1,721,045 research outputs found
Genetic determinants of Human Survival and Longevity: A cross-sectional association study in a population of Central Italy
No full textAim of the present thesis is to test the association of functional common variants located within possible candidate genes with human survival and longevity. Furthermore, we attempt to replicate and extend previous findings obtained on APOE, TNF-alpha and TP53 functional polymorphisms. The study has been conducted according to a cross-sectional approach and the polymorphisms have been determined for 1072 unrelated healthy individuals from Central Italy (18-106 years old) divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes. Since the search for longevity-determining genes in human has largely neglected the operation of genetic interactions, we also performed gene-gene interaction analysis to assess the contribute of epistatic phenomena to the definition of genetic architecture underlying the complex trait of human longevity
Gender-specific association of ADA genetic polymorphism with human longevity.
No full textAim of this study was to investigate whether the polymorphic ADA (Adenosine Deaminase, EC 3.5.4.4) gene, which determines the cellular level of adenosine and plays a crucial role in the regulation of the immune system and in the control of metabolic rates, is involved in longevity. 884 unrelated healthy individuals (age range 10-106 years, 400 males and 484 females) from central Italy were studied. ADA genotyping was performed by RFLP-PCR. Frequency distributions were compared using the chisquare test and a three-way contingency table analysis by a log linear model was applied to test independence between the variables. We found that ADA influences human life-span in a sex and age specific way. An increased frequency of ADA*2 carriers was found in males aged 80-85, and a decreased frequency in males over 85 (χ2 = 13.93; df = 3; P = 0.003); significant differences among the age groups was not found in females. A strong interaction among age groups, ADA genotype and sex (G = 15.086; df = 3; P = 0.0017) was found. Males aged 80-85 could be protected from ischemic stroke by higher levels of adenosine (determined by the ADA*2 allele). The decrease of ADA*2 carriers in males over 85 may depend essentially on immunological factors; reduced levels of adenosine protect from asthma and other pulmonary diseases and lead to a reduced activation of inflammatory cells and pro-inflammatory cytokines production. Moreover, the low level of adenosine may potentiate the activity of NKand other cellular effectors against tumor cells. The negligible effect of ADA genetic polymorphism in females suggest a marginal influence of genetic factors in determining longevity in this sex, confirming previous reports
Urinary p-cresol in autism spectrum disorder
No full textAutism spectrum disorder (ASD) is a neuropsychiatric disorder with onset during early childhood and life-long consequences in most cases. It is characterized by impairment in social interaction and communication, as well as by restricted patterns of interest and stereotyped behaviors. The etiology of autism is highly heterogeneous, encompassing a large range of genetic and environmental factors. Several lines of evidence suggest that, in addition to broader diagnostic criteria and increased awareness, also a real increase in incidence primarily due to greater gene-environment interactions may also be occurring. Environmental exposure to the organic aromatic compound p-cresol (4-methylphenol) is relatively common and occurs through the skin, as well as the gastrointestinal and respiratory systems. However, the largest and most widespread source of this compound is represented by some gut bacteria which express p-cresol synthesizing enzymes not found in human cells. Urinary p-cresol and its conjugated derivative p-cresylsulfate have been found elevated in an initial sample and recently in a replica sample of autistic children below 8 years of age, where it is associated with female sex, greater clinical severity regardless of sex, and history of behavioral regression. Potential sources of p-cresol excess in ASD, such as gut infection, chronic constipation, antibiotics, abnormal intestinal permeability, and environmental exposure, are being investigated. P-cresol may contribute to worsen autism severity and gut dysfunction, often present in autistic children. It may also contribute to a multibiomarker diagnostic panel useful in small autistic children
Autism genetics
No full textAutism spectrum disorder (ASD) is a severe neuropsychiatric disease with strong genetic underpinnings. However, genetic contributions to autism are extremely heterogeneous, with many different loci underlying the disease to a different extent in different individuals. Moreover, the phenotypic expression (i.e., "penetrance") of these genetic components is also highly variable, ranging from fully penetrant point mutations to polygenic forms with multiple gene-gene and gene-environment interactions. Furthermore, many genes involved in ASD are also involved in intellectual disability, further underscoring their lack of specificity in phenotypic expression. We shall hereby review current knowledge on the genetic basis of ASD, spanning genetic/genomic syndromes associated with autism, monogenic forms due to copy number variants (CNVs) or rare point mutations, mitochondrial forms, and polygenic autisms. Finally, the recent contributions of genome-wide association and whole exome sequencing studies will be highlighted
Whole-genome sequencing of alpaca revealed variants in KIT gene potentially associated with the white coat phenotype
Full text linkThe association between variants on TYRP1, TYRP2, MC1R, KITLG, KIT, ASIP and MITF genes and fleece color has been described for alpaca and llama (Zhu et al., 2019; Feeley et al., 2016; Chandramohan et al., 2015; Anello et al., 2022; Pallotti et al., 2020; Shah et al., 2023; Jones et al., 2019; Tan et al., 2022). In this regard, variants on KIT were associated to white and blue-eyed white phenotype in alpaca (Jones et al., 2019; Tan et al., 2022) due to its important role in melanogenesis (Roskoski, 2005). Moreover, previous segregation analysis suggested that the inheritance of white color in alpaca was due to a single gene which is completely dominant over black and brown pigmentation (Valbonesi et al., 2011).
In the present study, the segregation of KITLG, KIT and MITF genes was analyzed to find variants associated to white coat phenotype in alpaca. Six Peruvian alpacas belonging to two test-cross families were tested: white huacaya male × pigmented suri female and white suri male x pigmented huacaya female which gave birth to one white suri and one pigmented huacaya, respectively (Table 1). The animals were raised at the experimental station of the INIA (the Peruvian National Institute for Agronomic Innovation) located in Quimsachata, Peru. Sampling of the animals and genomics analysis were performed as reported in Pallotti et al. (2023). Briefly, genomic DNA extracted from skin biopsies underwent whole-genome sequencing on Illumina NovaSeq 6000 System, with a 150x2 bp mode, and an average sequencing depth of 25X. After quality control and alignment to VicPac3 reference genome, the variants were called using the standard joint-call GATK pipeline. All the variants were annotated using SNPeff and filtered according to the segregation of the white coat phenotype.
No segregating variants for white coat color were identified in KITLG and MITF. On the contrary, two different KIT variants segregated in white animals (Table 1): two white alpacas, belonging to family 1, were heterozygous (G/A) for the c.35G>A (p.Arg12His) variant, while one white alpaca, belonging to family 2, was heterozygotes (G/C) for c.982G>C (p.Val328Leu) variant. Conversely, all the pigmented animals showed a homozygous G/G genotype. The protein functional domains predicted using InterProScan (Quevillon et al., 2005) suggested that the two mutations were in the N-terminal region of the signal peptide and in the extracellular region which are essential for the binding of the appropriate ligand and consequent activation of KIT (Roskoski, 2005). In addition, such results may suggest a dominant inheritance for alpaca white color as proposed by previous segregation studies (Valbonesi et al., 2011).
Although these results must be validated on larger sample, our findings refine the current understanding of the association between gene variants and white color in alpaca and suggest new potential KIT variants as a starting point for further studies on the genetics of white color in alpaca
Infection burden and ALDH2 rs671, East Asian genetic diversity: A reply
No full textNo abstract availabl
Network propagation of rare variants in Alzheimer's disease reveals tissue-specific hub genes and communities
Full text linkState-of-the-art rare variant association testing methods aggregate the contribution of rare variants in biologically relevant genomic regions to boost statistical power. However, testing single genes separately does not consider the complex interaction landscape of genes, nor the downstream effects of non-synonymous variants on protein structure and function. Here we present the NETwork Propagation-based Assessment of Genetic Events (NETPAGE), an integrative approach aimed at investigating the biological pathways through which rare variation results in complex disease phenotypes. We applied NETPAGE to sporadic, late-onset Alzheimer's disease (AD), using whole-genome sequencing from the AD Neuroimaging Initiative (ADNI) cohort, as well as whole-exome sequencing from the AD Sequencing Project (ADSP). NETPAGE is based on network propagation, a framework that models information flow on a graph and simulates the percolation of genetic variation through tissue-specific gene interaction networks. The result of network propagation is a set of smoothed gene scores that can be tested for association with disease status through sparse regression. The application of NETPAGE to AD enabled the identification of a set of connected genes whose smoothed variation profile was robustly associated to case-control status, based on gene interactions in the hippocampus. Additionally, smoothed scores significantly correlated with risk of conversion to AD in Mild Cognitive Impairment (MCI) subjects. Lastly, we investigated tissue-specific transcriptional dysregulation of the core genes in two independent RNA-seq datasets, as well as significant enrichments in terms of gene sets with known connections to AD. We present a framework that enables enhanced genetic association testing for a wide range of traits, diseases, and sample sizes
Genetic Polymorphisms and Idiopathic Generalized Epilepsies
No full textIn recent years, progress in understanding the genetic basis of idiopathic generalized epilepsies has proven challenging because of their complex inheritance patterns and genetic heterogeneity. Genetic polymorphisms offer a convenient avenue for a better understanding of the genetic basis of idiopathic generalized epilepsy by providing evidence for the involvement of a given gene in these disorders, and by clarifying its pathogenetic mechanisms. Many of these genes encode for some important central nervous system ion channels (KCNJ10, KCNJ3, KCNQ2/KCNQ3, CLCN2, GABRG2, GABRA1, SCN1B, and SCN1A), while many others encode for ubiquitary enzymes that play crucial roles in various metabolic pathways (HP, ACP1, ME2, LGI4, OPRM1, GRIK1, BRD2, EFHC1, and EFHC2). We review the main genetic polymorphisms reported in idiopathic generalized epilepsy, and discusses their possible functional significance in the pathogenesis of seizures. © 2007 Elsevier Inc. All rights reserved
Contribution of infectious diseases to the selection of ADH1B and ALDH2 gene variants in Asian populations
No full textBackground: The gene variants ADH1B*2 (Arg48His, rs1229984) and ALDH2*2 (Glu504Lys, rs671) are common in East Asian populations but rare in other populations. We propose that selective pressures from pathogen exposure and dietary changes during the neolithic transition favored these variants. Thus, their current association with differences in alcohol sensitivity likely results from phenotypic plasticity rather than direct natural selection. Methods: Samples sourced from the Allele Frequency Database (ALFRED) were utilized to compute the average frequency of ADH1B*2 and ALDH2*2 across 88 and 61 countries, respectively. Following computation of the average national allele frequencies, we tested the significance of their correlations with ecological variables. Subsequently, we subjected them to Principal Component Analysis (PCA) and Elastic Net regularization. For comprehensive evaluation, we collected individual-level phenotypic associations, compiling a Phenome-Wide Association Study (PheWAS) spanning multiple ethnicities. Results: Following multiple testing correction, ADH1B*2 displayed significant correlations with Neolithic transition timing (r = 0.405, p.adj = 2.013e-03, n = 57) and historical trypanosome burden (r = -0.418, p.adj = 0.013, n = 57). The first two components of PCA explained 47.7% of the total variability across countries, with the top three contributors being the historical indices of population density and trypanosome and leprosy burdens. Historical burdens of the Mycobacteria tuberculosis and leprosy were the sole predictive variables with positive coefficients that survived Elastic Net regularization. Conclusions: Our analyses suggest that Mycobacteria may have played a role in the joint selection of ADH1B*2 and ALDH2*2, expanding the "toxic aldehyde hypothesis" to include Mycobacterium leprae. Additionally, our hypothesis, linked to dietary shifts from rice domestication, emphasizes nutritional deficiencies as a key element in the selective pressure exerted by Mycobacteria. This offers a plausible explanation for the high frequency of ADH1B*2 and ALDH2*2 in Asian populations
Genetic polymorphisms and idiopathic generalized epilepsies
No full textIn recent years, progress in understanding the genetic basis of idiopathic generalized epilepsies has proven challenging because of their complex inheritance patterns and genetic heterogeneity. Genetic polymorphisms offer a convenient avenue for a better understanding of the genetic basis of idiopathic generalized epilepsy by providing evidence for the involvement of a given gene in these disorders, and by clarifying its pathogenetic mechanisms. Many of these genes encode for some important central nervous system ion channels (KCNJ10, KCNJ3, KCNQ2/KCNQ3, CLCN2, GABRG2, GABRA1, SCN1B, and SCN1A), while many others encode for ubiquitary enzymes that play crucial roles in various metabolic pathways (HP, ACP1, ME2, LGI4, OPRM1, GRIK1, BRD2, EFHC1, and EFHC2). We review the main genetic polymorphisms reported in idiopathic generalized epilepsy, and discusses their possible functional significance in the pathogenesis of seizures
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