-
Genes Sep 2023Keratoconus is a corneal dystrophy that is one of the main causes of corneal transplantation and for which there is currently no effective treatment for all patients....
Keratoconus is a corneal dystrophy that is one of the main causes of corneal transplantation and for which there is currently no effective treatment for all patients. The presentation of this disease in pediatric age is associated with rapid progression, a worse prognosis and, in 15-20% of cases, the need for corneal transplantation. It is a multifactorial disease with genetic variability, which makes its genetic study difficult. Discovering new therapeutic targets is necessary to improve the quality of life of patients. In this manuscript, we present the results of whole-exome sequencing (WES) of 24 pediatric families diagnosed at the University Hospital La Paz (HULP) in Madrid. The results show an oligogenic inheritance of the disease. Genes involved in the structure, function, cell adhesion, development and repair pathways of the cornea are proposed as candidate genes for the disease. Further studies are needed to confirm the involvement of the candidate genes described in this article in the development of pediatric keratoconus.
Topics: Humans; Child; Keratoconus; Exome Sequencing; Quality of Life; Cornea; Corneal Dystrophies, Hereditary
PubMed: 37895187
DOI: 10.3390/genes14101838 -
Cell Genomics Apr 2024Polygenic risk scores (PRSs) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. We propose PRSmix, a framework that leverages the PRS...
Polygenic risk scores (PRSs) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. We propose PRSmix, a framework that leverages the PRS corpus of a target trait to improve prediction accuracy, and PRSmix+, which incorporates genetically correlated traits to better capture the human genetic architecture for 47 and 32 diseases/traits in European and South Asian ancestries, respectively. PRSmix demonstrated a mean prediction accuracy improvement of 1.20-fold (95% confidence interval [CI], [1.10; 1.3]; p = 9.17 × 10) and 1.19-fold (95% CI, [1.11; 1.27]; p = 1.92 × 10), and PRSmix+ improved the prediction accuracy by 1.72-fold (95% CI, [1.40; 2.04]; p = 7.58 × 10) and 1.42-fold (95% CI, [1.25; 1.59]; p = 8.01 × 10) in European and South Asian ancestries, respectively. Compared to the previously cross-trait-combination methods with scores from pre-defined correlated traits, we demonstrated that our method improved prediction accuracy for coronary artery disease up to 3.27-fold (95% CI, [2.1; 4.44]; p value after false discovery rate (FDR) correction = 2.6 × 10). Our method provides a comprehensive framework to benchmark and leverage the combined power of PRS for maximal performance in a desired target population.
Topics: Humans; Multifactorial Inheritance; Genetic Risk Score; Benchmarking; Coronary Artery Disease; Manipulation, Osteopathic
PubMed: 38508198
DOI: 10.1016/j.xgen.2024.100523 -
Molecular Autism Jun 2024Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in...
BACKGROUND
Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in phenotypically defined autism subgroups [e.g., autism with and without intellectually disability (ID)]. It is also unclear what proportion of the phenotypic AM can be explained by the genetic similarity between parents of children with an autism diagnosis, and the consequences of AM on the genetic structure of the population.
METHODS
To address these questions, we analyzed two family-based autism collections: the Simons Foundation Powering Autism Research for Knowledge (SPARK) (1575 families) and the Simons Simplex Collection (SSC) (2283 families).
RESULTS
We found a similar degree of phenotypic and ancestry-related AM in parents of children with an autism diagnosis regardless of the presence of ID. We did not find evidence of AM for autism based on autism polygenic scores (PGS) (at a threshold of |r|> 0.1). The adjustment of ancestry-related AM or autism PGS accounted for only 0.3-4% of the fractional change in the estimate of the phenotypic AM. The ancestry-related AM introduced higher long-range linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) on different chromosomes that are highly ancestry-informative compared to SNPs that are less ancestry-informative (D on the order of 1 × 10).
LIMITATIONS
We only analyzed participants of European ancestry, limiting the generalizability of our results to individuals of non-European ancestry. SPARK and SSC were both multicenter studies. Therefore, there could be ancestry-related AM in SPARK and SSC due to geographic stratification. The study participants from each site were unknown, so we were unable to evaluate for geographic stratification.
CONCLUSIONS
This study showed similar patterns of AM in autism with and without ID, and demonstrated that the common genetic influences of autism are likely relevant to both autism groups. The adjustment of ancestry-related AM and autism PGS accounted for < 5% of the fractional change in the estimate of the phenotypic AM. Future studies are needed to evaluate if the small increase of long-range LD induced by ancestry-related AM has impact on the downstream analysis.
Topics: Humans; Autistic Disorder; Phenotype; Male; Female; Linkage Disequilibrium; Multifactorial Inheritance; Child; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Adult; Intellectual Disability
PubMed: 38877467
DOI: 10.1186/s13229-024-00605-5 -
Plant-environment Interactions... Jun 2024A putative glufosinate-resistant population was reported in 2015 in Anson County, North Carolina. The results from dose-response assays conducted in the field suggested...
A putative glufosinate-resistant population was reported in 2015 in Anson County, North Carolina. The results from dose-response assays conducted in the field suggested plants were surviving lethal rates of glufosinate. Dose-response assays conducted in the glasshouse determined the Anson County accession exhibited reduced susceptibility to glufosinate compared to three glufosinate-susceptible populations. The LD values (210-316 g ai ha) for the Anson County population were always higher than the LD values (118-158 g ai ha) for the tested susceptible populations from the dose-response assays. Anson County plants that survived lethal glufosinate rates were reciprocally crossed with susceptible plants to create F genotypes and treated with a lethal rate of glufosinate (267 g ai ha; ascertained from glasshouse dose-response assay) to determine the distribution of injury and survival for each cross compared to a cross of susceptible parents. The distribution of injury was non-normal for the crosses containing an Anson County plant compared to the cross with a susceptible parent. Survival was 68%-84% for crosses containing an Anson County plant, whereas the survival was significantly reduced to 35% for the susceptible plant cross. Chi-square goodness of fit tests were used to test inheritance models to describe the responses of the genotypes. The resistant × susceptible crosses were best described with a heterozygous two loci with incomplete dominance model compared to the resistant × resistant cross that was best described with a heterozygous single locus with incomplete dominance model. The Anson County population has evolved resistance to glufosinate that is heritable and likely conferred by an oligogenic mechanism with incomplete dominance.
PubMed: 38933086
DOI: 10.1002/pei3.10154 -
Journal of Cardiovascular Development... Sep 2023Athletic performance is a multifactorial trait influenced by a complex interaction of environmental and genetic factors. Over the last decades, understanding and... (Review)
Review
Athletic performance is a multifactorial trait influenced by a complex interaction of environmental and genetic factors. Over the last decades, understanding and improving elite athletes' endurance and performance has become a real challenge for scientists. Significant tools include but are not limited to the development of molecular methods for talent identification, personalized exercise training, dietary requirements, prevention of exercise-related diseases, as well as the recognition of the structure and function of the genome in elite athletes. Investigating the genetic markers and phenotypes has become critical for elite endurance surveillance. The identification of genetic variants contributing to a predisposition for excellence in certain types of athletic activities has been difficult despite the relatively high genetic inheritance of athlete status. Metabolomics can potentially represent a useful approach for gaining a thorough understanding of various physiological states and for clarifying disorders caused by strength-endurance physical exercise. Based on a previous GWAS study, this manuscript aims to discuss the association of specific single-nucleotide polymorphisms (SNPs) located in the gene encoding for cardiac MyBP-C protein with endurance athlete status. is linked to elite athlete heart remodeling during or after exercise, but it could also be linked to the phenotype of cardiac hypertrophy (HCM). To make the distinction between both phenotypes, specific metabolites that are influenced by variants in the gene are analyzed in relation to elite athletic performance and HCM. These include theophylline, ursodeoxycholate, quinate, and decanoyl-carnitine. According to the analysis of effect size, theophylline, quinate, and decanoyl carnitine increase with endurance while decreasing with cardiovascular disease, whereas ursodeoxycholate increases with cardiovascular disease. In conclusion, and based on our metabolomics data, the specific effects on athletic performance for each SNP-associated metabolite are discussed.
PubMed: 37754829
DOI: 10.3390/jcdd10090400 -
Frontiers in Immunology 2023Asthma is a heterogeneous inflammatory disease often associated with other complex phenotypes. Identifying asthma-associated diseases and uncovering the molecular...
INTRODUCTION
Asthma is a heterogeneous inflammatory disease often associated with other complex phenotypes. Identifying asthma-associated diseases and uncovering the molecular mechanisms mediating their interaction can help detangle the heterogeneity of asthma. Network analysis is a powerful approach for untangling such inter-disease relationships.
METHODS
Here, we integrated information on physical contacts between common single nucleotide polymorphisms (SNPs) and gene expression with expression quantitative trait loci (eQTL) data from the lung and whole blood to construct two tissue-specific spatial gene regulatory networks (GRN). We then located the asthma GRN (level 0) within each tissue-specific GRN by identifying the genes that are functionally affected by asthma-associated spatial eQTLs. Curated protein interaction partners were subsequently identified up to four edges or levels away from the asthma GRN. The eQTLs spatially regulating genes on levels 0-4 were queried against the GWAS Catalog to identify the traits enriched (hypergeometric test; FDR ≤ 0.05) in each level.
RESULTS
We identified 80 and 82 traits significantly enriched in the lung and blood GRNs, respectively. All identified traits were previously reported to be comorbid or associated (positively or negatively) with asthma (e.g., depressive symptoms and lung cancer), except 8 traits whose association with asthma is yet to be confirmed (e.g., reticulocyte count). Our analysis additionally pinpoints the variants and genes that link asthma to the identified asthma-associated traits, a subset of which was replicated in a comorbidity analysis using health records of 26,781 asthma patients in New Zealand.
DISCUSSION
Our discovery approach identifies enriched traits in the regulatory space proximal to asthma, in the tissue of interest, without a priori selection of the interacting traits. The predictions it makes expand our understanding of possible shared molecular interactions and therapeutic targets for asthma, where no cure is currently available.
Topics: Humans; Multifactorial Inheritance; Asthma; Quantitative Trait Loci; Gene Regulatory Networks; Lung Neoplasms
PubMed: 37680636
DOI: 10.3389/fimmu.2023.1231492 -
Chinese Medical Journal Jul 2023A polygenic risk score (PRS) derived from 112 single-nucleotide polymorphisms (SNPs) for gastric cancer has been reported in Chinese populations (PRS-112). However, its...
BACKGROUND
A polygenic risk score (PRS) derived from 112 single-nucleotide polymorphisms (SNPs) for gastric cancer has been reported in Chinese populations (PRS-112). However, its performance in other populations is unknown. A functional PRS (fPRS) using functional SNPs (fSNPs) may improve the generalizability of the PRS across populations with distinct ethnicities.
METHODS
We performed functional annotations on SNPs in strong linkage disequilibrium (LD) with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation. Subsequently, we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort. Finally, the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer.
RESULTS
During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases, we found no significant association between the PRS-112 and gastric cancer risk in the European population (hazard ratio [HR] = 1.00 [95% confidence interval (CI) 0.93-1.09], P = 0.846). We identified 125 fSNPs, including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs, and used them to construct the fPRS-125. Our result showed that the fPRS-125 was significantly associated with gastric cancer risk (HR = 1.11 [95% CI, 1.03-1.20], P = 0.009). Compared to participants with a low fPRS-125 (bottom quintile), those with a high fPRS-125 (top quintile) had a higher risk of incident gastric cancer (HR = 1.43 [95% CI, 1.12-1.84], P = 0.005). Moreover, we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer (HR = 4.99 [95% CI, 1.55-16.10], P = 0.007) compared to those with both a favorable lifestyle and a low genetic risk.
CONCLUSION
These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.
Topics: Humans; Prospective Studies; Stomach Neoplasms; Genetic Predisposition to Disease; Risk Factors; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Genome-Wide Association Study
PubMed: 37394533
DOI: 10.1097/CM9.0000000000002716 -
PloS One 2024Researchers often claim that sibling analysis can be used to separate causal genetic effects from the assortment of biases that contaminate most downstream genetic...
Researchers often claim that sibling analysis can be used to separate causal genetic effects from the assortment of biases that contaminate most downstream genetic studies (e.g. polygenic score predictors). Indeed, typical results from sibling analysis show large (>50%) attenuations in the associations between polygenic scores and phenotypes compared to non-sibling analysis, consistent with researchers' expectations about bias reduction. This paper explores these expectations by using family (quad) data and simulations that include indirect genetic effect processes and evaluates the ability of sibling analysis to uncover direct genetic effects of polygenic scores. We find that sibling analysis, in general, fail to uncover direct genetic effects; indeed, these models have both upward and downward biases that are difficult to sign in typical data. When genetic nurture effects exist, sibling analysis creates "measurement error" that attenuates associations between polygenic scores and phenotypes. As the correlation between direct and indirect effect changes, this bias can increase or decrease. Our findings suggest that interpreting results from sibling analysis aimed at uncovering direct genetic effects should be treated with caution.
Topics: Humans; Siblings; Phenotype; Multifactorial Inheritance; Bias
PubMed: 38358994
DOI: 10.1371/journal.pone.0282212 -
Molecular Biology and Evolution Oct 2023Accurate inference of the time to the most recent common ancestor (TMRCA) between pairs of individuals and of the age of genomic variants is key in several population...
Accurate inference of the time to the most recent common ancestor (TMRCA) between pairs of individuals and of the age of genomic variants is key in several population genetic analyses. We developed a likelihood-free approach, called CoalNN, which uses a convolutional neural network to predict pairwise TMRCAs and allele ages from sequencing or SNP array data. CoalNN is trained through simulation and can be adapted to varying parameters, such as demographic history, using transfer learning. Across several simulated scenarios, CoalNN matched or outperformed the accuracy of model-based approaches for pairwise TMRCA and allele age prediction. We applied CoalNN to settings for which model-based approaches are under-developed and performed analyses to gain insights into the set of features it uses to perform TMRCA prediction. We next used CoalNN to analyze 2,504 samples from 26 populations in the 1,000 Genome Project data set, inferring the age of ∼80 million variants. We observed substantial variation across populations and for variants predicted to be pathogenic, reflecting heterogeneous demographic histories and the action of negative selection. We used CoalNN's predicted allele ages to construct genome-wide annotations capturing the signature of past negative selection. We performed LD-score regression analysis of heritability using summary association statistics from 63 independent complex traits and diseases (average N=314k), observing increased annotation-specific effects on heritability compared to a previous allele age annotation. These results highlight the effectiveness of using likelihood-free, simulation-trained models to infer properties of gene genealogies in large genomic data sets.
Topics: Humans; Neural Networks, Computer; Genome; Computer Simulation; Genomics; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Models, Genetic
PubMed: 37738175
DOI: 10.1093/molbev/msad211 -
Genetics in Medicine : Official Journal... Mar 2024DISP1 encodes a transmembrane protein that regulates the secretion of the morphogen, Sonic hedgehog, a deficiency of which is a major cause of holoprosencephaly (HPE)....
PURPOSE
DISP1 encodes a transmembrane protein that regulates the secretion of the morphogen, Sonic hedgehog, a deficiency of which is a major cause of holoprosencephaly (HPE). This disorder covers a spectrum of brain and midline craniofacial malformations. The objective of the present study was to better delineate the clinical phenotypes associated with division transporter dispatched-1 (DISP1) variants.
METHODS
This study was based on the identification of at least 1 pathogenic variant of the DISP1 gene in individuals for whom detailed clinical data were available.
RESULTS
A total of 23 DISP1 variants were identified in heterozygous, compound heterozygous or homozygous states in 25 individuals with midline craniofacial defects. Most cases were minor forms of HPE, with craniofacial features such as orofacial cleft, solitary median maxillary central incisor, and congenital nasal pyriform aperture stenosis. These individuals had either monoallelic loss-of-function variants or biallelic missense variants in DISP1. In individuals with severe HPE, the DISP1 variants were commonly found associated with a variant in another HPE-linked gene (ie, oligogenic inheritance).
CONCLUSION
The genetic findings we have acquired demonstrate a significant involvement of DISP1 variants in the phenotypic spectrum of midline defects. This underlines its importance as a crucial element in the efficient secretion of Sonic hedgehog. We also demonstrated that the very rare solitary median maxillary central incisor and congenital nasal pyriform aperture stenosis combination is part of the DISP1-related phenotype. The present study highlights the clinical risks to be flagged up during genetic counseling after the discovery of a pathogenic DISP1 variant.
PubMed: 38529886
DOI: 10.1016/j.gim.2024.101126