-
The Canadian Journal of Neurological... Sep 2019Migraine is a common disorder most typically presenting as headache and often associated with vertigo and motion sickness. It is a genetically complex condition with...
BACKGROUND
Migraine is a common disorder most typically presenting as headache and often associated with vertigo and motion sickness. It is a genetically complex condition with multiple genes ultimately contributing to the predisposition and development of this episodic neurological disorder. We identified a large American family of 29 individuals of which 17 members suffered from at least one of these disorders, migraine, vertigo, or motion sickness. Many of these individuals suffered from several simultaneously. We hypothesized that vertigo and motion sickness may involve genes that are independent to those directly contributing to migraine susceptibility.
METHODS
Genome-wide linkage analysis performed using 400 microsatellite repeat markers spaced at 10 cM throughout the genome. The members of this family were phenotyped for each condition, migraine, vertigo, and motion sickness and analyzed separately. Statistical analysis was performed using two-point and multipoint linkage analysis employing a number of models including autosomal recessive or dominant patterns of inheritance with high and low genetic penetrance.
RESULTS
We identified a novel locus for migraine, 9q13-q22 (maximum two-point logarithm of odds [LOD] score-2.51). In addition, there are suggestive LOD scores that localize to different chromosomes for each phenotype; vertigo (chromosome 18, LOD score of 1.82) and motion sickness (chromosome 4, LOD score of 2.09).
CONCLUSIONS
Our analysis supports our hypothesis that the migraine-associated vertigo and motion sickness may involve distinct susceptibility genes.
Topics: Adolescent; Child; Female; Genetic Linkage; Genetic Predisposition to Disease; Humans; Male; Migraine Disorders; Motion Sickness; Pedigree; Vertigo; Young Adult
PubMed: 31258098
DOI: 10.1017/cjn.2019.64 -
Analytical Sciences : the International... Sep 2023The sensitive, non-destructive constant wavelength (CW) and constant energy (CE) SFS techniques have been used for the simultaneous determination of 1-amino pyrene (AP)...
The sensitive, non-destructive constant wavelength (CW) and constant energy (CE) SFS techniques have been used for the simultaneous determination of 1-amino pyrene (AP) and 1-napthyl amine (NA) in their mixtures without prior separation via optimization of different experimental conditions (Δλ 70.0 nm, Δν 4000.0 cm, scan rate 240.0 nm/min, 25.0 °C, methanol). Amplitude-concentration plots have been linear for 1-amino pyrene, AP (0.01-0.1 mg/L) and 1-napthyl amine, NA (0.1-1.0 mg/L). In aqueous methanolic binary mixtures, the mean recoveries (RSD, LOD and LOQ) of AP were found to be 100.09% (0.053, 0.008 mg/L and 0.034 mg/L) for emission, 100.11% (0.141, 0.008 mg/L, 0.034 mg/L) for CWSFS, 100.05% (0.109, 0.007 mg/L and 0.032 mg/L) for first derivative CWSFS, 100.00% (0.148, 0.007 mg/L and 0.031 mg/L) for CESFS, 99.99% (0.109, 0.008 mg/L and 0.035 mg/L) for first derivative CESFS modes respectively. Additionally, for NA the mean recoveries (RSD, LOD and LOQ) were 100.29% (0.360, 0.046 mg/L and 0.204 mg/L) for emission, 100.06% (0.089, 0.098 mg/L, 0.436 mg/L) for CWSFS, 100.09% (0.144, 0.065 mg/L and 0.288 mg/L) for first derivative CWSFS, 100.05% (0.178, 0.077 mg/L and 0.339 mg/L) for CESFS, 100.03% (0.181, 0.082 mg/L and 0.364 mg/L) for first derivative CESFS modes respectively. Considering their safety and greenness, these methods might be considered as green tools using analytical eco-scale approaches (eco-scale score 88.0).
PubMed: 37244980
DOI: 10.1007/s44211-023-00368-8 -
Experimental Eye Research May 2023Nystagmus is an ocular condition characterized by bilateral involuntary ocular oscillation which can severely affect vision. When not associated with other ocular or...
Nystagmus is an ocular condition characterized by bilateral involuntary ocular oscillation which can severely affect vision. When not associated with other ocular or systemic diseases, it is referred to as idiopathic or congenital motor nystagmus (CMN). Genome-wide linkage studies have previously identified several loci associated with CMN, however the genes responsible for some of these loci have yet to be identified. We have examined a large, five-generation family with autosomal dominant CMN. Our purpose was to characterize the clinical manifestations and reveal the molecular basis of the disease in this family. In addition to full ophthalmic examination and imaging, molecular analysis included copy number variation analysis, linkage studies, and Sanger sequencing. Expression analyses of candidate genes was done by real-time PCR. Of the 68 family members, 27 subjects in five-generations had CMN, in line with an autosomal dominant inheritance pattern. Molecular analysis was performed on 27 members, 15 of them affected by CMN. Copy number variation analysis using array comparative genomic hybridization (aCGH) revealed a novel deletion located on 1q32 (NYS7) among affected individuals. Linkage analysis using polymorphic markers demonstrated full segregation with a heterozygous haplotype in all affected patients, with a LOD score of >5. Sanger sequencing of affected subjects revealed a novel deletion of 732,526 bp in the linkage interval. No protein-coding genes exist within the deleted region; however, the deletion disrupts topologically associated domains encompassing the gene NR5A2 and the non-protein coding MIR181A. Both are strongly associated with other genes expressed in the retina such as PROX1, which in turn is also associated with genes related to nystagmus such as PAX6. We therefore hypothesized that the deletion might affect NR5A2 and MIR181A expression, causing CMN. Expression analysis by real-time PCR showed significantly lower expression of NR5A2, and significantly higher expression of PROX1 among patients compared with controls. To conclude, among a large five-generation family with autosomal dominant CMN, a large deletion in the interval of NYS7 was linked with the disease. No protein-coding genes exist inside the deleted region, and so the exact mechanism in which CMN is caused is uncertain. Based on topological association and expression analyses we suggest a possible mechanism for the pathogenesis.
Topics: Humans; Comparative Genomic Hybridization; DNA Copy Number Variations; Genetic Linkage; Inheritance Patterns; Nystagmus, Congenital; Pedigree; Chromosome Deletion
PubMed: 37001852
DOI: 10.1016/j.exer.2023.109459 -
Journal of Genetics and Genomics = Yi... Jul 2019Precise mapping of quantitative trait loci (QTLs) is critical for assessing genetic effects and identifying candidate genes for quantitative traits. Interval and...
Precise mapping of quantitative trait loci (QTLs) is critical for assessing genetic effects and identifying candidate genes for quantitative traits. Interval and composite interval mappings have been the methods of choice for several decades, which have provided tools for identifying genomic regions harboring causal genes for quantitative traits. Historically, the concept was developed on the basis of sparse marker maps where genotypes of loci within intervals could not be observed. Currently, genomes of many organisms have been saturated with markers due to the new sequencing technologies. Genotyping by sequencing usually generates hundreds of thousands of single nucleotide polymorphisms (SNPs), which often include the causal polymorphisms. The concept of interval no longer exists, prompting the necessity of a norm change in QTL mapping technology to make use of the high-volume genomic data. Here we developed a statistical method and a software package to map QTLs by binning markers into haplotype blocks, called bins. The new method detects associations of bins with quantitative traits. It borrows the mixed model methodology with a polygenic control from genome-wide association studies (GWAS) and can handle all kinds of experimental populations under the linear mixed model (LMM) framework. We tested the method using both simulated data and data from populations of rice. The results showed that this method has higher power than the current methods. An R package named binQTL is available from GitHub.
Topics: Chromosome Mapping; Genetic Linkage; Genetics, Population; Genome-Wide Association Study; Genotype; Lod Score; Oryza; Quantitative Trait Loci; ROC Curve
PubMed: 31378650
DOI: 10.1016/j.jgg.2019.06.005 -
Frontiers in Veterinary Science 2023Near-infrared (NIR) fluorescence-guided surgery is increasingly utilized in humans and pets. As clinical imaging systems are optimized for Indocyanine green (ICG)...
INTRODUCTION
Near-infrared (NIR) fluorescence-guided surgery is increasingly utilized in humans and pets. As clinical imaging systems are optimized for Indocyanine green (ICG) detection, the usage of targeted dyes necessitates the validation of these systems for each dye. We investigated the impact of skin pigmentation and tissue overlay on the sensitivity of two NIR cameras (IC-Flow, Visionsense VS3 Iridum) for the detection of non-targeted (ICG, IRDye800) and targeted (Angiostamp, FAP-Cyan) NIR fluorophores in an big animal model.
METHODS
We quantitatively measured the limit of detection (LOD) and signal-to-background ratio (SBR) and implemented a semi-quantitative visual score to account for subjective interpretation of images by the surgeon.
RESULTS
Visionsense VS3 Iridum outperformed IC-Flow in terms of LOD and SBR for the detection of all dyes except FAP-Cyan. Median SBR was negatively affected by skin pigmentation and tissue overlay with both camera systems. Level of agreement between quantitative and semi-quantitative visual score and interobserver agreement were better with Visionsense VS3 Iridum.
CONCLUSION
The overlay of different tissue types and skin pigmentation may negatively affect the ability of the two tested camera systems to identify nanomolar concentrations of targeted-fluorescent dyes and should be considered when planning surgical applications.
PubMed: 37138917
DOI: 10.3389/fvets.2023.1091842 -
Kidney International Reports Jun 2021Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis....
INTRODUCTION
Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male predominance, accounting for approximately 65% of cases; yet, currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus. Identification of such risk locus may provide clues to the etiology of MN.
METHODS
We identified 3 families with 8 members affected by primary MN. Genotyping was performed using single-nucleotide polymorphism microarrays, and serum was sent for anti-phospholipase A2 receptor (PLA2R) antibody testing. All affected members were male and connected through the maternal line, consistent with X-linked inheritance. Genome-wide multipoint parametric linkage analysis using a model of X-linked recessive inheritance was conducted, and genetic risk scores (GRSs) based on known MN-associated variants were determined.
RESULTS
Anti-PLA2R testing was negative in all affected family members. Linkage analysis revealed a significant logarithm of the odds score (3.260) on the short arm of the X chromosome at a locus of approximately 11 megabases (Mb). Haplotype reconstruction further uncovered a shared haplotype spanning 2 Mb present in all affected individuals from the 3 families. GRSs in familial MN were significantly lower than in anti-PLA2R-associated MN and were not different from controls.
CONCLUSIONS
Our study identifies linkage of familial membranous nephropathy to chromosome Xp11.3-11.22. Family members affected with MN have a significantly lower GRS than individuals with anti-PLA2R-associated MN, suggesting that X-linked familial MN represents a separate etiologic entity.
PubMed: 34169208
DOI: 10.1016/j.ekir.2021.02.025 -
Scientific Reports Sep 2022Inborn errors of immunity are known to cause not only immunodeficiencies and allergies but also autoimmunity. Leukocyte immunoglobulin-like receptor B1 (LILRB1) is a...
Inborn errors of immunity are known to cause not only immunodeficiencies and allergies but also autoimmunity. Leukocyte immunoglobulin-like receptor B1 (LILRB1) is a receptor on leukocytes playing a role in regulating immune responses. No phenotypes have been reported to be caused by germline mutations in LILRB1. We aimed to identify the causative variant in a three-generation family with nine members suffering from one of the three autoimmune diseases-Graves' disease, Hashimoto's thyroiditis, or systemic lupus erythematosus. Whole-genome linkage study revealed a locus on chromosome 19q13.4 with the maximum LOD score of 2.71. Whole-exome sequencing identified a heterozygous missense variant, c.479G > A (p. G160E) in LILRB1, located within the chromosomal-linked region, in all nine affected members. The variant has never been previously reported. Jurkat cells transfected with the mutant LILRB1, compared with those with the wild-type LILRB1, showed decreased phosphorylation of both LILRB1 and its downstream protein, SHP-1. Flow cytometry was used to study immunophenotype and revealed that LILRB1 was significantly lower on the surface of activated regulatory T lymphocytes (Treg) cells of patients. Single-cell RNA sequencing showed substantially increased M1-like monocytes in peripheral blood mononuclear cells of affected individuals. This study, for the first time, implicates LILRB1 as a new disease gene for autoimmunity.
Topics: Antigens, CD; Graves Disease; Humans; Leukocyte Immunoglobulin-like Receptor B1; Leukocytes, Mononuclear; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Exome Sequencing
PubMed: 36104364
DOI: 10.1038/s41598-022-19334-x -
Genes Nov 2022High temperature is a major stress in rice production. Although considerable progress has been made in investigating heat tolerance (HT) in rice, the genetic basis of HT...
High temperature is a major stress in rice production. Although considerable progress has been made in investigating heat tolerance (HT) in rice, the genetic basis of HT at the heading stage remains largely unknown. In this study, a novel set of chromosome segment substitution lines (CSSLs) consisting of 113 lines derived from a heat-resistant variety N22 and a heat-sensitive variety 9311 was developed and used for the analysis of the genetic basis of HT. The heat sensitivity index (HSI) calculated based on seed-setting rates under natural and high-temperature environments was used to evaluate the influence of HT at the rice heading stage. In total, five quantitative trait loci (QTLs) associated with HT were detected based on seed-setting rate (SSR) evaluation; these were named , , , and located on chromosomes 6, 7, 8, 9 and 11, respectively. Heat-tolerant alleles of the QTLs were all derived from N22. Among them, overlapped with QTLs identified previously, while the remaining QTLs were found novel. In particular, explained a high phenotypic variation of 26.35% with a LOD score of 10.75, thus deserved to be further validated. These findings will increase our understanding of the genetic mechanism underlying HT and facilitate the breeding of heat-tolerant rice varieties.
Topics: Quantitative Trait Loci; Oryza; Thermotolerance; Phenotype; Plant Breeding; Chromosomes, Plant
PubMed: 36553515
DOI: 10.3390/genes13122248 -
Scientific Reports Jan 2022To compare the performance of high-sensitivity cardiac troponin I and T (hs-cTnI; hs-cTnT) in diagnosing obstructive coronary artery disease (CAD) in patients with...
To compare the performance of high-sensitivity cardiac troponin I and T (hs-cTnI; hs-cTnT) in diagnosing obstructive coronary artery disease (CAD) in patients with suspected chronic coronary syndrome (CCS). A total of 706 patients with suspected CCS, referred for Coronary Computed Tomography Angiography, were included. cTn concentrations were measured using the Singulex hs-cTnI (limit of detection [LoD] 0.08 ng/L) and Roche hs-cTnT (LoD 3 ng/L) assays. Obstructive coronary artery disease (CAD) was defined as ≥ 50% coronary stenosis. Cardiovascular risk was determined by the NORRISK2-score. Median age of the patients was 65 (range 28-87) years, 35% were women. All patients had hs-cTnI concentrations above the LoD (median 1.9 [Q1-3 1.2-3.6] ng/L), 72% had hs-cTnT above the LoD (median 5 [Q1-3 2-11] ng/L). There was a graded relationship between hs-cTn concentrations and coronary artery calcium. Only hs-cTnI remained associated with CAD in adjusted analyses (OR 1.20 95% Confidence Interval [1.05-1.38]), p = 0.009). The C-statistics for hs-cTnI and hs-cTnT were 0.65 (95% CI [0.60-0.69]) and 0.60 (0.56-0.64). The highest specificity and negative predictive values for CAD were in the lowest NORRISK2-tertile. hs-cTn concentrations provide diagnostic information in patients with suspected CCS, with superior performance of hs-cTnI compared to hs-cTnT in regard to CAD. The diagnostic performance appeared best in those with low cardiovascular risk.
Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Biomarkers; Computed Tomography Angiography; Coronary Artery Disease; Coronary Vessels; Female; Heart; Humans; Limit of Detection; Male; Middle Aged; Norway; Predictive Value of Tests; Troponin I; Troponin T
PubMed: 35042885
DOI: 10.1038/s41598-022-04850-7 -
Plant Cell Reports Dec 2021A total of three QTLs, responsible for A. brassicae resistance were introgressed into S. alba - B. juncea introgression lines from S. alba and mapped through donor...
A total of three QTLs, responsible for A. brassicae resistance were introgressed into S. alba - B. juncea introgression lines from S. alba and mapped through donor genome-specific SSR markers. Alternaria brassicae is a key pathogen of the Brassicaceae family causing severe blight disease to oilseed crops that leads to heavy yield losses due to lack of resistance source within cultivated Brassicas. However, the host resistance present in the Sinapis alba, an allied member of the Brassicaceae family is still unexplored precisely due to the unavailability of segregating population for Alternaria blight resistance and scarcity of donor genome-specific genetic markers. The present study was undertaken to identify quantitative trait loci governing resistance to Alternaria blight which was introgressed from S. alba to the backcross population of stable S. alba + B. juncea somatic hybrids (2n = 60; AABBSS). The second backcross population showed significant phenotypic variations for Alternaria blight ranging from immune to highly susceptible phenotype, thus suggesting quantitative nature of resistance for the disease. A subset of 154 BCF lines was used for disease screening and genotyping with 234 S. alba genome-specific microsatellite markers. As a result of the study, twelve linkage groups were developed corresponding to 12 chromosomes of S. alba (n = 12) covering a length of 1694.02 cM. The chromosomes 5 and 11 harbored a total of 1 (Abr-01), and 2 (Abr-02, and Abr-03) QTLs detected by ICIM-ADD mapping method at LOD score values 3.7, 5.12, and 6.74, respectively. The QTLs identified during the study have a range of 5.51-10.87 percent phenotypic variations for disease resistance. To the best of our knowledge, this is the first report of QTLs introgression for A. brassicae resistance in cultivated Brassica from an allied member of Brassicaceae.
Topics: Alternaria; Chimera; Chromosome Mapping; Disease Resistance; Genetic Introgression; Genetic Markers; Lod Score; Microsatellite Repeats; Mustard Plant; Plant Breeding; Plant Diseases; Ploidies; Quantitative Trait Loci; Sinapis
PubMed: 34533623
DOI: 10.1007/s00299-021-02785-3