. These genetic markers are especially useful in inferring ...the likely ancestral origin of an individual or estimating the apportionment of ancestry components in admixed individuals or populations. The study of AIMs is of great interest in clinical genetics research, particularly to detect and correct for population substructure effects in case-control association studies, but also in population and forensic genetics studies. This work presents a set of 46 ancestry-informative insertion deletion polymorphisms selected to efficiently measure population admixture proportions of four different origins (African, European, East Asian and Native American). All markers are analyzed in short fragments (under 230 basepairs) through a single PCR followed by capillary electrophoresis (CE) allowing a very simple one tube PCR-to-CE approach. HGDP-CEPH diversity panel samples from the four groups, together with Oceanians, were genotyped to evaluate the efficiency of the assay in clustering populations from different continental origins and to establish reference databases. In addition, other populations from diverse geographic origins were tested using the HGDP-CEPH samples as reference data. The results revealed that the AIM-INDEL set developed is highly efficient at inferring the ancestry of individuals and provides good estimates of ancestry proportions at the population level. In conclusion, we have optimized the multiplexed genotyping of 46 AIM-INDELs in a simple and informative assay, enabling a more straightforward alternative to the commonly available AIM-SNP typing methods dependent on complex, multi-step protocols or implementation of large-scale genotyping technologies.
The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of ...rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their “diagnostic odyssey,” improves disease management, and fosters ...genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.
Human identification is usually based on the study of STRs or SNPs depending on the particular characteristics of the investigation. However, other types of genetic variation such as ...insertion/deletion polymorphisms (indels) have considerable potential in the field of identification, since they can combine the desirable characteristics of both STRs and SNPs. In this study, a set of 38 non‐coding bi‐allelic autosomal indels reported to be polymorphic in African, European, and Asian populations were selected. We developed a sensitive genotyping assay, which is able to characterize all 38 bi‐allelic markers using a single multiplex PCR and detected with standard CE analyzers. Amplicon length was designed to be shorter than 160 bp. Complete profiles were obtained using 0.3 ng of DNA, and full genotyping of degraded samples was possible in cases where standard STR typing had partially failed. A total of 306 individuals from Angola, Mozambique, Portugal, Macau, and Taiwan were studied and population data are presented. All indels were polymorphic in the three population groups studied and the random match probabilities of the set ranged in orders of magnitude from 10−14 to 10−15. Therefore, the indel‐plex represents a valuable approach in human identification studies, especially in challenging DNA cases, as a more straightforward and efficient alternative to SNP typing.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder (NDD) defined by impairments in social communication and social interactions, accompanied by repetitive behavior and restricted ...interests. ASD is characterized by its clinical and etiological heterogeneity, which makes it difficult to elucidate the neurobiological mechanisms underlying its pathogenesis. Recently,
mutations (DNMs) have been recognized as strong source of genetic causality. Here, we review different aspects of the DNMs associated with ASD, including their functional annotation and classification. In addition, we also focus on the most recent advances in this area, such as the detection of PZMs (
), and we outline the main bioinformatics tools commonly employed to study these. Some of these approaches available allow DNMs to be analyzed in the context of gene networks and pathways, helping to shed light on the biological processes underlying ASD. To end this review, a brief insight into the future perspectives for genetic studies into ASD will be provided.
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