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1.
Curr Issues Mol Biol ; 45(10): 7862-7877, 2023 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-37886940

RESUMEN

DNA methylation is an epigenetic factor that is modifiable and can change over a lifespan. While many studies have identified methylation sites (CpGs) related to aging, the relationship of these to gene function and age-related disease phenotypes remains unclear. This research explores this question by testing for the conjoint association of age-related CpGs with gene expression and the relation of these to body fat phenotypes. The study included blood-based gene transcripts and intragenic CpG methylation data from Illumina 450 K arrays in 74 healthy adults from the Norfolk Island population. First, a series of regression analyses were performed to detect associations between gene transcript level and intragenic CpGs and their conjoint relationship with age. Second, we explored how these age-related expression CpGs (eCpGs) correlated with obesity-related phenotypes, including body fat percentage, body mass index, and waist-to-hip ratio. We identified 35 age-related eCpGs associated with age. Of these, ten eCpGs were associated with at least one body fat phenotype. Collagen Type XI Alpha 2 Chain (COL11A2), Complement C1s (C1s), and four and a half LIM domains 2 (FHL2) genes were among the most significant genes with multiple eCpGs associated with both age and multiple body fat phenotypes. The COL11A2 gene contributes to the correct assembly of the extracellular matrix in maintaining the healthy structural arrangement of various components, with the C1s gene part of complement systems functioning in inflammation. Moreover, FHL2 expression was upregulated under hypermethylation in both blood and adipose tissue with aging. These results suggest new targets for future studies and require further validation to confirm the specific function of these genes on body fat regulation.

2.
Nutr Metab Cardiovasc Dis ; 31(5): 1556-1563, 2021 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-33810959

RESUMEN

BACKGROUND AND AIMS: Natural variation in body fat is explained by both genetic and environmental effects. Epigenetic mechanisms such as DNA methylation can mediate these effects causing changes in gene expression leading to onset of obesity. Studies of genetic isolates have the potential to provide new epigenetic insights with advantages such as reduced genetic diversity and environmental exposures. METHODS AND RESULTS: This was an exploratory study of genome-wide DNA methylation in relation to body fat traits in 47 healthy adults from the genetic isolate of Norfolk Island. Quantitative body fat traits (body fat percentage, body mass index, hip circumference, waist circumference, waist-hip-ratio and weight) were carefully measured. DNA methylation data was obtained from peripheral blood using Illumina 450K arrays. Multi-trait analysis was performed using Principal Component Analysis (PCA). CpG by trait association testing was performed using stepwise linear regressions. Two components were identified that explained approximately 89% of the phenotypic variance. In total, 5 differential methylated positions (DMPs) were identified at genome-wide significance (P≤ 2.4 × 10-7), which mapped to GOT2-CDH8, LYSMD3, HIBADH, ADGRD1 and EBF4 genes. Gene set enrichment analysis of 848 genes containing suggestive DMPs (P≤ 1.0 × 10-4) implicated the Cadherin (28 genes, Padj = 6.76 × 10-7) and Wnt signaling pathways (38 genes, Padj = 7.78 × 10-6). CONCLUSION: This study provides new insights into the epigenetically influenced genes and pathways underlying body fat variation in a healthy cohort and provides targets for consideration in future studies of obesity risk.


Asunto(s)
Adiposidad/genética , Metilación de ADN , Epigénesis Genética , Herencia Multifactorial , Adulto , Índice de Masa Corporal , Peso Corporal/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Melanesia , Persona de Mediana Edad , Análisis de Componente Principal , Circunferencia de la Cintura/genética , Relación Cintura-Estatura
3.
Mol Genet Genomics ; 295(3): 751-763, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32146541

RESUMEN

It is thought that despite highly variable phenotypic expression, 70-80% of all epileptic cases are caused by one or more genetic mutations. Next generation sequencing technologies, such as whole exome sequencing (WES), can be used in a diagnostic or research setting to identify genetic mutations which may have significant prognostic implications for patients and their families. In this study, 398 genes associated with epilepsy or recurrent seizures were stratified into tiers based on genotype-phenotype concordance, tissue gene expression, frequency of affected individuals with mutations and evidence from functional and family studies. WES was completed on 14 DNA samples (2 with known mutations in SCN1A and 12 with no known mutations) from individuals diagnosed with epilepsy using an Ion AmpliSeq approach. WES confirmed positive SCN1A mutations in two samples. In n = 5/12 samples (S-3 to -14) we identified potentially causative mutations across five different genes. S-5 was identified to have a novel missense mutation in CCM2; S-6 a novel frameshift mutation identified in ADGRV1; S-10 had a previously reported pathogenic mutation in PCDH19, whilst a novel missense mutation in PCDH19 was shown in S-12; and S-13 identified to have separate missense mutations in KCNA2 and NPRL3. The application of WES followed by a targeted variant prioritization approach allowed for the discovery of potentially causative mutations in our cohort of previously undiagnosed epilepsy patients.


Asunto(s)
Biomarcadores/análisis , Epilepsia/diagnóstico , Epilepsia/genética , Secuenciación del Exoma/métodos , Exoma/genética , Mutación , Adolescente , Adulto , Cadherinas/genética , Niño , Preescolar , Estudios de Cohortes , Femenino , Proteínas Activadoras de GTPasa/genética , Pruebas Genéticas/métodos , Humanos , Lactante , Canal de Potasio Kv.1.2/genética , Masculino , Pronóstico , Protocadherinas
4.
J Hum Genet ; 63(1): 83-87, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29215094

RESUMEN

Primary open-angle glaucoma (POAG) is influenced by both genetic and environmental factors. Despite significant progress in identifying genetic variants associated with POAG, there remains a substantial amount of unexplained heritability. Study design features that may enhance knowledge of the genetic architecture include focusing on multiple quantitative traits related to ocular disorders (i.e. endophenotypes), targeting genetic variants that directly influence gene expression (i.e. cis-eQTLs) and utilising genetically isolated populations to reduce genetic and environmental noise and thus enhance association signals. In this study we performed heritability and blood-based eQTL association analysis of five key POAG endophenotypes in 330 individuals from the Norfolk Island (NI) isolate. Results showed evidence of heritability for all five traits, with H2 estimates ranging from 0.35 for intraocular pressure (IOP) to 0.82 for central corneal thickness (CCT) (P < 0.05). The primary finding was for BTN3A2, whereby both cis-SNP and transcript were significantly associated with disc size within a conditional regression model. Specifically, this model included rs853676 (ß = 0.23,P = 0.008) and transcript (ß = 0.23, P = 0.03). We also observed a cis-SNP association between optic disc size and LPCAT2 independent of transcript (P = 0.0004). These genes have specific functions in immune system pathways and suggest a role for an inherited immune component of POAG risk. This study also demonstrates an alternate approach to understanding the functional genetic basis of POAG and ocular health more generally.


Asunto(s)
1-Acilglicerofosfocolina O-Aciltransferasa , Butirofilinas , Regulación de la Expresión Génica , Glaucoma de Ángulo Abierto , Disco Óptico , Polimorfismo de Nucleótido Simple , Carácter Cuantitativo Heredable , 1-Acilglicerofosfocolina O-Aciltransferasa/biosíntesis , 1-Acilglicerofosfocolina O-Aciltransferasa/genética , 1-Acilglicerofosfocolina O-Aciltransferasa/inmunología , Butirofilinas/biosíntesis , Butirofilinas/genética , Butirofilinas/inmunología , Femenino , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Glaucoma de Ángulo Abierto/genética , Glaucoma de Ángulo Abierto/inmunología , Glaucoma de Ángulo Abierto/metabolismo , Glaucoma de Ángulo Abierto/patología , Humanos , Masculino , Melanesia , Disco Óptico/inmunología , Disco Óptico/metabolismo , Disco Óptico/patología , Fenotipo
5.
PLoS Genet ; 11(10): e1005593, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26474483

RESUMEN

Multiphenotype genome-wide association studies (GWAS) may reveal pleiotropic genes, which would remain undetected using single phenotype analyses. Analysis of large pedigrees offers the added advantage of more accurately assessing trait heritability, which can help prioritise genetically influenced phenotypes for GWAS analysis. In this study we performed a principal component analysis (PCA), heritability (h2) estimation and pedigree-based GWAS of 37 cardiovascular disease -related phenotypes in 330 related individuals forming a large pedigree from the Norfolk Island genetic isolate. PCA revealed 13 components explaining >75% of the total variance. Nine components yielded statistically significant h2 values ranging from 0.22 to 0.54 (P<0.05). The most heritable component was loaded with 7 phenotypic measures reflecting metabolic and renal dysfunction. A GWAS of this composite phenotype revealed statistically significant associations for 3 adjacent SNPs on chromosome 1p22.2 (P<1x10-8). These SNPs form a 42kb haplotype block and explain 11% of the genetic variance for this renal function phenotype. Replication analysis of the tagging SNP (rs1396315) in an independent US cohort supports the association (P = 0.000011). Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05). Gene set enrichment analysis of these genes revealed the most enriched pathway was purine metabolism (P = 0.0015). Overall, our findings provide convincing evidence for a major pleiotropic effect locus on chromosome 1p22.2 influencing risk of renal dysfunction via purine metabolism pathways in the Norfolk Island population. Further studies are now warranted to interrogate the functional relevance of this locus in terms of renal pathology and cardiovascular disease risk.


Asunto(s)
Enfermedades Cardiovasculares/genética , Pleiotropía Genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedades Cardiovasculares/patología , Femenino , Haplotipos , Humanos , Masculino , Melanesia , Fenotipo , Polimorfismo de Nucleótido Simple , Análisis de Componente Principal
6.
Mol Vis ; 23: 660-665, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28966548

RESUMEN

PURPOSE: Primary open-angle glaucoma (POAG) refers to a group of heterogeneous diseases involving optic nerve damage. Two well-established risk factors for POAG are elevated intraocular pressure (IOP) and a thinner central corneal thickness (CCT). These endophenotypes exhibit a high degree of heritability across populations. Large-scale genome-wide association studies (GWASs) of outbred populations have robustly implicated several susceptibility gene variants for both IOP and CCT. Despite this progress, a substantial amount of genetic variance remains unexplained. Population-specific variants that might be rare in outbred populations may also influence POAG endophenotypes. The Norfolk Island population is a founder-effect genetic isolate that has been well characterized for POAG endophenotypes. This population is therefore a suitable candidate for mapping new variants that influence these complex traits. METHODS: Three hundred and thirty participants from the Norfolk Island Eye Study (NIES) core pedigree provided DNA. Ocular measurements of CCT and IOP were also taken for analysis. Heritability analyses and genome-wide linkage analyses of short tandem repeats (STRs) were conducted using SOLAR. Pedigree-based GWASs of single-nucleotide polymorphisms (SNPs) were performed using the GenABEL software. RESULTS: CCT was the most heritable endophenotype in this cohort (h2 = 0.77, p = 6×10-6), while IOP showed a heritability of 0.39 (p = 0.008). A genome-wide linkage analysis of these POAG phenotypes identified a maximum logarithm of the odds (LOD) score of 1.9 for CCT on chromosome 20 (p = 0.0016) and 1.3 for IOP on chromosome 15 (p = 0.0072). The GWAS results revealed a study-wise significant association for IOP at rs790357, which is located within DLG2 on chr11q14.1 (p = 1.02×10-7). DLG2 is involved in neuronal signaling and development, and while it has not previously been associated with IOP, it has been associated with myopia. An analysis of 12 known SNPs for IOP showed that rs12419342 in RAPSN on chromosome 11 was nominally associated in Norfolk Island (NI; p = 0.0021). For CCT, an analysis of 26 known SNPs showed rs9938149 in BANP-ZNF469 on chromosome 16 was nominally associated in NI (p = 0.002). CONCLUSIONS: These study results indicate that CCT and IOP exhibit a substantial degree of heritability in the NI pedigree, indicating a genetic component. A genome-wide linkage analysis of POAG endophenotypes did not reveal any major effect loci, but the GWASs did implicate several known loci, as well as a potential new locus in DLG2, suggesting a role for neuronal signaling in development in IOP and perhaps POAG. These results also highlight the need to target rarer variants via whole genome sequencing in this genetic isolate.


Asunto(s)
Endofenotipos , Efecto Fundador , Predisposición Genética a la Enfermedad , Glaucoma de Ángulo Abierto/genética , Polimorfismo de Nucleótido Simple , Adulto , Femenino , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje , Humanos , Presión Intraocular , Masculino , Melanesia , Linaje , Tonometría Ocular
7.
Am J Hum Genet ; 93(6): 1087-99, 2013 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-24314549

RESUMEN

Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10(-7)) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations.


Asunto(s)
Enfermedades Cardiovasculares/genética , Mapeo Cromosómico , Expresión Génica , Sitios de Carácter Cuantitativo , Enfermedades Cardiovasculares/metabolismo , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Melanesia , Fenotipo , Polimorfismo de Nucleótido Simple , Mapas de Interacción de Proteínas , Carácter Cuantitativo Heredable , Factores de Riesgo , Transcripción Genética
8.
Hum Genet ; 134(10): 1079-87, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26220684

RESUMEN

Migraine has been defined as a common disabling primary headache disorder. Epidemiology studies have provided with the undeniable evidence of genetic components as active players in the development of the disease under a polygenic model in which multiple risk alleles exert modest individual effects. Our objective was to test the contribution of a polygenic effect to migraine risk in the Norfolk Island population using a panel of SNPs reported to be disease associated in published migraine GWAS. We also investigated whether individual SNPs were associated with gene expression levels measured in whole blood. Polygenic scores were calculated in a total of 285 related individuals (74 cases, 211 controls) from the Norfolk Island using 51 SNPs previously reported to be associated with migraine in published GWAS. The association between polygenic score and migraine case-control status was tested using logistic regression. Results indicate that a migraine polygenic risk score was associated with migraine case-control status in this population (P = 0.016). This supports the hypothesis that multiple SNPs with weak effects collectively contribute to migraine risk in this population. Amongst the SNPs included in the polygenic model, four were associated with the expression of the USMG5 gene, including rs171251 (P = 0.012). Results from this study provide evidence for a polygenic contribution to migraine risk in an isolated population and highlight specific SNPs that regulate the expression of USMG5, a gene critical for mitochondrial function.


Asunto(s)
Trastornos Migrañosos/genética , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Melanesia , Sitios de Carácter Cuantitativo
9.
BMC Oral Health ; 15: 167, 2015 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-26715445

RESUMEN

BACKGROUND: Expenditure on dental and oral health services in Australia is $3.4 billion AUD annually. This is the sixth highest health cost and accounts for 7 % of total national health expenditure. Approximately 49 % of Australian children aged 6 years have caries experience in their deciduous teeth and this is rising. The aetiology of dental caries involves a complex interplay of individual, behavioural, social, economic, political and environmental conditions, and there is increasing interest in genetic predisposition and epigenetic modification. METHODS: The Oral Health Sub-study; a cross sectional study of a birth cohort began in November 2012 by examining mothers and their children who were six years old by the time of initiation of the study, which is ongoing. Data from detailed questionnaires of families from birth onwards and data on mothers' knowledge, attitudes and practices towards oral health collected at the time of clinical examination are used. Subjects' height, weight and mid-waist circumference are taken and Body Mass Index (BMI) computed, using an electronic Bio-Impedance balance. Dental caries experience is scored using the International Caries Detection and Assessment System (ICDAS). Saliva is collected for physiological measures. Salivary Deoxyribose Nucleic Acid (DNA) is extracted for genetic studies including epigenetics using the SeqCap Epi Enrichment Kit. Targets of interest are being confirmed by pyrosequencing to identify potential epigenetic markers of caries risk. DISCUSSION: This study will examine a wide range of potential determinants for childhood dental caries and evaluate inter-relationships amongst them. The findings will provide an evidence base to plan and implement improved preventive strategies.


Asunto(s)
Caries Dental/epidemiología , Caries Dental/genética , Epigénesis Genética , Australia , Niño , Estudios Transversales , Índice CPO , Femenino , Humanos , Madres , Salud Bucal , Factores de Riesgo
10.
Genes Chromosomes Cancer ; 52(5): 467-79, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23341091

RESUMEN

We employed a Hidden-Markov-Model (HMM) algorithm in loss of heterozygosity (LOH) analysis of high-density single nucleotide polymorphism (SNP) array data from Non-Hodgkin's lymphoma (NHL) entities, follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). This revealed a high frequency of LOH over the chromosomal region 11p11.2, containing the gene encoding the protein tyrosine phosphatase receptor type J (PTPRJ). Although PTPRJ regulates components of key survival pathways in B-cells (i.e., BCR, MAPK, and PI3K signaling), its role in B-cell development is poorly understood. LOH of PTPRJ has been described in several types of cancer but not in any hematological malignancy. Interestingly, FL cases with LOH exhibited down-regulation of PTPRJ, in contrast no significant variation of expression was shown in DLBCLs. In addition, sequence screening in Exons 5 and 13 of PTPRJ identified the G973A (rs2270993), T1054C (rs2270992), A1182C (rs1566734), and G2971C (rs4752904) coding SNPs (cSNPs). The A1182 allele was significantly more frequent in FLs and in NHLs with LOH. Significant over-representation of the C1054 (rs2270992) and the C2971 (rs4752904) alleles were also observed in LOH cases. A haplotype analysis also revealed a significant lower frequency of haplotype GTCG in NHL cases, but it was only detected in cases with retention. Conversely, haplotype GCAC was over-representated in cases with LOH. Altogether, these results indicate that the inactivation of PTPRJ may be a common lymphomagenic mechanism in these NHL subtypes and that haplotypes in PTPRJ gene may play a role in susceptibility to NHL, by affecting activation of PTPRJ in these B-cell lymphomas.


Asunto(s)
Genes Supresores de Tumor , Linfoma no Hodgkin/genética , Estudios de Casos y Controles , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Genoma Humano , Haplotipos , Humanos , Pérdida de Heterocigocidad , Linfoma no Hodgkin/enzimología , Cadenas de Markov , Repeticiones de Microsatélite , Modelos Genéticos , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/genética , Análisis de Secuencia de ADN/métodos
11.
Mol Genet Genomic Med ; 12(1): e2285, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37740604

RESUMEN

BACKGROUND: Beta thalassemia, related to HBB mutation and associated with elevated hemoglobin A2 (HbA2), is an important genetic hemoglobinopathy with high incidences of disease and carrier rates in Singapore. Carrier screening is essential to facilitate prenatal counseling and testing. However, when individuals with elevated HbA2 do not have an identifiable HBB disease-associated variant, there is ambiguity on risk to their offspring. METHODS: We describe a case report of a proband with elevated HbA2, no identifiable HBB disease-associated variant, whose partner was a beta thalassemia carrier. Through clinical HBB gene sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis, as well as targeted Nanopore long read sequencing of selected genes, we performed a complete analysis of HBB including the promoter region, 5'UTR and coding gene sequence, as well as evaluation for potential modifier variants and other rare structural variants. RESULTS: This process identified that the proband was heterozygous for KLF1:c.544T>C (p.Phe182Leu), a potential functional polymorphism previously known to be associated with benign elevated HbA2 levels. The presence of disease variants in the HBB locus was excluded. CONCLUSION: This finding provided clarity and enabled family planning for the proband and her family.


Asunto(s)
Talasemia alfa , Talasemia beta , Humanos , Embarazo , Femenino , Talasemia beta/diagnóstico , Talasemia beta/genética , Asesoramiento Genético , Mutación , Talasemia alfa/genética , Heterocigoto
12.
Acta Neuropathol Commun ; 12(1): 51, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38576030

RESUMEN

DNA methylation analysis based on supervised machine learning algorithms with static reference data, allowing diagnostic tumour typing with unprecedented precision, has quickly become a new standard of care. Whereas genome-wide diagnostic methylation profiling is mostly performed on microarrays, an increasing number of institutions additionally employ nanopore sequencing as a faster alternative. In addition, methylation-specific parallel sequencing can generate methylation and genomic copy number data. Given these diverse approaches to methylation profiling, to date, there is no single tool that allows (1) classification and interpretation of microarray, nanopore and parallel sequencing data, (2) direct control of nanopore sequencers, and (3) the integration of microarray-based methylation reference data. Furthermore, no software capable of entirely running in routine diagnostic laboratory environments lacking high-performance computing and network infrastructure exists. To overcome these shortcomings, we present EpiDiP/NanoDiP as an open-source DNA methylation and copy number profiling suite, which has been benchmarked against an established supervised machine learning approach using in-house routine diagnostics data obtained between 2019 and 2021. Running locally on portable, cost- and energy-saving system-on-chip as well as gpGPU-augmented edge computing devices, NanoDiP works in offline mode, ensuring data privacy. It does not require the rigid training data annotation of supervised approaches. Furthermore, NanoDiP is the core of our public, free-of-charge EpiDiP web service which enables comparative methylation data analysis against an extensive reference data collection. We envision this versatile platform as a useful resource not only for neuropathologists and surgical pathologists but also for the tumour epigenetics research community. In daily diagnostic routine, analysis of native, unfixed biopsies by NanoDiP delivers molecular tumour classification in an intraoperative time frame.


Asunto(s)
Epigenómica , Neoplasias , Humanos , Aprendizaje Automático no Supervisado , Nube Computacional , Neoplasias/diagnóstico , Neoplasias/genética , Metilación de ADN
13.
Cephalalgia ; 33(14): 1139-47, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23674830

RESUMEN

BACKGROUND: Oestrogen receptor 1 ( ESR1) is located in region 6q25.1 and encodes a ligand-activated transcription factor composed of several domains important for hormone binding and transcription activation. Progesterone receptor ( PGR) is located in 11q22-23 and mediates the role of progesterone interacting with different transcriptional co-regulators. ESR1 and PGR have previously been implicated in migraine susceptibility. Here, we report the results of an association study of these genes in a migraine pedigree from the genetic isolate of Norfolk Island, a population descended from a small number of Isle of Man "Bounty Mutineer" and Tahitian founders. METHODS: A significant number of molecular markers in the ESR1 (143) and PGR (43) genes were evaluated in a sample of 285 related individuals (135 males; 150 females). A pedigree-based analysis in the GenABEL package was used to analyse the results. RESULTS AND CONCLUSIONS: A total of 10 markers in the ESR1 gene showed association with migraine ( P < 0.05) in the Norfolk Island population. No association was detected with PGR . Three haplotypes in ESR1 were found to be associated with migraine ( P = 0.004, 0.03, 0.005). Future genetic studies in larger populations and expression analysis are required to clarify the role of ESR1 in migraine susceptibility.


Asunto(s)
Receptor alfa de Estrógeno/genética , Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad/genética , Trastornos Migrañosos/genética , Polimorfismo Genético/genética , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Haplotipos/genética , Humanos , Masculino , Melanesia/epidemiología , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/epidemiología , Linaje
14.
Twin Res Hum Genet ; 16(6): 1079-86, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24054031

RESUMEN

Migraine is classified by the World Health Organization (WHO) as being one of the top 20 most debilitating diseases. According to the neurovascular hypothesis, neuroinflammation may promote the activation and sensitisation of meningeal nociceptors, inducing the persistent throbbing headache characterized in migraine. The tumor necrosis factor (TNF) gene cluster, made up of TNFα, lymphotoxin α (LTA), and lymphotoxin ß (LTB), has been implicated to influence the intensity and duration of local inflammation. It is thought that sterile inflammation mediated by LTA, LTB, and TNFα contributes to threshold brain excitability, propagation of neuronal hyperexcitability and thus initiation and maintenance of a migraine attack. Previous studies have investigated variants within the TNF gene cluster region in relation to migraine susceptibility, with largely conflicting results. The aim of this study was to expand on previous research and utilize a large case-control cohort and range of variants within the TNF gene cluster to investigate the role of the TNF gene cluster in migraine. Nine single nucleotide polymorphisms (SNPs) were selected for investigation as follows: rs1800683, rs2229094, rs2009658, rs2071590, rs2239704, rs909253, rs1800630, rs1800629, and rs3093664. No significant association with migraine susceptibility was found for any of the SNPs tested, with further testing according to migraine subtype and gender also showing no association for disease risk. Haplotype analysis showed that none of the tested haplotypes were significantly associated with migraine.


Asunto(s)
Citocinas/genética , Predisposición Genética a la Enfermedad , Mediadores de Inflamación/metabolismo , Linfotoxina-alfa/genética , Trastornos Migrañosos/genética , Polimorfismo de Nucleótido Simple/genética , Factor de Necrosis Tumoral alfa/genética , Estudios de Casos y Controles , Femenino , Humanos , Masculino
15.
J Forensic Sci ; 67(5): 1766-1775, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35855536

RESUMEN

Sanger sequencing of the mitochondrial DNA (mtDNA) control region was previously the only method available for forensic casework involving degraded samples from skeletal remains. The introduction of Next Generation Sequencing (NGS) has transformed genetic data generation and human identification using mtDNA. Whole mitochondrial genome (mtGenome) analysis is now being introduced into forensic laboratories around the world to analyze historical remains. Research into large pedigrees using the mtGenome is critical to evaluate currently available interpretation guidelines for mtDNA analysis, which were developed for comparisons using the control region. This study included mtGenomes from 225 individuals from the last four generations of the Norfolk Island (NI) genetic isolate pedigree consisting of 49 distinct maternal lineages. The data from these individuals were arranged into 2339 maternally related pairs separated by up to 18 meioses. Our results show that 97.3% of maternally related pairs were concordant at all nucleotide positions, resulting in the correct interpretation of "Cannot Exclude"; 2.7% of pairs produced an "Inconclusive" result, and there were no instances of false exclusion. While these results indicate that existing guidelines are suitable for multigenerational whole mtGenome analysis, we recommend caution be taken when classifying heteroplasmic changes as differences for human identification. Our data showed the classification of heteroplasmic changes as differences increases the prevalence of inconclusive identification by 6%, with false exclusions observed in 0.34% of pairs examined. Further studies of multigenerational pedigrees, however, are needed to validate mtGenome interpretation guidelines for historical case work to more fully utilize emerging advancements.


Asunto(s)
Genoma Mitocondrial , ADN Mitocondrial/análisis , ADN Mitocondrial/genética , Genética Forense/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Análisis de Secuencia de ADN/métodos
16.
Genes (Basel) ; 13(1)2021 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-35052430

RESUMEN

Conventional genome-wide association studies (GWASs) of complex traits, such as Multiple Sclerosis (MS), are reliant on per-SNP p-values and are therefore heavily burdened by multiple testing correction. Thus, in order to detect more subtle alterations, ever increasing sample sizes are required, while ignoring potentially valuable information that is readily available in existing datasets. To overcome this, we used penalised regression incorporating elastic net with a stability selection method by iterative subsampling to detect the potential interaction of loci with MS risk. Through re-analysis of the ANZgene dataset (1617 cases and 1988 controls) and an IMSGC dataset as a replication cohort (1313 cases and 1458 controls), we identified new association signals for MS predisposition, including SNPs above and below conventional significance thresholds while targeting two natural killer receptor loci and the well-established HLA loci. For example, rs2844482 (98.1% iterations), otherwise ignored by conventional statistics (p = 0.673) in the same dataset, was independently strongly associated with MS in another GWAS that required more than 40 times the number of cases (~45 K). Further comparison of our hits to those present in a large-scale meta-analysis, confirmed that the majority of SNPs identified by the elastic net model reached conventional statistical GWAS thresholds (p < 5 × 10-8) in this much larger dataset. Moreover, we found that gene variants involved in oxidative stress, in addition to innate immunity, were associated with MS. Overall, this study highlights the benefit of using more advanced statistical methods to (re-)analyse subtle genetic variation among loci that have a biological basis for their contribution to disease risk.


Asunto(s)
Antígenos HLA/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Receptores de Células Asesinas Naturales/genética , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Esclerosis Múltiple/patología , Análisis de Regresión
17.
Sci Rep ; 11(1): 19425, 2021 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-34593906

RESUMEN

Chronic kidney disease (CKD) is a persistent impairment of kidney function. Genome-wide association studies (GWAS) have revealed multiple genetic loci associated with CKD susceptibility but the complete genetic basis is not yet clear. Since CKD shares risk factors with cardiovascular diseases and diabetes, there may be pleiotropic loci at play but may go undetected when using single phenotype GWAS. Here, we used multi-phenotype GWAS in the Norfolk Island isolate (n = 380) to identify new loci associated with CKD. We performed a principal components analysis on different combinations of 29 quantitative traits to extract principal components (PCs) representative of multiple correlated phenotypes. GWAS of a PC derived from glomerular filtration rate, serum creatinine, and serum urea identified a suggestive peak (pmin = 1.67 × 10-7) that mapped to KCNIP4. Inclusion of other secondary CKD measurements with these three kidney function traits identified the KCNIP4 locus with GWAS significance (pmin = 1.59 × 10-9). Finally, we identified a group of two SNPs with increased minor allele frequencies as potential functional variants. With the use of genetic isolate and the PCA-based multi-phenotype GWAS approach, we have revealed a potential pleotropic effect locus for CKD. Further studies are required to assess functional relevance of this locus.


Asunto(s)
Insuficiencia Renal Crónica , Adulto , Femenino , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Melanesia , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genética , Factores de Riesgo
18.
PLoS One ; 15(11): e0241367, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33147241

RESUMEN

Epigenetics plays a fundamental role in cellular development and differentiation; epigenetic mechanisms, such as DNA methylation, are involved in gene regulation and the exquisite nuance of expression changes seen in the journey from pluripotency to final differentiation. Thus, DNA methylation as a marker of cell identify has the potential to reveal new insights into cell biology. We mined publicly available DNA methylation data with a machine-learning approach to identify differentially methylated loci between different white blood cell types. We then interrogated the DNA methylation and mRNA expression of candidate loci in CD4+, CD8+, CD14+, CD19+ and CD56+ fractions from 12 additional, independent healthy individuals (6 male, 6 female). 'Classic' immune cell markers such as CD8 and CD19 showed expected methylation/expression associations fitting with established dogma that hypermethylation is associated with the repression of gene expression. We also observed large differential methylation at loci which are not established immune cell markers; some of these loci showed inverse correlations between methylation and mRNA expression (such as PARK2, DCP2). Furthermore, we validated these observations further in publicly available DNA methylation and RNA sequencing datasets. Our results highlight the value of mining publicly available data, the utility of DNA methylation as a discriminatory marker and the potential value of DNA methylation to provide additional insights into cell biology and developmental processes.


Asunto(s)
Metilación de ADN/genética , Leucocitos Mononucleares/metabolismo , Adulto , Biomarcadores/metabolismo , Islas de CpG/genética , Epigénesis Genética , Femenino , Humanos , Masculino , Anotación de Secuencia Molecular , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados
19.
Transl Psychiatry ; 10(1): 114, 2020 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-32321915

RESUMEN

Cannabis use is of increasing public health interest globally. Here we examined the effect of heavy cannabis use, with and without tobacco, on genome-wide DNA methylation in a longitudinal birth cohort (Christchurch Health and Development Study, CHDS). A total of 48 heavy cannabis users were selected from the CHDS cohort, on the basis of their adult exposure to cannabis and tobacco, and DNA methylation assessed from whole blood samples, collected at approximately age 28. Methylation in heavy cannabis users was assessed, relative to non-users (n = 48 controls) via the Illumina Infinium® MethylationEPIC BeadChip. We found the most differentially methylated sites in cannabis with tobacco users were in the AHRR and F2RL3 genes, replicating previous studies on the effects of tobacco. Cannabis-only users had no evidence of differential methylation in these genes, or at any other loci at the epigenome-wide significance level (P < 10-7). However, there were 521 sites differentially methylated at P < 0.001 which were enriched for genes involved in neuronal signalling (glutamatergic synapse and long-term potentiation) and cardiomyopathy. Further, the most differentially methylated loci were associated with genes with reported roles in brain function (e.g. TMEM190, MUC3L, CDC20 and SP9). We conclude that the effects of cannabis use on the mature human blood methylome differ from, and are less pronounced than, the effects of tobacco use, and that larger sample sizes are required to investigate this further.


Asunto(s)
Cannabis , Adulto , Islas de CpG , Metilación de ADN , Epigénesis Genética , Estudio de Asociación del Genoma Completo , Humanos , Nueva Zelanda
20.
Obesity (Silver Spring) ; 28(3): 570-580, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32090515

RESUMEN

OBJECTIVE: Adipose tissue plays a key role in obesity-related metabolic dysfunction. MicroRNA (miRNA) are gene regulatory molecules involved in intercellular and inter-organ communication. It was hypothesized that miRNA levels in adipose tissue would change after gastric bypass surgery and that this would provide insights into their role in obesity-induced metabolic dysregulation. METHODS: miRNA profiling (Affymetrix GeneChip miRNA 2.0 Array) of omental and subcutaneous adipose (n = 15 females) before and after gastric bypass surgery was performed. RESULTS: One omental and thirteen subcutaneous adipose miRNAs were significantly differentially expressed after gastric bypass, including downregulation of miR-223-3p and its antisense relative miR-223-5p in both adipose tissues. mRNA levels of miR-223-3p targets NLRP3 and GLUT4 were decreased and increased, respectively, following gastric bypass in both adipose tissues. Significantly more NLRP3 protein was observed in omental adipose after gastric bypass (P = 0.02). Significant hypomethlyation of NLRP3 and hypermethylation of miR-223 were observed in both adipose tissues after gastric bypass. In subcutaneous adipose, significant correlations were observed between both miR-223-3p and miR-223-5p and glucose and between NLRP3 mRNA and protein levels and blood lipids. CONCLUSIONS: This is the first report detailing genome-wide miRNA profiling of omental adipose before and after gastric bypass, and it further highlights the association of miR-223-3p and the NLRP3 inflammasome with obesity.


Asunto(s)
Inflamasomas/metabolismo , MicroARNs/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Obesidad/genética , Pérdida de Peso/genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo
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