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Disease-causing mutations in subunits of OXPHOS complex I affect certain physical interactions.
Barshad, G, Zlotnikov-Poznianski, N, Gal, L, Schuldiner, M, Mishmar, D
Scientific reports. 2019;(1):9987
Abstract
Mitochondrial complex I (CI) is the largest multi-subunit oxidative phosphorylation (OXPHOS) protein complex. Recent availability of a high-resolution human CI structure, and from two non-human mammals, enabled predicting the impact of mutations on interactions involving each of the 44 CI subunits. However, experimentally assessing the impact of the predicted interactions requires an easy and high-throughput method. Here, we created such a platform by cloning all 37 nuclear DNA (nDNA) and 7 mitochondrial DNA (mtDNA)-encoded human CI subunits into yeast expression vectors to serve as both 'prey' and 'bait' in the split murine dihydrofolate reductase (mDHFR) protein complementation assay (PCA). We first demonstrated the capacity of this approach and then used it to examine reported pathological OXPHOS CI mutations that occur at subunit interaction interfaces. Our results indicate that a pathological frame-shift mutation in the MT-ND2 gene, causing the replacement of 126 C-terminal residues by a stretch of only 30 amino acids, resulted in loss of specificity in ND2-based interactions involving these residues. Hence, the split mDHFR PCA is a powerful assay for assessing the impact of disease-causing mutations on pairwise protein-protein interactions in the context of a large protein complex, thus offering a possible mechanistic explanation for the underlying pathogenicity.
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Association between oral cleft and transcobalamin 2 polymorphism in a sample study from Nassiriya, Iraq.
Carinci, F, Palmieri, A, Scapoli, L, Cura, F, Abenavoli, F, Giannì, AB, Russillo, A, Docimo, R, Martinelli, M
International journal of immunopathology and pharmacology. 2019;:2058738419855571
Abstract
Orofacial clefts are common congenital defects whose prevalence differs between geographical regions and ethnic groups. The inheritance is complex, involving the contribution of both genetic and environmental factors. The involvement of genes belonging to the folate pathway is still matter of debate, with strong evidences of association and conflicting results. After demonstrating the contribution, for a sample from the Italian population, of common mutations mapping on three genes of the folate pathway, our group tried to unravel their contribution in independent sample studies with different ethnicity. In the present investigation a set of 34 triads with oral cleft from Nassiriya, Iraq, has been genotyped for rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS polymorphisms. Association analysis evidenced a decreased risk of cleft for children carrying the 667G allele at TCN2 gene (P = 0.02). This evidence further supported the relationship between polymorphisms of folate related genes and oral clefts, and outlined the relevance of studying populations having different ethnicity.
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A Case Report of Primary Neonatal Hypocholinesterase Caused by Homozygous Frameshift Mutation of the utyrylcholinesterase (BCHE) Gene and Review of Literature.
Lv, HY, Yang, LH, Bu, LN, Wang, QL, Gu, XL, Wang, ZY, Ren, PS, Li, LX
Clinical laboratory. 2019;(7)
Abstract
BACKGROUND Primary neonatal hypocholinesterase is rare; its genetic pattern and mutation still need to be further studied. METHODS The patient and his parents are studied using next-generation sequencing technology. RESULTS A boy one day after birth is admitted to the Neonatal Intensive Care Unit at our hospital after experiencing intermittent vomiting for 12 hours. The patient's serum cholinesterase level (113 - 283 U/L) is lower than normal value (4,000 - 12,600 U/L). Many factors of low serum cholinesterase are excluded. We highly suspect that it may be related to congenital factors. Molecular genetic test results show that the patient carried the BCHE gene (NM_000055.2) and has homozygous frameshift mutations at exon 2 c.401dupA (p.Asn134fs) of chromosome 3q26. It is a pathogenicity mutation. This locus mutation belongs to a novel pathogenic mutation. As a result of this mutation, the 134th amino acid Asn began to frameshift and the translation is terminated early. It can cause the Encoding of protein to truncate and lose its normal function. His parents' serum cholinesterase levels (father: 5,135 U/L; mother: 4,367 U/L) are in the normal value range, but his parents carried a heterozygous BCHE gene. CONCLUSIONS This study suggests that gene sequence detection should be carried out early in hypocholinesterase of nknown cause in neonates. This study can not only improve understanding of the etiology and pathological mechanism of hypocholinesterase, but also it can enlarge the hypocholinesterase gene mutation spectrum.
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Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.
Demontis, D, Walters, RK, Martin, J, Mattheisen, M, Als, TD, Agerbo, E, Baldursson, G, Belliveau, R, Bybjerg-Grauholm, J, Bækvad-Hansen, M, et al
Nature genetics. 2019;(1):63-75
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Abstract
Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
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SCN5A mutation status increases the risk of major arrhythmic events in Asian populations with Brugada syndrome: systematic review and meta-analysis.
Rattanawong, P, Chenbhanich, J, Mekraksakit, P, Vutthikraivit, W, Chongsathidkiet, P, Limpruttidham, N, Prasitlumkum, N, Chung, EH
Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc. 2019;(1):e12589
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Abstract
BACKGROUND Brugada syndrome (BrS) is an inherited arrhythmic disease linked to SCN5A mutations. It is controversial whether SCN5A mutation carriers possess a greater risk of major arrhythmic events (MAE). We examined the association of SCN5A mutations and MAE in BrS patients. METHODS We comprehensively searched the databases of MEDLINE and EMBASE from inception to September 2017. Included studies were published cohort and case-control studies that compared MAE in BrS patients with and without SCN5A mutations. Data from each study were combined using the random-effects model. Generic inverse variance method of DerSimonian and Laird was employed to calculate the risk ratios (RR) and 95% confidence intervals (CI). RESULTS Seven studies from March 2002 to October 2017 were included (1,049 BrS subjects). SCN5A mutations were associated with MAE in Asian populations (RR = 2.03, 95% CI: 1.37-3.00, p = 0.0004, I2 = 0.0%), patients who were symptomatic (RR = 2.66, 95% CI: 1.62-4.36, p = 0.0001, I2 = 23.0%), and individuals with spontaneous type-1 Brugada pattern (RR = 1.84, 95% CI: 1.05-3.23, p = 0.03, I2 = 0.0%). CONCLUSIONS SCN5A mutations in BrS increase the risk of MAE in Asian populations, symptomatic BrS patients, and individuals with spontaneous type-1 Brugada pattern. Our study suggests that SCN5A mutation status should be an important tool for risk assessment in BrS patients.
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Genetic predisposition to higher body fat yet lower cardiometabolic risk in children and adolescents.
Viitasalo, A, Schnurr, TM, Pitkänen, N, Hollensted, M, Nielsen, TRH, Pahkala, K, Lintu, N, Lind, MV, Atalay, M, Frithioff-Bøjsøe, C, et al
International journal of obesity (2005). 2019;(10):2007-2016
Abstract
BACKGROUND Most obese children show cardiometabolic impairments, such as insulin resistance, dyslipidemia, and hypertension. Yet some obese children retain a normal cardiometabolic profile. The mechanisms underlying this variability remain largely unknown. We examined whether genetic loci associated with increased insulin sensitivity and relatively higher fat storage on the hip than on the waist in adults are associated with a normal cardiometabolic profile despite higher adiposity in children. METHODS We constructed a genetic score using variants previously linked to increased insulin sensitivity and/or decreased waist-hip ratio adjusted for body mass index (BMI), and examined the associations of this genetic score with adiposity and cardiometabolic impairments in a meta-analysis of six cohorts, including 7391 European children aged 3-18 years. RESULTS The genetic score was significantly associated with increased degree of obesity (higher BMI-SDS beta = 0.009 SD/allele, SE = 0.003, P = 0.003; higher body fat mass beta = 0.009, SE = 0.004, P = 0.031), yet improved body fat distribution (lower WHRadjBMI beta = -0.014 SD/allele, SE = 0.006, P = 0.016), and favorable concentrations of blood lipids (higher HDL cholesterol: beta = 0.010 SD/allele, SE = 0.003, P = 0.002; lower triglycerides: beta = -0.011 SD/allele, SE = 0.003, P = 0.001) adjusted for age, sex, and puberty. No differences were detected between prepubertal and pubertal/postpubertal children. The genetic score predicted a normal cardiometabolic profile, defined by the presence of normal glucose and lipid concentrations, among obese children (OR = 1.07 CI 95% 1.01-1.13, P = 0.012, n = 536). CONCLUSIONS Genetic predisposition to higher body fat yet lower cardiometabolic risk exerts its influence before puberty.
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Comprehensive identification of pleiotropic loci for body fat distribution using the NHGRI-EBI Catalog of published genome-wide association studies.
Kaur, Y, Wang, DX, Liu, HY, Meyre, D
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2019;(3):385-406
Abstract
We conducted a hypothesis-free cross-trait analysis for waist-to-hip ratio adjusted for body mass index (WHRadjBMI ) loci derived through genome-wide association studies (GWAS). Summary statistics from published GWAS were used to capture all WHRadjBMI single-nucleotide polymorphisms (SNPs), and their proxy SNPs were identified. These SNPs were used to extract cross-trait associations between WHRadjBMI SNPs and other traits through the NHGRI-EBI GWAS Catalog. Pathway analysis was conducted for pleiotropic WHRadjBMI SNPs. We found 160 WHRadjBMI SNPs and 3675 proxy SNPs. Cross-trait analysis identified 239 associations, of which 100 were for obesity traits. The remaining 139 associations were filtered down to 101 unique linkage disequilibrium block associations, which were grouped into 13 categories: lipids, red blood cell traits, white blood cell counts, inflammatory markers and autoimmune diseases, type 2 diabetes-related traits, adiponectin, cancers, blood pressure, height, neuropsychiatric disorders, electrocardiography changes, urea measurement, and others. The highest number of cross-trait associations were found for triglycerides (n = 10), high-density lipoprotein cholesterol (n = 9), and reticulocyte counts (n = 8). Pathway analysis for WHRadjBMI pleiotropic SNPs found immune function pathways as the top canonical pathways. Results from our original methodology indicate a novel genetic association between WHRadjBMI and reticulocyte counts and highlight the pleiotropy between abdominal obesity, immune pathways, and other traits.
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Non-syndromic cleft palate: Association analysis on three gene polymorphisms of the folate pathway in Asian and Italian populations.
Carinci, F, Palmieri, A, Scapoli, L, Cura, F, Borelli, F, Morselli, PG, Nouri, N, Abdali, H, Gianni, AB, Russillo, A, et al
International journal of immunopathology and pharmacology. 2019;:2058738419858572
Abstract
Periconceptional folic acid supplementation can reduce the risk of inborn malformations, including orofacial clefts. Polymorphisms of MTHFR, TCN2, and CBS folate-related genes seem to modulate the risk of cleft lip with or without cleft palate (CL/P) in some populations. CL/P and cleft palate only (CPO) are different malformations that share several features and possibly etiological causes. In the present investigation, we conducted a family-based, candidate gene association study of non-syndromic CPO. Three single nucleotide polymorphisms, namely, rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS, were investigated in a sample that included 129 Italian and 65 Asian families. No evidence of association between the three genotyped polymorphisms and CPO was found in the Italian and Asian cases, indeed the transmission disequilibrium test did not detect any asymmetry of transmission of alleles. This investigation, although with some limitation, further supports that CL/P and CPO diverge in their genetic background.
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Vitamin D receptor polymorphisms and the susceptibility of Parkinson's disease.
Wang, X, Shen, N, Lu, Y, Tan, K
Neuroscience letters. 2019;:206-211
Abstract
Epidemiological evidence concerning the association between vitamin D receptor (VDR) polymorphisms, including rs2228570, rs731236, rs7975232, rs1544410 and Parkinson's disease (PD) risk is inconsistent. A meta-analysis was performed to evaluate these associations via searching PubMed and EMBASE databases up to Jan 4, 2019. Odds ratio (OR) with 95% confidence interval (CI) were applied to assess the strength of these associations. 6 studies with 1391 PD cases and 1570 controls for rs2228570, 7 studies with 1881 PD cases and 2135 controls for rs731236, 5 studies with 1298 PD cases and 1536 controls for rs7975232, and 6 studies with 932 PD cases and 1377 controls for rs1544410 were included in this meta-analysis. Significant associations between rs2228570 and PD risk were found in allelic, dominant, and additive models but not in recessive model. Stratified study revealed that rs2228570 was associated with PD susceptibility in Asian population, while no significant association was observed in Caucasian population. Sensitivity analysis showed stable results for rs2228570 and no publication bias existed. Rs731236 was associated with increased PD risk in dominant model, however, this result was unstable. No significant association was found between rs7975232 or rs1544410 and PD.
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Opportunities and challenges for transcriptome-wide association studies.
Wainberg, M, Sinnott-Armstrong, N, Mancuso, N, Barbeira, AN, Knowles, DA, Golan, D, Ermel, R, Ruusalepp, A, Quertermous, T, Hao, K, et al
Nature genetics. 2019;(4):592-599
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Abstract
Transcriptome-wide association studies (TWAS) integrate genome-wide association studies (GWAS) and gene expression datasets to identify gene-trait associations. In this Perspective, we explore properties of TWAS as a potential approach to prioritize causal genes at GWAS loci, by using simulations and case studies of literature-curated candidate causal genes for schizophrenia, low-density-lipoprotein cholesterol and Crohn's disease. We explore risk loci where TWAS accurately prioritizes the likely causal gene as well as loci where TWAS prioritizes multiple genes, some likely to be non-causal, owing to sharing of expression quantitative trait loci (eQTL). TWAS is especially prone to spurious prioritization with expression data from non-trait-related tissues or cell types, owing to substantial cross-cell-type variation in expression levels and eQTL strengths. Nonetheless, TWAS prioritizes candidate causal genes more accurately than simple baselines. We suggest best practices for causal-gene prioritization with TWAS and discuss future opportunities for improvement. Our results showcase the strengths and limitations of using eQTL datasets to determine causal genes at GWAS loci.