scholarly journals Genetic Variants of the NF-κB Pathway: Unraveling the Genetic Architecture of Psoriatic Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 13004
Author(s):  
Rubén Queiro ◽  
Pablo Coto-Segura ◽  
Leire González-Lara ◽  
Eliecer Coto
Keyword(s):  
Genetic Variants ◽  
Genetic Architecture ◽  
Genetic Basis ◽  
Genetic Factors ◽  
Disease Susceptibility ◽  
Cell Types ◽  
Psoriatic Disease ◽  
Pharmacological Response ◽  
Light Chain Enhancer ◽  
Shared Genetic

Psoriasis is a multifactorial genetic disease for which the genetic factors explain about 70% of disease susceptibility. Up to 30–40% of psoriasis patients develop psoriatic arthritis (PsA). However, PsA can be considered as a “disease within a disease”, since in most cases psoriasis is already present when joint complaints begin. This has made studies that attempt to unravel the genetic basis for both components of psoriatic disease enormously difficult. Psoriatic disease is also accompanied by a high burden of comorbid conditions, mainly of the cardiometabolic type. It is currently unclear whether these comorbidities and psoriatic disease have a shared genetic basis or not. The nuclear factor of kappa light chain enhancer of activated B cells (NF-κB) is a transcription factor that regulates a plethora of genes in response to infection, inflammation, and a wide variety of stimuli on several cell types. This mini-review is focused on recent findings that highlight the importance of this pathway both in the susceptibility and in the determinism of some features of psoriatic disease. We also briefly review the importance of genetic variants of this pathway as biomarkers of pharmacological response. All the above may help to better understand the etiopathogenesis of this complex entity.

scholarly journals Genomic and phenomic insights from an atlas of genetic effects on DNA methylation

2020 ◽  
Author(s):  
Josine L Min ◽  
Gibran Hemani ◽  
Eilis Hannon ◽  
Koen F Dekkers ◽  
Juan Castillo-Fernandez ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variants ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Genetic Variance ◽  
Genetic Factors ◽  
Additive Genetic Variance ◽  
Genetic Influences ◽  
Methylation Quantitative Trait Loci ◽  
Shared Genetic

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both blood DNAm levels and complex diseases but in most cases these associations do not reflect causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than has previously been hypothesised.

scholarly journals Shared genetic background between children and adults with attention deficit/hyperactivity disorder

2019 ◽  
Author(s):  
Paula Rovira ◽  
Ditte Demontis ◽  
Cristina Sánchez-Mora ◽  
Tetyana Zayats ◽  
Marieke Klein ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Genetic Variants ◽  
Genetic Background ◽  
Genetic Architecture ◽  
Neurodevelopmental Disorder ◽  
Genome Wide Association Studies ◽  
Hyperactivity Disorder ◽  
Common Genetic Variants ◽  
Shared Genetic

AbstractAttention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

scholarly journals Visualizing genetic similarity at the symptom level: The example of learning disabilities

2010 ◽  
Vol 33 (2-3) ◽  
pp. 155-157
Author(s):  
Oliver S. P. Davis ◽  
Robert Plomin
Keyword(s):  
Learning Disabilities ◽  
Cognitive Abilities ◽  
Genetic Similarity ◽  
Structural Equation ◽  
Genetic Architecture ◽  
Genetic Factors ◽  
Psychological Traits ◽  
Equation Modelling ◽  
Symptom Level ◽  
Shared Genetic

AbstractPsychological traits and disorders are often interrelated through shared genetic influences. A combination of maximum-likelihood structural equation modelling and multidimensional scaling enables us to open a window onto the genetic architecture at the symptom level, rather than at the level of latent genetic factors. We illustrate this approach using a study of cognitive abilities involving over 5,000 pairs of twins.

scholarly journals Insights into the genetic architecture of the human face

2020 ◽  
Author(s):  
Julie D. White ◽  
Karlijne Indencleef ◽  
Sahin Naqvi ◽  
Ryan J. Eller ◽  
Jasmien Roosenboom ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genetic Architecture ◽  
Cell Types ◽  
Human Face ◽  
Normal Range ◽  
Enhancer Activity ◽  
Limb Morphogenesis ◽  
Cranial Neural Crest Cells ◽  
Genomic Regions

AbstractThe human face is complex and multipartite, and characterization of its genetic architecture remains intriguingly challenging. Applying GWAS to multivariate shape phenotypes, we identified 203 genomic regions associated with normal-range facial variation, 117 of which are novel. The associated regions are enriched for both genes relevant to craniofacial and limb morphogenesis and enhancer activity in cranial neural crest cells and craniofacial tissues. Genetic variants grouped by their contribution to similar aspects of facial variation show high within-group correlation of enhancer activity, and four SNP pairs display evidence of epistasis, indicating potentially coordinated actions of variants within the same cell types or tissues. In sum, our analyses provide new insights for understanding how complex morphological traits are shaped by both individual and coordinated genetic actions.

Population-based approaches to genetics of migraine

Cephalalgia ◽  
2016 ◽  
Vol 36 (7) ◽  
pp. 692-703 ◽  
Author(s):  
Daniel I Chasman ◽  
Markus Schürks ◽  
Tobias Kurth
Keyword(s):  
Genetic Variants ◽  
Genetic Architecture ◽  
Clinical Characteristics ◽  
Genetic Basis ◽  
Primary Headache ◽  
Population Based ◽  
Accurate Diagnosis ◽  
Future Success ◽  
Alternative Approach ◽  
Common Genetic Variants

Background While the most accurate diagnosis of migraine typically requires a clinical interview guided by strict diagnostic criteria, an alternative approach that ascertains migraine by questionnaire in population-based settings has been instrumental in the discovery of common genetic variants influencing migraine risk. This result may be surprising. Population-based approaches are often criticized for limited ability to distinguish migraine from other forms of primary headache. It is thus useful to revisit prevailing ideas about population-based ascertainment of migraine to evaluate the extent to which this approach has potential for additional insights into migraine genetics and therefore pathophysiology. Overview We review recent findings suggesting that the success of the population-based approach is derived from the possibility of collecting much larger samples than in the clinic-based setting even at the risk of introducing phenotypic and genetic heterogeneity. The findings are also consistent with new appreciations for the genetic basis of many other common, complex clinical characteristics. However, clinic-based ascertainment and other settings will remain more effective than population-based approaches for investigating certain, often very specific aspects of migraine genetics. Conclusion We argue that the detailed genetic architecture of migraine, various aspects of methodology, and the ultimate sample size achieved by population-based ascertainment will be critical determinants of the future success of this approach to genetic analysis of migraine and its comorbidities.

scholarly journals The genetic basis for ecological adaptation of the Atlantic herring revealed by genome sequencing

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Alvaro Martinez Barrio ◽  
Sangeet Lamichhaney ◽  
Guangyi Fan ◽  
Nima Rafati ◽  
Mats Pettersson ◽  
...  
Keyword(s):  
Genetic Differentiation ◽  
Genetic Architecture ◽  
Genetic Basis ◽  
Genetic Factors ◽  
Geographic Origin ◽  
Natural Populations ◽  
Ecological Adaptation ◽  
Timing Of Reproduction ◽  
Haplotype Blocks ◽  
Subdivided Populations

Ecological adaptation is of major relevance to speciation and sustainable population management, but the underlying genetic factors are typically hard to study in natural populations due to genetic differentiation caused by natural selection being confounded with genetic drift in subdivided populations. Here, we use whole genome population sequencing of Atlantic and Baltic herring to reveal the underlying genetic architecture at an unprecedented detailed resolution for both adaptation to a new niche environment and timing of reproduction. We identify almost 500 independent loci associated with a recent niche expansion from marine (Atlantic Ocean) to brackish waters (Baltic Sea), and more than 100 independent loci showing genetic differentiation between spring- and autumn-spawning populations irrespective of geographic origin. Our results show that both coding and non-coding changes contribute to adaptation. Haplotype blocks, often spanning multiple genes and maintained by selection, are associated with genetic differentiation.

scholarly journals Evidence for shared genetic risk factors between lymphangioleiomyomatosis and pulmonary function

2021 ◽  
pp. 00375-2021
Author(s):  
Xavier Farré ◽  
Roderic Espín ◽  
Alexandra Baiges ◽  
Eline Blommaert ◽  
Wonji Kim ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Genetic Variants ◽  
Genetic Basis ◽  
Association Studies ◽  
Genetic Correlations ◽  
Forced Expiratory Volume ◽  
Low Grade ◽  
Genome Wide Association Studies ◽  
Cell Of Origin ◽  
Shared Genetic

IntroductionLymphangioleiomyomatosis (LAM) is a rare low-grade metastasising disease characterised by cystic lung destruction. The genetic basis of LAM remains incompletely determined, and the disease cell-of-origin is uncertain. We analysed the possibility of a shared genetic basis between LAM and cancer, and LAM and pulmonary function.MethodsThe results of genome-wide association studies (GWASs) of LAM, 17 cancer types, and spirometry measures (forced expiratory volume in 1-second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and peak expiratory flow (PEF)) were analysed for genetic correlations, shared genetic variants, and causality. Genomic and transcriptomic data were examined, and immunodetection assays were performed to evaluate pleiotropic genes.ResultsThere were no significant overall genetic correlations between LAM and cancer, but LAM correlated negatively with FVC and PEF, and a trend in the same direction was observed for FEV1. Twenty-two shared genetic variants were uncovered between LAM and pulmonary function, while seven shared variants were identified between LAM and cancer. The LAM-pulmonary function shared genetics identified four pleiotropic genes previously recognised in LAM single-cell transcriptomes: ADAM12, BNC2, NR2F2, and SP5. We had previously associated NR2F2 variants with LAM, and we identified its functional partner NR3C1 as another pleotropic factor. NR3C1 expression was confirmed in LAM lung lesions. Another candidate pleiotropic factor, CNTN2, was found more abundant in plasma of LAM patients than that of healthy women.ConclusionsThis study suggests the existence of a common genetic aetiology between LAM and pulmonary function.

scholarly journals Genetic factors contributing to extensive variability of sex-specific hepatic gene expression in Diversity Outbred mice

2020 ◽  
Author(s):  
Tisha Melia ◽  
David J. Waxman
Keyword(s):  
Gene Expression ◽  
Growth Hormone ◽  
Sex Differences ◽  
Genetic Variants ◽  
Genetic Factors ◽  
Disease Susceptibility ◽  
Gene Clusters ◽  
Individual Variability ◽  
Diversity Outbred ◽  
The Individual

AbstractSex-specific transcription characterizes hundreds of genes in mouse liver, many implicated in sex-differential drug and lipid metabolism and disease susceptibility. While the regulation of liver sex differences by growth hormone-activated STAT5 is well established, little is known about autosomal genetic factors regulating the sex-specific liver transcriptome. Here we show, using genotyping and expression data from a large population of Diversity Outbred mice, that genetic factors work in tandem with growth hormone to control the individual variability of hundreds of sex-biased genes, including many lncRNA genes. Significant associations between single nucleotide polymorphisms and sex-specific gene expression were identified as expression quantitative trait loci (eQTLs), many of which showed strong sex-dependent associations. Remarkably, autosomal genetic modifiers of sex-specific genes were found to account for more than 200 instances of gain or loss of sex-specificity across eight Diversity Outbred mouse founder strains. Sex-biased STAT5 binding sites and open chromatin regions with strain-specific variants were significantly enriched at eQTL regions regulating correspondingly sex-specific genes, supporting the proposed functional regulatory nature of the eQTL regions identified. Binding of the male-biased, growth hormone-regulated repressor BCL6 was most highly enriched at trans-eQTL regions controlling female-specific genes. Co-regulated gene clusters defined by overlapping eQTLs included sets of highly correlated genes from different chromosomes, further supporting trans-eQTL action. These findings elucidate how an unexpectedly large number of autosomal factors work in tandem with growth hormone signaling pathways to regulate the individual variability associated with sex differences in liver metabolism and disease.Author summaryMale-female differences in liver gene expression confer sex differences in many biological processes relevant to health and disease, including lipid and drug metabolism and liver disease susceptibility. While the role of hormonal factors, most notably growth hormone, in regulating hepatic sex differences is well established, little is known about how autosomal genetic factors impact sex differences on an individual basis. Here, we harness the power of mouse genetics provided by the Diversity Outbred mouse model to discover significant genome-wide associations between genetic variants and sex-specific liver gene expression. Remarkably, we found that autosomal expression quantitative trait loci with a strong sex-bias account for the loss or gain of sex-specific expression of more than 200 autosomal genes seen across eight founder mice strains. Genetic associations with sex-specific genes were enriched for sex-biased and growth hormone-dependent regulatory regions harboring strain-specific genetic variants. Co-regulated gene clusters identified by overlapping regulatory regions included highly correlated genes from different chromosomes. These findings reveal the extensive regulatory role played by autosomal genetic variants, working in tandem with growth hormone signaling pathways, in the transcriptional control of sex-biased genes, many of which have been implicated in sex differential outcomes in liver metabolism and disease susceptibility.

scholarly journals Enhanced Identification of Novel Potential Variants for Appendicular Lean Mass by Leveraging Pleiotropy With Bone Mineral Density

2021 ◽  
Vol 12 ◽  
Author(s):  
Cheng Peng ◽  
Feng Liu ◽  
Kuan-Jui Su ◽  
Xu Lin ◽  
Yu-Qian Song ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Lean Mass ◽  
Genetic Variants ◽  
Genetic Basis ◽  
Functional Enrichment ◽  
Genome Wide Association Studies ◽  
Mineral Density ◽  
Appendicular Lean Mass ◽  
Shared Genetic

Strong relationships have been found between appendicular lean mass (ALM) and bone mineral density (BMD). It may be due to a shared genetic basis, termed pleiotropy. By leveraging the pleiotropy with BMD, the aim of this study was to detect more potential genetic variants for ALM. Using the conditional false discovery rate (cFDR) methodology, a combined analysis of the summary statistics of two large independent genome wide association studies (GWAS) of ALM (n = 73,420) and BMD (n = 10,414) was conducted. Strong pleiotropic enrichment and 26 novel potential pleiotropic SNPs were found for ALM and BMD. We identified 156 SNPs for ALM (cFDR <0.05), of which 74 were replicates of previous GWASs and 82 were novel SNPs potentially-associated with ALM. Eleven genes annotated by 31 novel SNPs (13 pleiotropic and 18 ALM specific) were partially validated in a gene expression assay. Functional enrichment analysis indicated that genes corresponding to the novel potential SNPs were enriched in GO terms and/or KEGG pathways that played important roles in muscle development and/or BMD metabolism (adjP <0.05). In protein–protein interaction analysis, rich interactions were demonstrated among the proteins produced by the corresponding genes. In conclusion, the present study, as in other recent studies we have conducted, demonstrated superior efficiency and reliability of the cFDR methodology for enhanced detection of trait-associated genetic variants. Our findings shed novel insight into the genetic variability of ALM in addition to the shared genetic basis underlying ALM and BMD.

scholarly journals A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

2021 ◽  
Author(s):  
Anurag Verma ◽  
Noah L. Tsao ◽  
Lauren O. Thomann ◽  
Yuk-Lam Ho ◽  
Rotonya Carr ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Variants ◽  
Genetic Architecture ◽  
Association Studies ◽  
Missense Variant ◽  
International Classification Of Diseases ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Significant Difference ◽  
Shared Genetic

Background There are certain pre-existing conditions which leads in increased risk of coronavirus disease 2019 (COVID-19) severity and mortality. The objective of this study is to determine shared genetic architecture between COVID-19 severity and other medical conditions using electronic health record (EHR) data from diverse patient populations. Methods and Findings: We conducted Phenome-wide association study (PheWAS) of genetic variants associated with severe COVID-19 in two biobanks with EHR and genomic data: 1) Veteran Affairs (VA) Million Veteran Program (MVP), 2) United Kingdom Biobank (UKBB). Genetic variants associated with critical illness (n=48) or hospitalization (n=39) due to COVID-19 from COVID-19 Host Genetics Initiative genome-wide association studies. Phenotypes defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods; pre-COVID-19 data used to avoid potential confounding. Among 455,683 US Veterans from MVP, variants associated with severe COVID-19 tested for association across 1,559 phenotypes; 353,365 UK Biobank participants, and 1,064 phenotypes tested. Genetic variants at ABO locus (rs550057, rs505922) associated with the largest number of phenotypes (nrs55057= 53 and nrs505922=61); strongest association with venous embolism, odds ratio (OR)rs550057 1.27 (p=5.28 x 10-116), and thrombosis ORrs505922 1.31, p=3.5 x10-183. Among 67 respiratory conditions tested, only idiopathic pulmonary fibrosis, OR rs2277732 1.17, p=1.3410-05, and asthma ORrs143334143 0.94, p=2.31 x10-04, shared variants with severe COVID-19. The RAVER1 locus (rs74956615) associated with reduced risk for autoimmune conditions, e.g. psoriasis OR 0.71, p= 1.53 x10-22, rheumatoid arthritis, OR 0.78, p=1.04 x 10-09; findings replicated in UKBB. A known functional missense variant (rs34536443, TYK2) in the region had the highest linkage disequilibrium with rs74956615, suggesting signal was likely from TYK2. In MVP, PheWAS results stratified by genetic ancestry did not demonstrate significant difference in associations across ancestry. Conclusions Shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes; associations similar across genetic ancestries. Divergent association between inflammatory conditions and severe COVID may be explained by known pathway impairing signaling of inflammatory cytokines, reducing risk for autoimmunity; same pathway reduces type 1 interferon signaling, critical for viral host defense. Caution needed when targeting pathways that may balance immune tolerance and immunodeficiency to treat COVID-19.

Sign in / Sign up

Export Citation Format

Share Document