scholarly journals Genetics of psoriasis: a basis for precision medicine

2019 ◽  
Vol 2 (2) ◽  
pp. 120-130 ◽  
Author(s):  
Delin Ran ◽  
Minglong Cai ◽  
Xuejun Zhang
Keyword(s):  
Genetic Variation ◽  
Precision Medicine ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Direct Sequencing ◽  
Disease Prediction ◽  
Inflammatory Skin Disease ◽  
Polygenic Inheritance ◽  
Genome Wide

AbstractPsoriasis is an inflammatory skin disease with a background of polygenic inheritance. Both environmental and genetic factors are involved in the etiology of the disease. In the last two decades, numerous studies have been conducted through linkage analysis, genome-wide association study (GWAS), and direct sequencing to explore the role of genetic variation in disease pathogenesis and progression. To date, >80 psoriasis susceptibility genes have been identified, including HLA-Cw6, IL12B, IL23R, and LCE3B/3C. Some genetic markers have been applied in disease prediction, clinical diagnosis, treatment, and new drug development, which could further explain the pathogenesis of psoriasis and promote the development of precision medicine. This review summarizes related research on genetic variation in psoriasis and explores implications of the findings in clinical application and the promotion of a personalized medicine project.

scholarly journals Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

2021 ◽  
Author(s):  
Doris Skoric-Milosavljevic ◽  
Rafik Tadros ◽  
Fernanda M Bosada ◽  
Federico Tessadori ◽  
Jan Hendrik van Weerd ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Regulatory Element ◽  
Susceptibility Locus ◽  
Mouse Heart ◽  
Polygenic Risk Score ◽  
Polygenic Inheritance ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.

O-118 New insight into the genetic contribution of common variants to the development of extreme phenotypes of unexplained male infertility: a multicenter genome-wide association study

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
M Cerván Martín ◽  
F Tüttelmann ◽  
A M Lopes ◽  
L Bossini-Castillo ◽  
N Garrido ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Amino Acid ◽  
Male Infertility ◽  
Mhc Class Ii ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Common Genetic Variation ◽  
Genome Wide ◽  
Mhc Alleles

Abstract Study question What is the contribution of the common genetic variation to the development of unexplained male infertility due to severe spermatogenic failure (SPGF)? Summary answer Genetic polymorphisms of key immune and spermatogenesis loci are involved in the etiology of the most severe SPGF cases, defined by Sertoli cell-only (SCO) phenotype. What is known already Male infertility is a rising worldwide concern that affects millions of couples. Non-obstructive azoospermia (NOA) and severe oligospermia (SO) are two extreme manifestations characterized by SPGF. A genetic cause can be established in only around 20% of affected men, with the remaining cases being classified as otherwise unexplained. To date, the genome-wide association study (GWAS) strategy, although already successfully applied in several other complex traits and diseases, was less fruitful in studies that attempted to decipher the genetic component of unexplained SPGF, mainly due to both a lack of well-powered samples in different ancestries and limitations in study design. Study design, size, duration We designed a GWAS for unexplained male infertility due to SPGF including a total of 1,274 affected cases and 1,951 fertile controls from the Iberian Peninsula (Spain and Portugal) and Germany. Different biostatistics and bioinformatics approaches were used to evaluate the possible effect of single-nucleotide polymorphisms (SNPs) across the whole genome in the susceptibility to specific subtypes of unexplained SPGF. Participants/materials, setting, methods The case cohort comprised 502 SO and 772 NOA patients, who were subdivided according to histological phenotypes (SCO, maturation arrest, and hypospermatogenesis) and the outcome of testicular sperm extraction techniques (TESE) from testis biopsies. Genotyping was performed with the GSA platform (Illumina). After quality-control and genotype imputation, 6,539,982 SNPs remained for the analysis, which was performed by logistic regression models. The datasets went through a meta-analysis by the inverse variance weighted method under fixed effects. Main results and the role of chance Genetic associations with SCO at the genome-wide-level of significance were identified in the major histocompatibility (MHC) class II region (rs1136759, OR = 1.80, P = 1.32E-08) and in a regulatory region of chromosome 14 nearby the vaccinia-related kinase 1 (VRK1) gene (rs115054029, OR = 3.14, P = 4.37-08). VRK1 is a relevant proliferative factor for spermatogenesis that causes progressive loss of spermatogonia when disrupted in mouse models. The role of the MHC system in SCO susceptibility was comprehensively evaluated through a validated imputation method that infers classical MHC alleles and polymorphic amino acid positions. A serine at position 13 of the HLA-DRβ1 protein (defined by the risk allele of the lead variant rs1136759) explained most of the SCO association signals within the MHC class II region. This residue is located in the binding pocket of the HLA-DR molecule and interacts directly with the presented antigen. Interestingly, position 13 of HLA-DRβ1 is the most relevant risk amino acid position for a wide spectrum of immune-mediated disorders. The HLA-DRB1*13 haplotype (which includes the serine at position 13 and represents the strongest NOA-associated marker in Asians to date) was the strongest signal amongst the classical MHC alleles in our study cohort (OR = 1.93, P = 9.90E-07). Limitations, reasons for caution Although the statistical power for the overall analysis was appropriate, the subphenotype analyses performed had considerably lower counts, which may influence the identification of genetic variants conferring low to moderate risk effects. Independent studies in larger SCO study cohorts should be performed to confirm our findings. Wider implications of the findings The molecular mechanisms underlying unexplained SPGF are largely unknown. Our data suggest a relevant role of common genetic variation in the development of SCO, the most extreme histological phenotype of NOA. SCO is characterized by the loss of germ cells and, therefore, implies a considerably higher probability of unsuccessful TESE. Trial registration number N/A

scholarly journals Genetic Determinants of Paget’s Disease of Bone

2021 ◽  
Author(s):  
Navnit S. Makaram ◽  
Stuart H. Ralston
Keyword(s):  
Genetic Factors ◽  
Association Studies ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Genome Wide Association Studies ◽  
Paget's Disease Of Bone ◽  
Genome Wide ◽  
Family Based

Abstract Purpose of Review To provide an overview of the role of genes and loci that predispose to Paget’s disease of bone and related disorders. Recent Findings Studies over the past ten years have seen major advances in knowledge on the role of genetic factors in Paget’s disease of bone (PDB). Genome wide association studies have identified six loci that predispose to the disease whereas family based studies have identified a further eight genes that cause PDB. This brings the total number of genes and loci implicated in PDB to fourteen. Emerging evidence has shown that a number of these genes also predispose to multisystem proteinopathy syndromes where PDB is accompanied by neurodegeneration and myopathy due to the accumulation of abnormal protein aggregates, emphasising the importance of defects in autophagy in the pathogenesis of PDB. Summary Genetic factors play a key role in the pathogenesis of PDB and the studies in this area have identified several genes previously not suspected to play a role in bone metabolism. Genetic testing coupled to targeted therapeutic intervention is being explored as a way of halting disease progression and improving outcome before irreversible skeletal damage has occurred.

Identification of Potential Pleiotropic Genes for Immune and Skeletal Diseases Using Multivariate MetaCCA Analysis

2021 ◽  
Vol 23 ◽  
Author(s):  
Pei He ◽  
Rong- Rong Cao ◽  
Fei- Yan Deng ◽  
Shu- Feng Lei
Keyword(s):  
Association Study ◽  
Canonical Correlation ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Summary Statistics ◽  
Immune Disease ◽  
Histocompatibility Complex ◽  
Genome Wide ◽  
Genetic Mechanisms ◽  
Shared Genetic

Background: Immune and skeletal systems physiologically and pathologically interact with each other. The immune and skeletal diseases may share potential pleiotropic genetics factors, but the shared specific genes are largely unknown Objective: This study aimed to investigate the overlapping genetic factors between multiple diseases (including rheumatoid arthritis (RA), psoriasis, osteoporosis, osteoarthritis, sarcopenia and fracture) Methods: The canonical correlation analysis (metaCCA) approach was used to identify the shared genes for six diseases by integrating genome-wide association study (GWAS)-derived summary statistics. Versatile Gene-based Association Study (VEGAS2) method was further applied to refine and validate the putative pleiotropic genes identified by metaCCA. Results: About 157 (p<8.19E-6), 319 (p<3.90E-6) and 77 (p<9.72E-6) potential pleiotropic genes were identified shared by two immune disease, four skeletal diseases, and all of the six diseases, respectively. The top three significant putative pleiotropic genes shared by both immune and skeletal diseases, including HLA-B, TSBP1 and TSBP1-AS1 (p<E-300) were located in the major histocompatibility complex (MHC) region. Nineteen of 77 putative pleiotropic genes identified by metaCCA analysis were associated with at least one disease in the VEGAS2 analysis. Specifically, majority (18) of these 19 putative validated pleiotropic genes were associated with RA. Conclusion: The metaCCA method identified some pleiotropic genes shared by the immune and skeletal diseases. These findings help to improve our understanding of the shared genetic mechanisms and signaling pathways underlying immune and skeletal diseases.

scholarly journals Genetic variation associated with chromosomal aberration frequency: A genome-wide association study

2018 ◽  
Vol 60 (1) ◽  
pp. 17-28 ◽  
Author(s):  
Yasmeen Niazi ◽  
Hauke Thomsen ◽  
Bozena Smolkova ◽  
Ludmila Vodickova ◽  
Sona Vodenkova ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Association Study ◽  
Chromosomal Aberration ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Aberration Frequency ◽  
Genome Wide ◽  
A Genome

scholarly journals The crucial role of genome-wide genetic variation in conservation

2021 ◽  
Vol 118 (48) ◽  
pp. e2104642118
Author(s):  
Marty Kardos ◽  
Ellie E. Armstrong ◽  
Sarah W. Fitzpatrick ◽  
Samantha Hauser ◽  
Philip W. Hedrick ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Environmental Changes ◽  
Population Viability ◽  
Adaptive Potential ◽  
Biodiversity Crisis ◽  
Genome Wide ◽  
Simulation Based ◽  
Functional Genetic Variation

The unprecedented rate of extinction calls for efficient use of genetics to help conserve biodiversity. Several recent genomic and simulation-based studies have argued that the field of conservation biology has placed too much focus on conserving genome-wide genetic variation, and that the field should instead focus on managing the subset of functional genetic variation that is thought to affect fitness. Here, we critically evaluate the feasibility and likely benefits of this approach in conservation. We find that population genetics theory and empirical results show that conserving genome-wide genetic variation is generally the best approach to prevent inbreeding depression and loss of adaptive potential from driving populations toward extinction. Focusing conservation efforts on presumably functional genetic variation will only be feasible occasionally, often misleading, and counterproductive when prioritized over genome-wide genetic variation. Given the increasing rate of habitat loss and other environmental changes, failure to recognize the detrimental effects of lost genome-wide genetic variation on long-term population viability will only worsen the biodiversity crisis.

scholarly journals Inflammation and JNK's Role in Niacin-GPR109A Diminished Flushed Effect in Microglial and Neuronal Cells With Relevance to Schizophrenia

2021 ◽  
Vol 12 ◽  
Author(s):  
Sabrina H. Ansarey
Keyword(s):  
Inflammatory Mediators ◽  
Neuronal Death ◽  
Microglial Activation ◽  
Negative Symptoms ◽  
Genome Wide Association Study ◽  
Genetic Mutation ◽  
Genome Wide ◽  
Ultra High Risk ◽  
Altered Proteins

Schizophrenia is a neuropsychiatric illness with no single definitive aetiology, making its treatment difficult. Antipsychotics are not fully effective because they treat psychosis rather than the cognitive or negative symptoms. Antipsychotics fail to alleviate symptoms when patients enter the chronic stage of illness. Topical application of niacin showed diminished skin flush in the majority of patients with schizophrenia compared to the general population who showed flushing. The niacin skin flush test is useful for identifying patients with schizophrenia at their ultra-high-risk stage, and understanding this pathology may introduce an effective treatment. This review aims to understand the pathology behind the diminished skin flush response, while linking it back to neurons and microglia. First, it suggests that there are altered proteins in the GPR109A-COX-prostaglandin pathway, inflammatory imbalance, and kinase signalling pathway, c-Jun N-terminal kinase (JNK), which are associated with diminished flush. Second, genes from the GPR109A-COX-prostaglandin pathway were matched against the 128-loci genome wide association study (GWAS) for schizophrenia using GeneCards, suggesting that G-coupled receptor-109A (GPR109A) may have a genetic mutation, resulting in diminished flush. This review also suggests that there may be increased pro-inflammatory mediators in the GPR109A-COX-prostaglandin pathway, which contributes to the diminished flush pathology. Increased levels of pro-inflammatory markers may induce microglial-activated neuronal death. Lastly, this review explores the role of JNK on pro-inflammatory mediators, proteins in the GPR109A-COX-prostaglandin pathway, microglial activation, and neuronal death. Inhibiting JNK may reverse the changes observed in the diminished flush response, which might make it a good therapeutic target.

scholarly journals Identification of genetic factors controlling phosphorus utilization efficiency in wheat by genome-wide association study with principal component analysis

2020 ◽  
Author(s):  
Luqman Bin Safdar ◽  
Muhammad Jawad Umer ◽  
Fakhrah Almas ◽  
Siraj Uddin ◽  
Qurra-tul-Ain Safdar ◽  
...  
Keyword(s):  
Association Study ◽  
Candidate Genes ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Principal Component ◽  
Utilization Efficiency ◽  
Genome Wide Association ◽  
Genome Wide ◽  
P Utilization ◽  
P Utilization Efficiency

ABSTRACTDespite the economic importance of P utilization efficiency, information on genetic factors underlying this trait remains elusive. To address that, we performed a genome-wide association study in a spring wheat diversity panel ranging from landraces to elite varieties. We evaluated the phenotype variation for P utilization efficiency in controlled conditions and genotype variation using wheat 90K SNP array. Phenotype variables were transformed into a smaller set of uncorrelated principal components that captured the most important variation data. We identified two significant loci associated with both P utilization efficiency and the 1st principal component on chromosomes 3A and 4A: qPE1-3A and qPE2-4A. Annotation of genes at these loci revealed 53 wheat genes, among which 6 were identified in significantly enriched pathways. The expression pattern of these 6 genes indicated that TraesCS4A02G481800, involved in pyruvate metabolism and TCA cycle, had a significantly higher expression in the P efficient variety under limited P conditions. Further characterization of these loci and candidate genes can help stimulate P utilization efficiency in wheat.KEY MESSAGEWe report two new loci for P utilization efficiency on chromosomes 3A and 4A of wheat. The prioritized candidate genes at these loci can be investigated by molecular biology techniques to improve P efficiency in wheat and grass relatives.

scholarly journals The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

2020 ◽  
Vol 6 (43) ◽  
pp. eabb3063
Author(s):  
Wei Xu ◽  
Si-Da Han ◽  
Can Zhang ◽  
Jie-Qiong Li ◽  
Yan-Jiang Wang ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Genome Wide Association Study ◽  
In Vitro Study ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Pathophysiological Role ◽  
Independent Cohort

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10−12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

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