Metabolic and genetic contributions to NAFLD: really distinct and homogeneous?

In the panorama of inflammatory arthritis, gout is the most common and studied disease. It is known that hyperuricemia and monosodium urate (MSU) crystal-induced inflammation provoke crystal deposits in joints. However, since hyperuricemia alone is not sufficient to develop gout, molecular-genetic contributions are necessary to better clinically frame the disease. Herein, we review the autoinflammatory features of gout, from clinical challenges and differential diagnosis, to the autoinflammatory mechanisms, providing also emerging therapeutic options available for targeting the main inflammatory pathways involved in gout pathogenesis. This has important implication as treating the autoinflammatory aspects and not only the dysmetabolic side of gout may provide an effective and safer alternative for patients even in the prevention of possible gouty attacks.

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Prediction of Genetic Contributions and Generation Intervals in Populations With Overlapping Generations Under Selection

Genetics ◽

10.1093/genetics/151.3.1197 ◽

1999 ◽

Vol 151 (3) ◽

pp. 1197-1210 ◽

Cited By ~ 3

Author(s):

Piter Bijma ◽

John A Woolliams

Keyword(s):

Gene Flow ◽

Overlapping Generations ◽

Selective Advantage ◽

Turnover Time ◽

Breeding Value ◽

Age Classes ◽

Generation Interval ◽

Young Parents ◽

Genetic Contributions

Abstract A method to predict long-term genetic contributions of ancestors to future generations is studied in detail for a population with overlapping generations under mass or sib index selection. An existing method provides insight into the mechanisms determining the flow of genes through selected populations, and takes account of selection by modeling the long-term genetic contribution as a linear regression on breeding value. Total genetic contributions of age classes are modeled using a modified gene flow approach and long-term predictions are obtained assuming equilibrium genetic parameters. Generation interval was defined as the time in which genetic contributions sum to unity, which is equal to the turnover time of genes. Accurate predictions of long-term genetic contributions of individual animals, as well as total contributions of age classes were obtained. Due to selection, offspring of young parents had an above-average breeding value. Long-term genetic contributions of youngest age classes were therefore higher than expected from the age class distribution of parents, and generation interval was shorter than the average age of parents at birth of their offspring. Due to an increased selective advantage of offspring of young parents, generation interval decreased with increasing heritability and selection intensity. The method was compared to conventional gene flow and showed more accurate predictions of long-term genetic contributions.

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Genetic factors explain a significant part of associations between adolescent well-being and the social environment

European Child & Adolescent Psychiatry ◽

10.1007/s00787-021-01798-3 ◽

2021 ◽

Author(s):

Margot P. van de Weijer ◽

Dirk H. M. Pelt ◽

Catharina E. M. van Beijsterveldt ◽

Gonneke Willemsen ◽

Meike Bartels

Keyword(s):

Family Conflict ◽

Generalized Estimating Equations ◽

Leisure Time ◽

Genetic Factors ◽

Well Being ◽

Causal Association ◽

Difference Scores ◽

The Social ◽

Time Variables ◽

Genetic Contributions

AbstractSocio-environmental factors play an important role in adolescent well-being, but potential genetic contributions to these associations are rarely assessed. To address this gap in the literature, associations between well-being and family conflict and functioning, number of friends, friendship importance and satisfaction, and leisure time variables were studied in N = ~ 4700 twin pairs from the Netherlands Twin Register, us ing generalized estimating equations and twin-difference scores. When twin-difference scores indicated a role for genetic factors, we used bivariate genetic models to quantify genetic and environmental contributions to these associations. We identify significant associations between well-being and family functioning, family conflict, different leisure time activities, number of friends, and satisfaction with friendships. Additionally, we find evidence for large (73–91%) genetic influence on the associations between well-being and family conflict and functioning, leisure time sport/scouting clubs, and satisfaction with friendships. Finally, findings support the hypothesis of a causal association between well-being and family conflict and functioning. These findings have important implications for research into the social correlates of well-being in adolescence, as not taking genetic factors into account leads to overestimations of the influence of identified correlates and consequently to recommendations of these correlates as intervention targets.

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NAPG mutation in family members with hereditary hemorrhagic telangiectasia in China

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01524-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yu Xu ◽

Yong-Biao Zhang ◽

Li-Jun Liang ◽

Jia-Li Tian ◽

Jin-Ming Lin ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hereditary Hemorrhagic Telangiectasia ◽

Sanger Sequencing ◽

Conformational Stability ◽

Sequencing Analysis ◽

Large Pedigree ◽

Whole Exome ◽

Variant Filtering ◽

Genetic Contributions

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations in the skin and mucous membranes. We enrolled a large pedigree comprising 32 living members, and screened for mutations responsible for HHT. Methods We performed whole-exome sequencing to identify novel mutations in the pedigree after excluding three previously reported HHT-related genes using Sanger sequencing. We then performed in silico functional analysis of candidate mutations that were obtained using a variant filtering strategy to identify mutations responsible for HHT. Results After screening the HHT-related genes, activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and SMAD family member 4 (SMAD4), we did not detect any co-segregated mutations in this pedigree. Whole-exome sequencing analysis of 7 members and Sanger sequencing analysis of 16 additional members identified a mutation (c.784A > G) in the NSF attachment protein gamma (NAPG) gene that co-segregated with the disease. Functional prediction showed that the mutation was deleterious and might change the conformational stability of the NAPG protein. Conclusions NAPG c.784A > G may potentially lead to HHT. These results expand the current understanding of the genetic contributions to HHT pathogenesis.

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Discovery and refinement of muscle weight QTLs in B6 × D2 advanced intercross mice

Physiological Genomics ◽

10.1152/physiolgenomics.00055.2014 ◽

2014 ◽

Vol 46 (16) ◽

pp. 571-582 ◽

Cited By ~ 9

Author(s):

P. Carbonetto ◽

R. Cheng ◽

J. P. Gyekis ◽

C. C. Parker ◽

D. A. Blizard ◽

...

Keyword(s):

Inbred Strains ◽

Mouse Strains ◽

Missense Mutations ◽

Muscle Weight ◽

Hindlimb Muscles ◽

Hindlimb Muscle ◽

Causal Genes ◽

Snp Panel ◽

Genomic Regions ◽

Genetic Contributions

The genes underlying variation in skeletal muscle mass are poorly understood. Although many quantitative trait loci (QTLs) have been mapped in crosses of mouse strains, the limited resolution inherent in these conventional studies has made it difficult to reliably pinpoint the causal genetic variants. The accumulated recombination events in an advanced intercross line (AIL), in which mice from two inbred strains are mated at random for several generations, can improve mapping resolution. We demonstrate these advancements in mapping QTLs for hindlimb muscle weights in an AIL ( n = 832) of the C57BL/6J (B6) and DBA/2J (D2) strains, generations F8–F13. We mapped muscle weight QTLs using the high-density MegaMUGA SNP panel. The QTLs highlight the shared genetic architecture of four hindlimb muscles and suggest that the genetic contributions to muscle variation are substantially different in males and females, at least in the B6D2 lineage. Out of the 15 muscle weight QTLs identified in the AIL, nine overlapped the genomic regions discovered in an earlier B6D2 F2 intercross. Mapping resolution, however, was substantially improved in our study to a median QTL interval of 12.5 Mb. Subsequent sequence analysis of the QTL regions revealed 20 genes with nonsense or potentially damaging missense mutations. Further refinement of the muscle weight QTLs using additional functional information, such as gene expression differences between alleles, will be important for discerning the causal genes.

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Predicting Rates of Inbreeding in Populations Undergoing Selection

Genetics ◽

10.1093/genetics/154.4.1851 ◽

2000 ◽

Vol 154 (4) ◽

pp. 1851-1864 ◽

Cited By ~ 5

Author(s):

John A Woolliams ◽

Piter Bijma

Keyword(s):

Overlapping Generations ◽

Linear Models ◽

Selection Process ◽

Correction Term ◽

Random Mating ◽

Nonrandom Mating ◽

Selection Processes ◽

Genetic Contributions ◽

The Relationship

AbstractTractable forms of predicting rates of inbreeding (ΔF) in selected populations with general indices, nonrandom mating, and overlapping generations were developed, with the principal results assuming a period of equilibrium in the selection process. An existing theorem concerning the relationship between squared long-term genetic contributions and rates of inbreeding was extended to nonrandom mating and to overlapping generations. ΔF was shown to be ~¼(1 − ω) times the expected sum of squared lifetime contributions, where ω is the deviation from Hardy-Weinberg proportions. This relationship cannot be used for prediction since it is based upon observed quantities. Therefore, the relationship was further developed to express ΔF in terms of expected long-term contributions that are conditional on a set of selective advantages that relate the selection processes in two consecutive generations and are predictable quantities. With random mating, if selected family sizes are assumed to be independent Poisson variables then the expected long-term contribution could be substituted for the observed, providing ¼ (since ω = 0) was increased to ½. Established theory was used to provide a correction term to account for deviations from the Poisson assumptions. The equations were successfully applied, using simple linear models, to the problem of predicting ΔF with sib indices in discrete generations since previously published solutions had proved complex.

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Genetic components of human pain sensitivity: a protocol for a genome-wide association study of experimental pain in healthy volunteers

BMJ Open ◽

10.1136/bmjopen-2018-025530 ◽

2019 ◽

Vol 9 (4) ◽

pp. e025530 ◽

Cited By ~ 2

Author(s):

Annina B Schmid ◽

Kaustubh Adhikari ◽

Luis Miguel Ramirez-Aristeguieta ◽

Juan-Camilo Chacón-Duque ◽

Giovanni Poletti ◽

...

Keyword(s):

Latin American ◽

Pain Sensitivity ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Healthy Individuals ◽

Genetic Components ◽

Genome Wide ◽

A Genome ◽

The University ◽

Genetic Contributions

IntroductionPain constitutes a major component of the global burden of diseases. Recent studies suggest a strong genetic contribution to pain susceptibility and severity. Whereas most of the available evidence relies on candidate gene association or linkage studies, research on the genetic basis of pain sensitivity using genome-wide association studies (GWAS) is still in its infancy. This protocol describes a proposed GWAS on genetic contributions to baseline pain sensitivity and nociceptive sensitisation in a sample of unrelated healthy individuals of mixed Latin American ancestry.Methods and analysisA GWAS on genetic contributions to pain sensitivity in the naïve state and following nociceptive sensitisation will be conducted in unrelated healthy individuals of mixed ancestry. Mechanical and thermal pain sensitivity will be evaluated with a battery of quantitative sensory tests evaluating pain thresholds. In addition, variation in mechanical and thermal sensitisation following topical application of mustard oil to the skin will be evaluated.Ethics and disseminationThis study received ethical approval from the University College London research ethics committee (3352/001) and from the bioethics committee of the Odontology Faculty at the University of Antioquia (CONCEPTO 01–2013). Findings will be disseminated to commissioners, clinicians and service users via papers and presentations at international conferences.

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GENETIC HETEROZYGOSITY IN UNREPLICATED BACTERIOPHAGE Λ RECOMBINANTS

Genetics ◽

10.1093/genetics/81.1.33 ◽

1975 ◽

Vol 81 (1) ◽

pp. 33-50

Author(s):

Raymond L White ◽

Maurice S Fox

Keyword(s):

Dna Synthesis ◽

Base Pair ◽

Recombinant Dna ◽

Dna Molecules ◽

Bacteriophage Λ ◽

Negative Interference ◽

Genetic Interval ◽

Parental Material ◽

Genetic Heterozygosity ◽

Genetic Contributions

ABSTRACT Bacteriophage crosses using density-labeled parents have been carried out under conditions restricting DNA synthesis. The parental material and genetic contributions to progeny manifesting recombination within a genetic interval sufficiently short to exhibit high negative interference have been examined. The unreplicated products of recombination isolated as phage particles appear to contain long continuous heteroduplex regions which are heterozygous for the closely linked markers. Recombination between closely linked markers seems to be the consequence of the removal of base-pair mismatches that are present within the heteroduplex regions. This localized reduction of heterozygosity within the heteroduplex regions that join the parental components of recombinant DNA molecules can account for high negative interference.

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Genetic parkinsonisms and cancer: a systematic review and meta-analysis

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0083 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Andrea Sturchio ◽

Alok K. Dwivedi ◽

Joaquin A. Vizcarra ◽

Martina Chirra ◽

Elizabeth G. Keeling ◽

...

Keyword(s):

Head And Neck ◽

Meta Analysis ◽

Head And Neck Cancers ◽

Breast Cancers ◽

Asymptomatic Carriers ◽

Skin Cancers ◽

Prostate Cancers ◽

Meta Analyses ◽

Genetic Contributions ◽

Nonmelanoma Skin Cancers

AbstractGenes associated with parkinsonism may also be implicated in carcinogenesis, but their interplay remains unclear. We systematically reviewed studies (PubMed 1967–2019) reporting gene variants associated with both parkinsonism and cancer. Somatic variants were examined in cancer samples, whereas germline variants were examined in cancer patients with both symptomatic and asymptomatic (carriers) genetic parkinsonisms. Pooled proportions were calculated with random-effects meta-analyses. Out of 9,967 eligible articles, 60 were included. Of the 28 genetic variants associated with parkinsonism, six were also associated with cancer. In cancer samples, SNCA was predominantly associated with gastrointestinal cancers, UCHL1 with breast cancer, and PRKN with head-and-neck cancers. In asymptomatic carriers, LRRK2 was predominantly associated with gastrointestinal and prostate cancers, PRKN with prostate and genitourinary tract cancers, GBA with sarcoma, and 22q11.2 deletion with leukemia. In symptomatic genetic parkinsonism, LRRK2 was associated with nonmelanoma skin cancers and breast cancers, and PRKN with head-and-neck cancers. Cancer was more often manifested in genetic parkinsonisms compared to asymptomatic carriers. These results suggest that intraindividual genetic contributions may modify the co-occurrence of cancer and neurodegeneration.

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Expected Genetic Contributions and Their Impact on Gene Flow and Genetic Gain

Genetics ◽

10.1093/genetics/153.2.1009 ◽

1999 ◽

Vol 153 (2) ◽

pp. 1009-1020 ◽

Cited By ~ 4

Author(s):

J A Woolliams ◽

P Bijma ◽

B Villanueva

Keyword(s):

Gene Flow ◽

Genetic Gain ◽

Overlapping Generations ◽

Predictive Accuracy ◽

Index Theory ◽

Previous Theory ◽

Selection Indices ◽

Breeding Groups ◽

Genetic Contributions

Abstract Long-term genetic contributions (ri) measure lasting gene flow from an individual i. By accounting for linkage disequilibrium generated by selection both within and between breeding groups (categories), assuming the infinitesimal model, a general formula was derived for the expected contribution of ancestor i in category q (μi(q)), given its selective advantages (si(q)). Results were applied to overlapping generations and to a variety of modes of inheritance and selection indices. Genetic gain was related to the covariance between ri and the Mendelian sampling deviation (ai), thereby linking gain to pedigree development. When si(q) includes ai, gain was related to E[μi(q)ai], decomposing it into components attributable to within and between families, within each category, for each element of si(q). The formula for μi(q) was consistent with previous index theory for predicting gain in discrete generations. For overlapping generations, accurate predictions of gene flow were obtained among and within categories in contrast to previous theory that gave qualitative errors among categories and no predictions within. The generation interval was defined as the period for which μi(q), summed over all ancestors born in that period, equaled 1. Predictive accuracy was supported by simulation results for gain and contributions with sib-indices, BLUP selection, and selection with imprinted variation.

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