Perspectives on the Genetic Associations of Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex polygenic aetiology. Genome-wide association studies have identified more than 100 loci, including some involved in antigen presentation (HLA-B27, ERAP1, and ERAP2), some in Th17 responses (IL6R, IL23R, TYK2, and STAT3), and others in macrophages and T-cells (IL7R, CSF2, RUNX3, and GPR65). Such observations have already helped identify potential new therapies targeting IL-17 and GM-CSF. Most AS genetic associations are not in protein-coding sequences but lie in intergenic regions where their direct relationship to particular genes is difficult to assess. They most likely reflect functional polymorphisms concerned with cell type-specific regulation of gene expression. Clarifying the nature of these associations should help to understand the pathogenic pathways involved in AS better and suggest potential cellular and molecular targets for drug therapy. However, even identifying the precise mechanisms behind the extremely strong HLA-B27 association with AS has so far proved elusive. Polygenic risk scores (using all the known genetic associations with AS) can be effective for the diagnosis of AS, particularly where there is a relatively high pre-test probability of AS. Genetic prediction of disease outcomes and response to biologics is not currently practicable.

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Functional polymorphisms and transcriptional analysis in the 5' region of the human serotonin receptor 1B gene (HTR1B) and their associations with psychiatric disorders

10.21203/rs.3.rs-21296/v3 ◽

2020 ◽

Author(s):

Xi Xia ◽

Mei Ding ◽

Jin-feng Xuan ◽

Jia-xin Xing ◽

Jun Yao ◽

...

Keyword(s):

Gene Expression ◽

Behavioral Disorders ◽

Association Studies ◽

Regulation Of Gene Expression ◽

Regulatory Region ◽

Transcriptional Analysis ◽

Luciferase Reporter ◽

Genome Wide Association Studies ◽

Functional Polymorphisms ◽

Mental And Behavioral Disorders

Abstract Background The 5-hydroxytryptamine 1B receptor (5-HT1B) plays an essential role in the serotonin (5-HT) system and is widely involved in a variety of brain activities. HTR1B is the gene encoding 5-HT1B. Genome-wide association studies have shown that HTR1B polymorphisms are closely related to multiple mental and behavioral disorders; however, the functional mechanisms underlying these associations are unknown. This study investigated the effect of several HTR1B haplotypes on regulation of gene expression in vitro and the functional sequences in the 5' regulatory region of HTR1B to determine their potential association with mental and behavioral disorders.MethodsSix haplotypes consisting of rs4140535, rs1778258, rs17273700, rs1228814, rs11568817, and rs130058 and several truncated fragments of the 5' regulatory region of HTR1B were transfected into SK-N-SH and HEK-293 cells. The relative fluorescence intensities of the different haplotypes and truncated fragments were detected using a dual-luciferase reporter assay system.Results Compared to the major haplotype T-G-T-C-T-A, the relative fluorescence intensities of haplotypes C-A-T-C-T-A, C-G-T-C-T-A, C-G-C-A-G-T, and C-G-T-A-T-A were significantly lower, and that of haplotype C-G-C-A-G-A was significantly higher. Furthermore, the effects of the rs4140535T allele, the rs17273700C-rs11568817G linkage combination, and the rs1228814A allele made their relative fluorescence intensities significantly higher than their counterparts at each locus. Conversely, the rs1778258A and rs130058T alleles decreased the relative fluorescence intensities. In addition, we found that regions from -1587 to -1371 bp (TSS, +1), -1149 to -894 bp, -39 to +130 bp, +130 to +341 bp, and +341 to +505 bp upregulated gene expression. In contrast, regions -603 to -316 bp and +130 to +341 bp downregulated gene expression. Region +341 to +505 bp played a decisive role in gene transcription.Conclusions HTR1B 5' regulatory region polymorphisms have regulatory effects on gene expression and potential correlate with several pathology and physiology conditions. This study suggests that a crucial sequence for transcription is located in region +341~+505 bp. Regions -1587 to -1371 bp, -1149 to -894 bp, -603 to -316 bp, -39 to +130 bp, and +130 to +341 bp contain functional sequences that can promote or suppress the HTR1B gene expression.

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Association of ankylosing spondylitis activity indicators in a Russian population of patients with STAT4 rs7574865 gene polymorphism

Modern Rheumatology Journal ◽

10.14412/1996-7012-2019-2-55-60 ◽

2019 ◽

Vol 13 (2) ◽

pp. 55-60

Author(s):

M. Yu. Krylov ◽

A. S. Starkova ◽

E. Yu. Samarkina ◽

T. V. Dubinina ◽

Sh. F. Erdes

Keyword(s):

Ankylosing Spondylitis ◽

Gene Polymorphism ◽

Autoimmune Diseases ◽

Disease Activity ◽

Topoisomerase I ◽

Association Studies ◽

Russian Population ◽

Control Group ◽

Genome Wide Association Studies ◽

Hla B27

Family and twin studies have shown that ankylosing spondylitis (AS) has a hereditary nature that is based on a strong association with the leukocyte antigen HLA-B27. However, only 1–5% of HLA-B27 carriers develop AS, which indicates that there are other genetic markers involved in the formation of a predisposition to this disease. A number of genome-wide association studies have convincingly confirmed the role of the STAT4 gene. This gene encodes the protein – the signal transducer and activator of transcription (STAT) protein, which is a predisposing factor for the development of many autoimmune diseases. There are not so many studies of the relationship of STAT4 polymorphisms to the predisposition to AS, and there are no these studies regarding the Russian population.Objective: to study whether there is a possible association of STAT4 rs7574865 gene polymorphism with the predisposition to AS and to assess the activity of this disease using BASDAI and ASDAS scores in the Russian patient population.Patients and methods. A cohort of 203 individuals, including 100 patients (79 men and 21 women) with AS, and 103 healthy volunteers (a control group) was surveyed. Age, gender, duration, and specific features of AS onset, ESR, and CRP levels were assessed. BASDAI and ASDAS scores were calculated to evaluate disease activity.Results and discussion. There was a significant relationship between STAT4 polymorphism and C-reactive protein (CRP) levels and BASDAI and ASDAS-CRP scores. The TT genotype carriers had significantly higher mean activity indices compared to the GG (p=0.001) and GT (p=0.005) genotype carriers for CRP, BASDAI (p=0.0001 and p=0.009, respectively) and ASDAS-CRP (p=0.009 and p=0.001, respectively). High disease activity (BASDAI >4 and ASDAS-CRP >3.5) was also associated with the high frequency of the T allele (p=0.046 and p=0.004, respectively). The value of STAT4 rs7574865 gene polymorphism in the pathogenesis of autoimmune diseases is confirmed by a study in which the T allele in STAT4 rs7574865 enhances mRNA transcription and protein expression. Italian authors have shown that there is a relationship between the minor T allele of rs7574865 and the high risk of arthritis. We have previously established a relationship between the T allele and the predisposition to diffuse systemic scleroderma, interstitial lung damage, and elevated anti-topoisomerase I antibody levels.Conclusion. The present study has shown for the first time a significant association of STAT4 rs7574865 polymorphism with the main AS activity indicators: CRP levels, BASDAI and ASDAS-CRP scores. The studied polymorphism may be a new genetic marker for predicting the severity of AS.

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Functional polymorphisms and transcriptional analysis in the 5' region of the human serotonin receptor 1B gene (HTR1B) and their associations with psychiatric disorders

10.21203/rs.3.rs-21296/v4 ◽

2020 ◽

Author(s):

Xi Xia ◽

Mei Ding ◽

Jin-feng Xuan ◽

Jia-xin Xing ◽

Jun Yao ◽

...

Keyword(s):

Gene Expression ◽

Behavioral Disorders ◽

Association Studies ◽

Regulation Of Gene Expression ◽

Regulatory Region ◽

Transcriptional Analysis ◽

Luciferase Reporter ◽

Genome Wide Association Studies ◽

Functional Polymorphisms ◽

Mental And Behavioral Disorders

Abstract Background The 5-hydroxytryptamine 1B receptor (5-HT1B) plays an essential role in the serotonin (5-HT) system and is widely involved in a variety of brain activities. HTR1B is the gene encoding 5-HT1B. Genome-wide association studies have shown that HTR1B polymorphisms are closely related to multiple mental and behavioral disorders; however, the functional mechanisms underlying these associations are unknown. This study investigated the effect of several HTR1B haplotypes on regulation of gene expression in vitro and the functional sequences in the 5' regulatory region of HTR1B to determine their potential association with mental and behavioral disorders. Methods Six haplotypes consisting of rs4140535, rs1778258, rs17273700, rs1228814, rs11568817, and rs130058 and several truncated fragments of the 5' regulatory region of HTR1B were transfected into SK-N-SH and HEK-293 cells. The relative fluorescence intensities of the different haplotypes and truncated fragments were detected using a dual-luciferase reporter assay system. Results Compared to the major haplotype T-G-T-C-T-A, the relative fluorescence intensities of haplotypes C-A-T-C-T-A, C-G-T-C-T-A, C-G-C-A-G-T, and C-G-T-A-T-A were significantly lower, and that of haplotype C-G-C-A-G-A was significantly higher. Furthermore, the effects of the rs4140535T allele, the rs17273700C-rs11568817G linkage combination, and the rs1228814A allele made their relative fluorescence intensities significantly higher than their counterparts at each locus. Conversely, the rs1778258A and rs130058T alleles decreased the relative fluorescence intensities. In addition, we found that regions from -1587 to -1371 bp (TSS, +1), -1149 to -894 bp, -39 to +130 bp, +130 to +341 bp, and +341 to +505 bp upregulated gene expression. In contrast, regions -603 to -316 bp and +130 to +341 bp downregulated gene expression. Region +341 to +505 bp played a decisive role in gene transcription. Conclusions HTR1B 5' regulatory region polymorphisms have regulatory effects on gene expression and potential correlate with several pathology and physiology conditions. This study suggests that a crucial sequence for transcription is located in region +341~+505 bp. Regions -1587 to -1371 bp, -1149 to -894 bp, -603 to -316 bp, -39 to +130 bp, and +130 to +341 bp contain functional sequences that can promote or suppress the HTR1B gene expression.

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Functional Annotation of Putative Regulatory Elements at Cancer Susceptibility Loci

Cancer Informatics ◽

10.4137/cin.s13789 ◽

2014 ◽

Vol 13s2 ◽

pp. CIN.S13789

Author(s):

Stephanie A. Rosse ◽

Paul L. Auer ◽

Christopher S. Carlson

Keyword(s):

Cancer Susceptibility ◽

Association Studies ◽

Regulatory Elements ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Functional Polymorphisms ◽

Functional Variants ◽

Genome Wide ◽

Regulatory Variant ◽

Causal Variants

Most cancer-associated genetic variants identified from genome-wide association studies (GWAS) do not obviously change protein structure, leading to the hypothesis that the associations are attributable to regulatory polymorphisms. Translating genetic associations into mechanistic insights can be facilitated by knowledge of the causal regulatory variant (or variants) responsible for the statistical signal. Experimental validation of candidate functional variants is onerous, making bioinformatic approaches necessary to prioritize candidates for laboratory analysis. Thus, a systematic approach for recognizing functional (and, therefore, likely causal) variants in noncoding regions is an important step toward interpreting cancer risk loci. This review provides a detailed introduction to current regulatory variant annotations, followed by an overview of how to leverage these resources to prioritize candidate functional polymorphisms in regulatory regions.

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A brief history of ankylosing spondylitis

10.1093/med/9780198755296.003.0002 ◽

2016 ◽

Author(s):

Stefan Siebert ◽

Sengupta Raj ◽

Alexander Tsoukas

Keyword(s):

Ankylosing Spondylitis ◽

Clinical Features ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Hla B27 ◽

The Past ◽

Genome Wide ◽

Clinical Radiology ◽

History Of

The history of ankylosing spondylitis (AS) dates back to the discovery of skeletons with characteristic spinal changes. The disease was further defined by correlating pathological and clinical features, and the development of clinical radiology. Subsequent epidemiology and familial studies highlighted the association with other related conditions as part of the spondyloarthritides. The discovery of HLA-B27 confirmed this association. Over the past two decades, genome-wide association studies, and advances in imaging and immunology have yielded dramatic insights into the disease and the development of highly effective therapies.

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Functional polymorphisms and transcriptional analysis in the 5′ region of the human serotonin receptor 1B gene (HTR1B) and their associations with psychiatric disorders

BMC Psychiatry ◽

10.1186/s12888-020-02906-4 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Xi Xia ◽

Mei Ding ◽

Jin-feng Xuan ◽

Jia-xin Xing ◽

Jun Yao ◽

...

Keyword(s):

Gene Expression ◽

Behavioral Disorders ◽

Association Studies ◽

Regulation Of Gene Expression ◽

Regulatory Region ◽

Transcriptional Analysis ◽

Luciferase Reporter ◽

Genome Wide Association Studies ◽

Functional Polymorphisms ◽

Mental And Behavioral Disorders

Abstract Background The 5-hydroxytryptamine 1B receptor (5-HT1B) plays an essential role in the serotonin (5-HT) system and is widely involved in a variety of brain activities. HTR1B is the gene encoding 5-HT1B. Genome-wide association studies have shown that HTR1B polymorphisms are closely related to multiple mental and behavioral disorders; however, the functional mechanisms underlying these associations are unknown. This study investigated the effect of several HTR1B haplotypes on regulation of gene expression in vitro and the functional sequences in the 5′ regulatory region of HTR1B to determine their potential association with mental and behavioral disorders. Methods Six haplotypes consisting of rs4140535, rs1778258, rs17273700, rs1228814, rs11568817, and rs130058 and several truncated fragments of the 5′ regulatory region of HTR1B were transfected into SK-N-SH and HEK-293 cells. The relative fluorescence intensities of the different haplotypes and truncated fragments were detected using a dual-luciferase reporter assay system. Results Compared to the major haplotype T-G-T-C-T-A, the relative fluorescence intensities of haplotypes C-A-T-C-T-A, C-G-T-C-T-A, C-G-C-A-G-T, and C-G-T-A-T-A were significantly lower, and that of haplotype C-G-C-A-G-A was significantly higher. Furthermore, the effects of the rs4140535T allele, the rs17273700C-rs11568817G linkage combination, and the rs1228814A allele made their relative fluorescence intensities significantly higher than their counterparts at each locus. Conversely, the rs1778258A and rs130058T alleles decreased the relative fluorescence intensities. In addition, we found that regions from − 1587 to − 1371 bp (TSS, + 1), − 1149 to − 894 bp, − 39 to + 130 bp, + 130 to + 341 bp, and + 341 to + 505 bp upregulated gene expression. In contrast, regions − 603 to − 316 bp and + 130 to + 341 bp downregulated gene expression. Region + 341 to + 505 bp played a decisive role in gene transcription. Conclusions HTR1B 5′ regulatory region polymorphisms have regulatory effects on gene expression and potential correlate with several pathology and physiology conditions. This study suggests that a crucial sequence for transcription is located in region + 341 ~ + 505 bp. Regions − 1587 to − 1371 bp, − 1149 to − 894 bp, − 603 to − 316 bp, − 39 to + 130 bp, and + 130 to + 341 bp contain functional sequences that can promote or suppress the HTR1B gene expression.

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Analysis of 47 Non-MHC Ankylosing Spondylitis Susceptibility Loci Regarding Associated Variants across Whites and Han Chinese

The Journal of Rheumatology ◽

10.3899/jrheum.190184 ◽

2019 ◽

Vol 47 (5) ◽

pp. 674-681

Author(s):

Xuqi Zheng ◽

Qiuxia Li ◽

Xiaomin Li ◽

Yanli Zhang ◽

Xinyu Wu ◽

...

Keyword(s):

Ankylosing Spondylitis ◽

Interaction Analysis ◽

Association Studies ◽

Critical Role ◽

Population Attributable Risk ◽

Han Chinese ◽

Systematic Evaluation ◽

Genome Wide Association Studies ◽

Hla B27 ◽

Susceptibility Loci

Objective.To present a systematic evaluation of 47 non-MHC ankylosing spondylitis (AS) susceptibility loci that have been initially discovered through white genome-wide association studies in Han Chinese.Methods.Originally, 10,743 samples representing north and south Chinese in 4 datasets were obtained. After data quality control and imputation, metaanalysis results of 94,621 variants within 47 loci were extracted. Four ERAP1 single-nucleotide polymorphisms (SNP) and HLA-B27 tag SNP rs13202464 were used for interaction analysis. Population-attributable risk percentages of AS-associated variants were compared. Functional annotations of AS-associated variants were conducted using HaploReg, RegulomeDB, and rVarBase databases.Results.We revealed 16 AS-associated variants with nominal evidence in Han Chinese, including rs10865331 (p = 6.30 × 10−10), rs10050860 (p = 4.09 × 10−5) and rs8070463 (p = 1.03 × 10−4). Potential susceptible SNP within these 47 loci were also identified, such as rs13024541 (2p15), rs17401719 (5q15), and rs62074054 (17q21). Epistatic interactions between 3 ERAP1 SNP (rs17401719, rs30187, and rs10050860) and HLA-B27 were confirmed. Among the 16 AS-associated variants, rs30187 showed weaker risk effect, while rs10050860 and rs12504282 seemed to attribute more risk in Han Chinese than in whites. Further genomic annotation pinpointed 35 candidate functional SNP, especially in the 2p15, ERAP1, and NPEPPS-TBKBP1 regions.Conclusion.Our results provided a detailed spectrum of all the reported non-MHC AS susceptibility loci in Han Chinese, which comprehensively exhibited the ethnic heterogeneity of AS susceptibility and highlighted that 2p15, ERAP1, and NPEPPS-TBKBP1 regions may play a critical role in AS pathogenesis across diverse populations.

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Genetic architecture of schizophrenia: a review of major advancements

Psychological Medicine ◽

10.1017/s0033291720005334 ◽

2021 ◽

pp. 1-10

Author(s):

Sophie E. Legge ◽

Marcos L. Santoro ◽

Sathish Periyasamy ◽

Adeniran Okewole ◽

Arsalan Arsalan ◽

...

Keyword(s):

Genetic Architecture ◽

Association Studies ◽

Copy Number Variants ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Genetic Loci ◽

Significant Enrichment ◽

High Heritability ◽

Coding Variants

Abstract Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

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Penalized partial least squares for pleiotropy

BMC Bioinformatics ◽

10.1186/s12859-021-03968-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Camilo Broc ◽

Therese Truong ◽

Benoit Liquet

Keyword(s):

Least Squares ◽

Partial Least Squares ◽

Association Studies ◽

A Priori ◽

Simulated Data ◽

Real Data ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Multiple Traits ◽

Application Fields

Abstract Background The increasing number of genome-wide association studies (GWAS) has revealed several loci that are associated to multiple distinct phenotypes, suggesting the existence of pleiotropic effects. Highlighting these cross-phenotype genetic associations could help to identify and understand common biological mechanisms underlying some diseases. Common approaches test the association between genetic variants and multiple traits at the SNP level. In this paper, we propose a novel gene- and a pathway-level approach in the case where several independent GWAS on independent traits are available. The method is based on a generalization of the sparse group Partial Least Squares (sgPLS) to take into account groups of variables, and a Lasso penalization that links all independent data sets. This method, called joint-sgPLS, is able to convincingly detect signal at the variable level and at the group level. Results Our method has the advantage to propose a global readable model while coping with the architecture of data. It can outperform traditional methods and provides a wider insight in terms of a priori information. We compared the performance of the proposed method to other benchmark methods on simulated data and gave an example of application on real data with the aim to highlight common susceptibility variants to breast and thyroid cancers. Conclusion The joint-sgPLS shows interesting properties for detecting a signal. As an extension of the PLS, the method is suited for data with a large number of variables. The choice of Lasso penalization copes with architectures of groups of variables and observations sets. Furthermore, although the method has been applied to a genetic study, its formulation is adapted to any data with high number of variables and an exposed a priori architecture in other application fields.

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Polygenic Risk Score of Longevity Predicts Longer Survival Across an Age Continuum

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa289 ◽

2020 ◽

Author(s):

Niccolo’ Tesi ◽

Sven J van der Lee ◽

Marc Hulsman ◽

Iris E Jansen ◽

Najada Stringa ◽

...

Keyword(s):

Older Adults ◽

Cellular Response ◽

Molecular Mechanisms ◽

Association Studies ◽

Risk Scores ◽

Human Longevity ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Age Related

Abstract Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

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