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Addiction Neuroscience Dec 2022Impulsive behavior and impulsivity are heritable phenotypes that are strongly associated with risk for substance use disorders. Identifying the neurogenetic mechanisms...
Impulsive behavior and impulsivity are heritable phenotypes that are strongly associated with risk for substance use disorders. Identifying the neurogenetic mechanisms that influence impulsivity may also reveal novel biological insights into addiction vulnerability. Our past studies using the BXD and Collaborative Cross (CC) recombinant inbred mouse panels have revealed that behavioral indicators of impulsivity measured in a reversal-learning task are heritable and are genetically correlated with aspects of intravenous cocaine self-administration. Genome-wide linkage studies in the BXD panel revealed a quantitative trait locus (QTL) on chromosome 10, but we expect to identify additional QTL by testing in a population with more genetic diversity. To this end, we turned to Diversity Outbred (DO) mice; 392 DO mice (156 males, 236 females) were phenotyped using the same reversal learning test utilized previously. Our primary indicator of impulsive responding, a measure that isolates the relative difficulty mice have with reaching performance criteria under reversal conditions, revealed a genome-wide significant QTL on chromosome 7 (max LOD score = 8.73, genome-wide corrected p<0.05). A measure of premature responding akin to that implemented in the 5-choice serial reaction time task yielded a suggestive QTL on chromosome 17 (max LOD score = 9.14, genome-wide corrected <0.1). Candidate genes were prioritized ( based upon expression QTL data we collected in DO and CC mice and analyses using publicly available gene expression and phenotype databases. These findings may advance understanding of the genetics that drive impulsive behavior and enhance risk for substance use disorders.
PubMed: 36714272
DOI: 10.1016/j.addicn.2022.100045 -
European Journal of Human Genetics :... Oct 2017Keloids result from abnormal proliferative scar formation with scar tissue expanding beyond the margin of the original wound and are mostly found in individuals of...
Keloids result from abnormal proliferative scar formation with scar tissue expanding beyond the margin of the original wound and are mostly found in individuals of sub-Saharan African descent. The etiology of keloids has not been resolved but previous studies suggest that keloids are a genetically heterogeneous disorder. Although possible candidate genes have been suggested by genome-wide association studies using common variants, by upregulation in keloids or their involvement in syndromes that include keloid formation, rare coding variants that contribute to susceptibility in non-syndromic keloid formation have not been previously identified. Through analysis of whole-genome data we mapped a locus to chromosome 8p23.3-p21.3 with a statistically significant maximum multipoint LOD score of 4.48. This finding was followed up using exome sequencing and led to the identification of a c.1202T>C (p.(Leu401Pro)) variant in the N-acylsphingosine amidohydrolase (ASAH1) gene that co-segregates with the keloid phenotype in a large Yoruba family. ASAH1 is an acid ceramidase known to be involved in tumor formation by controlling the ratio of ceramide and sphingosine. ASAH1 is also involved in cell proliferation and inflammation, and may affect the development of keloids via multiple mechanisms. Functional studies need to clarify the role of the ASAH1 variant in wound healing.
Topics: Acid Ceramidase; Adult; Female; Humans; Keloid; Male; Mutation, Missense; Pedigree
PubMed: 28905881
DOI: 10.1038/ejhg.2017.121 -
European Journal of Human Genetics :... Aug 2017Twelve individuals of consanguineous Bedouin kindred presented with autosomal recessive progressive spastic paraplegia evident as of age 0-24 months, with spasticity of...
Twelve individuals of consanguineous Bedouin kindred presented with autosomal recessive progressive spastic paraplegia evident as of age 0-24 months, with spasticity of lower limbs, hyperreflexia, toe walking and equinus deformity. Kyphoscolisois was evident in older patients. Most had atrophy of the lateral aspects of the tongue and few had intellectual disability. Nerve conduction velocity, electromyography and head and spinal cord magnetic resonance imaging were normal in tested subjects. Muscle biopsy showed occasional central nuclei and fiber size variability with small angular fibers. Genome-wide linkage analysis identified a 6.7Mbp disease-associated locus on chromosome 3q21.3-3q22.2 (LOD score 9.02; D3S1290). Whole-exome sequencing identified a single homozygous variant within this locus, c.51_52ins(28); p.(V18fs56*) in KY, segregating in the family as expected and not found in 190 Bedouin controls. High KY transcript levels were demonstrated in muscular organs with lower expression in the CNS. The phenotype is reminiscent of kyphoscoliosis seen in Ky null mice. Two recent studies done independently and parallel to ours describe somewhat similar phenotypes in one and two patients with KY mutations. KY encodes a tranglutaminase-like peptidase, which interacts with muscle cytoskeletal proteins and is part of a Z-band protein complex, suggesting the disease mechanism may resemble myofibrillar myopathy. However, the mixed myopathic-neurologic features caused by human and mouse Ky mutations are difficult to explain by loss of KY sarcomere stabilizing function alone. KY transcription in CNS tissues may imply that it also has a role in neuromotor function, in line with the irregularity of neuromuscular junction in Ky null mutant mice.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Homozygote; Humans; Infant; Infant, Newborn; Male; Middle Aged; Muscle, Skeletal; Mutation; Pedigree; Peptide Hydrolases; Phenotype; Spastic Paraplegia, Hereditary; Spinal Cord
PubMed: 28488683
DOI: 10.1038/ejhg.2017.85 -
Journal of Medical Genetics Jul 2019A single variant in (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify...
BACKGROUND
A single variant in (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia.
METHODS
Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in were evaluated using quantitative PCR and RNAseq.
RESULTS
Genetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included . Exome sequencing identified a hemizygous polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced mRNA levels and abnormal 3' UTRs in affected individuals. Targeted sequencing of in 376 additional affected individuals failed to identify variants in the PAS.
CONCLUSION
These data show that PAS variants are the most common variant type in -associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yields.
Topics: 3' Untranslated Regions; Alleles; Anophthalmos; Female; Genes, X-Linked; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Lod Score; Male; Microphthalmos; N-Terminal Acetyltransferase A; N-Terminal Acetyltransferase E; Pedigree; Poly A; Sequence Analysis, DNA; X Chromosome Inactivation
PubMed: 30842225
DOI: 10.1136/jmedgenet-2018-105836 -
Nature Communications Dec 2018Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease... (Meta-Analysis)
Meta-Analysis
Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Topics: ADAMTS9 Protein; Amino Acid Oxidoreductases; Carotid Intima-Media Thickness; Coronary Disease; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Lod Score; Plaque, Atherosclerotic; Polymorphism, Single Nucleotide; Protein-Lysine 6-Oxidase; Quantitative Trait Loci; Risk Factors
PubMed: 30510157
DOI: 10.1038/s41467-018-07340-5 -
Chemicke Zvesti 2023In this study an efficient and environment friendly electrochemical sensor has been designed for the analysis of acetaminophen (APAP) drug. Electrochemical impedance...
UNLABELLED
In this study an efficient and environment friendly electrochemical sensor has been designed for the analysis of acetaminophen (APAP) drug. Electrochemical impedance spectroscopy, differential pulse voltammetry and cyclic voltammetric techniques were used to demonstrate the fabricated erGO/GCE sensor performance. Voltammetric assessment of acetaminophen drug was done using bare GC electrode, drop-casted GO/GC electrode and erGO/GCE electrochemical sensor. Proposed sensor was precisely validated for APAP detection by differential pulse voltammetric technique. Subsequently LOD, LOQ, sensitivity and linearity were determined and found to be 7.23 nM, 21.909 nM, 20.14 μA nM cm and 0.0219-2.30 μM, respectively. The diffusion coefficient of APAP was determined by chronoamperometry, and it was found to be 2.24 × 10 cm.s. The synthetic and analytical steps were assessed as per the Green Chemistry's 12 Principles giving a 66 score (acceptable) and 93 score (excellent) for the said steps, respectively.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s11696-022-02628-9.
PubMed: 36589858
DOI: 10.1007/s11696-022-02628-9 -
Psychogeriatrics : the Official Journal... May 2016Alzheimer's disease (AD) and major depressive disorder are the two most common psychogeriatric disorders. Late-onset depression (LOD) is the most common cause of... (Comparative Study)
Comparative Study
BACKGROUND
Alzheimer's disease (AD) and major depressive disorder are the two most common psychogeriatric disorders. Late-onset depression (LOD) is the most common cause of emotional suffering in the elderly and is associated with a poor quality of life in caregivers. Although the burden on caregivers of individuals suffering from AD has been well studied, there is a paucity of comparative studies on caregiver burden between AD and LOD. The objectives of this study were to compare the caregiver burden in LOD and AD and to identify factors associated with caregiver burden in LOD.
METHODS
The study included two groups of 25 patients and their caregivers. Group 1 consisted of LOD patients diagnosed with major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision, with onset after age 60, and their caregivers. Group 2 consisted of AD patients and their caregivers. Caregiver burden was assessed by the Zarit Caregiver Burden Interview. Sociodemographic and clinical correlates of caregiver burden in LOD and AD were analyzed.
RESULTS
There was no significant difference in caregiver burden between LOD and AD (P = 0.27). In LOD, the factors positively associated with caregiver burden included the patient's education and the caregiver being a woman, married, unmarried, and a student. Factors negatively associated with caregiver burden included being the son of the patient and high income status. Multivariate stepwise regression analysis showed that caregiver burden in AD is predicted by the Behavioural Pathology in Alzheimer's Disease Scale score, income, presence of diabetes, and in-laws as caregivers (adjusted R(2) = 0.847, P < 0.001). In LOD, caregiver burden is predicted by income, the patient's education, and whether the caregiver is a student or spouse (adjusted R(2) = 0.388, P < 0.001).
CONCLUSION
This study highlights the finding that caregiver burden in LOD is comparable to that in AD and requires interventions to reduce the caregiver strain.
Topics: Activities of Daily Living; Adaptation, Psychological; Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Caregivers; Cost of Illness; Cross-Sectional Studies; Depressive Disorder, Major; Emotions; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Quality of Life; Regression Analysis
PubMed: 27148797
DOI: 10.1111/psyg.12141 -
PloS One 2019Hypotrichosis simplex (HS) with and without woolly hair (WH) comprises a group of rare, monogenic disorders of hair loss. Patients present with a diffuse loss of scalp...
Hypotrichosis simplex (HS) with and without woolly hair (WH) comprises a group of rare, monogenic disorders of hair loss. Patients present with a diffuse loss of scalp and/or body hair, which usually begins in early childhood and progresses into adulthood. Some of the patients also show hair that is tightly curled. Approximately 10 genes for autosomal recessive and autosomal dominant forms of HS have been identified in the last decade, among them five genes for the dominant form. We collected blood and buccal samples from 17 individuals of a large British family with HS and WH. After having sequenced all known dominant genes for HS in this family without the identification of any disease causing mutation, we performed a genome-wide scan, using the HumanLinkage-24 BeadChip, followed by a classical linkage analysis; and whole exome-sequencing (WES). Evidence for linkage was found for a region on chromosome 4q35.1-q35.2 with a maximum LOD score of 3.61. WES led to the identification of a mutation in the gene SORBS2, encoding sorbin and SH3 domain containing 2. Unfortunately, we could not find an additional mutation in any other patient/family with HS; and in cell culture, we could not observe any difference between cloned wildtype and mutant SORBS2 using western blotting and immunofluorescence analyses. Therefore, at present, SORBS2 cannot be considered a definite disease gene for this phenotype. However, the locus on chromosome 4q is a robust and novel finding for hypotrichosis with woolly hair. Further fine mapping and sequencing efforts are therefore warranted in order to confirm SORBS2 as a plausible HS disease gene.
Topics: Alleles; Chromosome Mapping; Chromosomes, Human, Pair 4; Female; Genes, Dominant; Genetic Association Studies; Genetic Linkage; Genetic Predisposition to Disease; Humans; Hypotrichosis; Male; Mutation; Pedigree; Phenotype; Quantitative Trait Loci; United Kingdom; Whole Genome Sequencing
PubMed: 31790498
DOI: 10.1371/journal.pone.0225943 -
Emergency Medicine Journal : EMJ Nov 2022High-sensitivity cardiac troponin I (hs-cTnI) assays promise high diagnostic accuracy for myocardial infarction (MI). In an ED where conventional cTnI was in use, we...
BACKGROUND
High-sensitivity cardiac troponin I (hs-cTnI) assays promise high diagnostic accuracy for myocardial infarction (MI). In an ED where conventional cTnI was in use, we evaluated an assessment pathway using the new Access hsTnI assay.
METHODS
This retrospective analysis recruited ED patients with suspected MI between June and September 2019. All patients received routine care with a conventional cTnI assay (AccuTnI +3: limit of detection (LoD) 10 ng/L, 99th centile upper reference limit (URL) 40 ng/L, abnormal elevation cut-point 80 ng/L). Arrival, then 90-minute or 360-minute cTnI levels for low and non-low risk patients, respectively (ED Assessment of Chest pain score) guided diagnosis and disposition which was at treating physician discretion. The same patients had arrival and 90-minute or 180-minute samples drawn for hs-cTnI levels (Access hsTnI: LoD 2 ng/L, 99th centile URL 10 ng/L (females) and 20 ng/L (males); abnormal elevation above the URL and delta >30%). Treating physicians were blinded to the hs-cTnI results. Using the hs-cTnI values, investigators retrospectively assigned likely diagnosis, disposition and likelihood of a 30-day major adverse cardiac event (MACE). Admission was recommended for significantly rising hs-cTnI elevations. The primary objective was to demonstrate an acceptable unexpected 30-day post-discharge MACE rate of <1%. cTnI elevation rates, diagnostic outcomes and ED disposition were also compared between pathways.
RESULTS
For the 935 patients, unexpected 30-day post-discharge MACE rates were 0/935 (0%, 95% CI 0% to 0.4%) with the conventional or novel pathway. For the high-sensitivity and conventional assays, respectively, abnormal elevation rates were 29% (95% CI 26% to 32%) and 19% (95% CI 17% to 22%), for MI were 9% (95% CI 8% to 11%) and 8% (95% CI 6% to 10%), and for hospital admission were 42% (95% CI 39% to 45%) and 43% (95% CI 40% to 47%).
CONCLUSION
The novel pathway using the Access hsTnI assay has an acceptably low 30-day MACE rate.
Topics: Male; Female; Humans; Troponin I; Retrospective Studies; Aftercare; Patient Discharge; Myocardial Infarction; Biomarkers
PubMed: 34759013
DOI: 10.1136/emermed-2020-210812 -
Computational and Structural... 2022Although methodologies and software packages for bulked segregant analysis (BSA) are well established, it is difficult to detect extremely over-dominant and small-effect...
Although methodologies and software packages for bulked segregant analysis (BSA) are well established, it is difficult to detect extremely over-dominant and small-effect genes for quantitative traits in F population. To address this issue, we proposed a combinatorial strategy to identify all types of quantitative trait loci (QTLs) using extreme phenotype individuals in F. To popularize this strategy, we developed an R software package dQTG.seq v1.0.1. It has some features not found in other BSA software packages: 1) new (dQTG-seq1 and dQTG-seq2) and existing (G', deltaSNP, Euclidean distance (ED), and SmoothLOD) methods are available to identify all types of QTLs in bi-parental segregation populations, one data file with two BSA and three QTL-mapping data formats was inputted, and two *.csv files and one figure were outputted; 2) main smoothing methods (AIC, Window size, and Block) have been incorporated into each of the above-mentioned methods; 3) the threshold value of LOD score for significant QTLs is determined by permutation experiments. To save running time, vroom function was used to read the dataset, and parallel operation was used to estimate parameters. In real data analyses, users should select a suitable initial value of window size, depending on the species, and appropriate smoothing methods to obtain the best result. dQTG-seq2 detects more known loci and genes for rice grain number per panicle than composite interval mapping (CIM) and inclusive CIM, especially extremely over-dominant and small-effect genes. A handbook for our software package (https://cran.r-project.org/web/packages/dQTG.seq/index.html) has been provided in the supplemental materials for the users' convenience.
PubMed: 35615028
DOI: 10.1016/j.csbj.2022.05.009