RESUMEN
Both genetic and environmental factors contribute to the aetiology of multiple sclerosis (MS). More than 50 genomic regions have been associated with MS susceptibility and vitamin D status also influences the risk of this complex disease. However, how these factors interact in disease causation is unclear. We aimed to investigate the relationship between vitamin D receptor (VDR) binding in lymphoblastoid cell lines (LCLs), chromatin states in LCLs and MS-associated genomic regions. Using the Genomic Hyperbrowser, we found that VDR-binding regions overlapped with active regulatory regions [active promoter (AP) and strong enhancer (SE)] in LCLs more than expected by chance [45.3-fold enrichment for SE (P < 2.0e-05) and 63.41-fold enrichment for AP (P < 2.0e-05)]. Approximately 77% of VDR regions were covered by either AP or SE elements. The overlap between VDR binding and regulatory elements was significantly greater in LCLs than in non-immune cells (P < 2.0e-05). VDR binding also occurred within MS regions more than expected by chance (3.7-fold enrichment, P < 2.0e-05). Furthermore, regions of joint overlap SE-VDR and AP-VDR were even more enriched within MS regions and near to several disease-associated genes. These findings provide relevant insights into how vitamin D influences the immune system and the risk of MS through VDR interactions with the chromatin state inside MS regions. Furthermore, the data provide additional evidence for an important role played by B cells in MS. Further analyses in other immune cell types and functional studies are warranted to fully elucidate the role of vitamin D in the immune system.
Asunto(s)
Cromatina/metabolismo , Esclerosis Múltiple/genética , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Linfocitos B/citología , Emparejamiento Base , Línea Celular , Elementos de Facilitación Genéticos , Genoma Humano , Humanos , Regiones Promotoras Genéticas , Sitio de Iniciación de la TranscripciónRESUMEN
Initially thought to play a restricted role in calcium homeostasis, the pleiotropic actions of vitamin D in biology and their clinical significance are only now becoming apparent. However, the mode of action of vitamin D, through its cognate nuclear vitamin D receptor (VDR), and its contribution to diverse disorders, remain poorly understood. We determined VDR binding throughout the human genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). After calcitriol stimulation, we identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D. VDR binding sites were significantly enriched near autoimmune and cancer associated genes identified from genome-wide association (GWA) studies. Notable genes with VDR binding included IRF8, associated with MS, and PTPN2 associated with Crohn's disease and T1D. Furthermore, a number of single nucleotide polymorphism associations from GWA were located directly within VDR binding intervals, for example, rs13385731 associated with SLE and rs947474 associated with T1D. We also observed significant enrichment of VDR intervals within regions of positive selection among individuals of Asian and European descent. ChIP-seq determination of transcription factor binding, in combination with GWA data, provides a powerful approach to further understanding the molecular bases of complex diseases.
Asunto(s)
Enfermedades Autoinmunes/genética , Inmunoprecipitación de Cromatina , Evolución Molecular , Estudio de Asociación del Genoma Completo , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Sitios de Unión , Enfermedad de Crohn/genética , Diabetes Mellitus Tipo 1/genética , Humanos , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Esclerosis Múltiple/genética , Unión Proteica , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 2/metabolismo , Análisis de Secuencia de ADN/métodosRESUMEN
Several lines of evidence support a role for Epstein-Barr virus (EBV) in the aetiology of multiple sclerosis (MS). This includes the observation that nearly all MS patients show serological markers of past EBV infection. Given the well-known association between MS prevalence and latitude, we investigated whether EBV seropositivity also increases with distance from the equator. We found that the proportion of EBV positive individuals is positively associated with latitude independently of MS status (odds ratio = 1.06, 95% CI = 1.02-1.09, p = 0.002). Latitude-related factors may be implicated in the immune response to EBV and its role in MS aetiology.
Asunto(s)
Infecciones por Virus de Epstein-Barr/epidemiología , Geografía , Herpesvirus Humano 4/patogenicidad , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/virología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Humanos , Esclerosis Múltiple/etiologíaRESUMEN
Genetic-epidemiological studies on monozygotic (MZ) twins have been used for decades to tease out the relative contributions of genes and the environment to a trait. Phenotypic discordance in MZ twins has traditionally been ascribed to non-shared environmental factors acting after birth, however recent data indicate that this explanation is far too simple. In this paper, we review other reasons for discordance, including differences in the in utero environment, genetic mosaicism, and stochastic factors, focusing particularly on epigenetic discordance. Epigenetic differences are gaining increasing recognition. Although it is clear that in specific cases epigenetic alterations provide a causal factor in disease etiology, the overall significance of epigenetics in twin discordance remains unclear. It is also challenging to determine the causality and relative contributions of environmental, genetic, and stochastic factors to epigenetic variability. Epigenomic profiling studies have recently shed more light on the dynamics of temporal methylation change and methylome heritability, yet have not given a definite answer regarding their relevance to disease, because of limitations in establishing causality. Here, we explore the subject of epigenetics as another component in human phenotypic variability and its links to disease focusing particularly on evidence from MZ twin studies.
Asunto(s)
Epigénesis Genética , Interacción Gen-Ambiente , Gemelos Monocigóticos/genética , Metilación de ADN , Enfermedades en Gemelos/genética , Feto , Humanos , Procesos EstocásticosRESUMEN
BACKGROUND: A season of birth effect in immune-mediated diseases (ID) such as multiple sclerosis and type 1 diabetes has been consistently reported. We aimed to investigate whether season of birth influences the risk of rheumatoid arthritis, Crohn's disease, ulcerative colitis and systemic lupus erythematosus in addition to multiple sclerosis, and to explore the correlation between the risk of ID and predicted ultraviolet B (UVB) light exposure and vitamin D status during gestation. METHODS: The monthly distribution of births of patients with ID from the UK (n = 115,172) was compared to that of the general population using the Cosinor test. Predicted UVB radiation and vitamin D status in different time windows during pregnancy were calculated for each month of birth and correlated with risk of ID using the Spearman's correlation coefficient. RESULTS: The distributions of ID births significantly differed from that of the general population (P = 5e-12) with a peak in April (odds ratio = 1.045, 95% confidence interval = 1.024, 1.067, P < 0.0001) and a trough in October (odds ratio = 0.945, 95% confidence interval = 0.925, 0.966, P < 0.0001). Stratification by disease subtype showed seasonality in all ID but Crohn's disease. The risk of ID was inversely correlated with predicted second trimester UVB exposure (Spearman's rho = -0.49, P = 0.00005) and third trimester vitamin D status (Spearman's rho = -0.44, P = 0.0003). CONCLUSIONS: The risk of different ID in the UK is significantly influenced by the season of birth, suggesting the presence of a shared seasonal risk factor or factors predisposing to ID. Gestational UVB and vitamin D exposure may be implicated in the aetiology of ID.
Asunto(s)
Enfermedades Autoinmunes/epidemiología , Estaciones del Año , Vitamina D/sangre , Adulto , Enfermedades Autoinmunes/sangre , Estudios de Casos y Controles , Colitis Ulcerosa/sangre , Colitis Ulcerosa/epidemiología , Enfermedad de Crohn/sangre , Enfermedad de Crohn/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/epidemiología , Oportunidad Relativa , Factores de Riesgo , Luz Solar , Rayos UltravioletaRESUMEN
OBJECTIVE: Multiple sclerosis (MS) is a complex neurological disease. Genetic linkage analysis and genotyping of candidate genes in families with 4 or more affected individuals more heavily loaded for susceptibility genes has not fully explained familial disease clustering. METHODS: We performed whole exome sequencing to further understand the heightened prevalence of MS in these families. RESULTS: Forty-three individuals with MS (1 from each family) were sequenced to find rare variants in candidate MS susceptibility genes. On average, >58,000 variants were identified in each individual. A rare variant in the CYP27B1 gene causing complete loss of gene function was identified in 1 individual. Homozygosity for this mutation results in vitamin D-dependent rickets I (VDDR1), whereas heterozygosity results in lower calcitriol levels. This variant showed significant heterozygous association in 3,046 parent-affected child trios (p = 1 × 10(-5)). Further genotyping in >12,500 individuals showed that other rare loss of function CYP27B1 variants also conferred significant risk of MS, Peto odds ratio = 4.7 (95% confidence interval, 2.3-9.4; p = 5 × 10(-7)). Four known VDDR1 mutations were identified, all overtransmitted. Heterozygous parents transmitted these alleles to MS offspring 35 of 35× (p = 3 × 10(-9)). INTERPRETATION: A causative role for CYP27B1 in MS is supported; the mutations identified are known to alter function having been shown in vivo to result in rickets when 2 copies are present. CYP27B1 encodes the vitamin D-activating 1-alpha hydroxylase enzyme, and thus a role for vitamin D in MS pathogenesis is strongly implicated.
Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Mutación/genética , Edad de Inicio , Estudios de Cohortes , Exoma/genética , Salud de la Familia , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Ligamiento Genético , Genotipo , Humanos , Masculino , Esclerosis Múltiple/complicaciones , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/genéticaRESUMEN
INTRODUCTION: Most analyses of blood DNA in sporadic neuromuscular disorders have been inconclusive. This may be because some genetic variants occur only in brain tissue. We therefore looked for copy number variants (CNVs) in both blood and brain in patients with sporadic amyotrophic lateral sclerosis (SALS). METHODS: Genome-wide CNVs were compared in blood and brain from 32 SALS patients and from 26 normal (control) brains, using Affymetrix 6.0 arrays. RESULTS: There were 410 CNVs present in brain but not blood (somatic CNVs) in 94% of the patients (median 8 CNVs per patient). Twenty-four of the somatic CNVs were rare, were not found in control brains, and overlapped with genes. CONCLUSIONS: Brain-specific CNVs may be common and appear to be present in a proportion of patients with SALS. The more detailed copy number analysis that is becoming available with massively parallel sequencing may uncover brain-specific CNVs that underlie some cases of SALS.
Asunto(s)
Esclerosis Amiotrófica Lateral , Sangre/metabolismo , Encéfalo/metabolismo , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Femenino , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos/métodosRESUMEN
Genetic variants may underlie sporadic amyotrophic lateral sclerosis (SALS), but in only a few percent of patients have causative mutations been found. This is possibly because SALS is more often due to a variation in DNA methylation, an epigenetic phenomenon involved in gene silencing. Methylation across the whole genome was examined in brain DNA of 10 SALS patients and 10 neurologically-normal controls. Methylated DNA was immunoprecipitated and interrogated by Affymetrix GeneChip Human Tiling 2.0R Arrays. Methylation levels were compared between SALS patients and controls at each region of methylation across the genome. SALS patients had either hypo- or hyper-methylation at 38 methylation sites (p = 0.01). Of these, 23 were associated with genes and three with CpG islands. Pathway analysis showed that genes with different methylation in SALS were particularly involved in calcium homeostasis, neurotransmission and oxidative stress. In conclusion, a number of genes, either unsuspected in SALS or in potential cell death pathways, showed altered methylation in SALS brains. The possibility of epigenetic therapy for SALS should encourage confirmation of these initial results in a future larger whole-genome DNA methylation study.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Encéfalo/fisiología , Metilación de ADN , Genoma Humano , Estudio de Asociación del Genoma Completo , Anciano , Islas de CpG , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras GenéticasRESUMEN
Mutations in the superoxide dismutase 1 gene (SOD1) are associated with familial ALS but the role of SOD1 in sporadic ALS (SALS) is unclear. We therefore sequenced the entire SOD1 gene in 23 patients with SALS. DNA was extracted from frozen pre-frontal cerebral cortex and from blood. The 5 exons, 4 introns and 1 kb upstream and downstream of SOD1 were sequenced. Novel genetic variants were found in 30% (7 of 23) brains and known variants in 91% (21 of 23) brains from patients with SALS. Two novel variants found in SALS patients and not controls were located in the SOD1 promoter and intron 1, with the promoter variant having potential functional implications. A previously described silent variant in exon 5 in one SALS patient appears to abolish an exonic splicing enhancer. All changes found in brain DNA were also found in blood DNA. In conclusion, sequencing the entire SOD1 gene revealed 3 variants in SALS patients that were not detected in controls. Although no unequivocal mutations were found, some of these variants have potential consequences for SALS pathogenesis.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Variación Genética , Superóxido Dismutasa/genética , Anciano , Esclerosis Amiotrófica Lateral/patología , Exones/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Corteza Prefrontal/metabolismo , Regiones Promotoras Genéticas/genética , Análisis de Secuencia de ADN/métodos , Superóxido Dismutasa/sangre , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1Asunto(s)
Epigénesis Genética/inmunología , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/patología , Complicaciones del Embarazo/inmunología , Deficiencia de Vitamina D/inmunología , Animales , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Femenino , Humanos , Ratones , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Embarazo , Complicaciones del Embarazo/genética , Complicaciones del Embarazo/patología , Deficiencia de Vitamina D/genética , Deficiencia de Vitamina D/patologíaRESUMEN
Sporadic amyotrophic lateral sclerosis (SALS) causes progressive muscle weakness because of the loss of motor neurons. SALS has been associated with exposure to environmental toxins, including pesticides and chemical warfare agents, many of which are organophosphates. The enzyme paraoxonase 1 (PON1) detoxifies organophosphates and the efficacy of this enzyme varies with polymorphisms in the PON1 gene. To determine if an impaired ability to break down organophosphates underlies some cases of SALS, we compared the frequencies of PON1 polymorphisms in SALS patients and controls and investigated gene-environment interactions with self-reported pesticide/herbicide exposure. The PON1 coding polymorphisms L55M, Q192R and I102V, and the promoter polymorphisms -909c>g, -832g>a, -162g>a and -108c>t, were genotyped in 143 SALS patients and 143 matched controls. Statistical comparisons were carried out at allele, genotype and haplotype levels. The PON1 promoter allele -108t, which reduces PON1 expression, was strongly associated with SALS. Overall, promoter haplotypes that decrease PON1 expression were associated with SALS, whereas haplotypes that increase expression were associated with controls. Coding polymorphisms did not correlate with SALS. Gene-environment interactions were identified at the allele level for some promoter SNPs and pesticide/herbicide exposure, but not at the genotype or haplotype level. In conclusion, some PON1 promoter polymorphisms may predispose to SALS, possibly by making motor neurons more susceptible to organophosphate-containing toxins.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Arildialquilfosfatasa/genética , Contaminantes Ambientales/toxicidad , Plaguicidas/toxicidad , Anciano , Alelos , Ambiente , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Organofosfatos/toxicidad , Polimorfismo Genético/efectos de los fármacos , Polimorfismo de Nucleótido SimpleRESUMEN
Sporadic amyotrophic lateral sclerosis (SALS) results from the death of motor neurons in the brain and spinal cord. Environmental exposure to heavy metals has been implicated in SALS and impaired detoxification of these metals may cause susceptibility to the disease. The metallothionein (MT) family of proteins are the primary detoxification mechanism for heavy metals and MT-Ia and MT-IIa are the most common human isoforms. Inappropriate methylation at the promoters of these genes could lead to silencing of transcription and reduce the availability of MTs. We therefore measured the level of methylation in the promoters of MT-Ia and MT-IIa in 25 leukocyte and six brain DNA samples from SALS patients and compared these with controls. No promoter methylation was evident in any SALS or control samples. In conclusion, it is unlikely that methylation at these gene promoters is a common cause of SALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Metalotioneína/genética , Encéfalo/metabolismo , Islas de CpG/genética , Metilación de ADN , Femenino , Silenciador del Gen , Humanos , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas/genéticaRESUMEN
Sporadic Parkinson's disease (PD) is thought to have a major genetic component, but the variants involved remain mostly unknown. One possible reason for the difficulty in finding mutations underlying PD is that rare predominantly brain-situated somatic mutations underlie the disease; these mutations would be missed by analysing blood DNA only. To test the feasibility of looking for somatic mutations in PD brain tissue, we compared copy number variants (CNVs) between 8 PD and 26 control brains using Affymetrix 6.0 arrays. The median number of CNVs per brain, and the overall proportion of amplifications and deletions, were similar in PD and control brains. In 7 of the 8 PD brains, however, a total of 45 CNVs were found that were not present in control brains. Twelve of these CNVs overlapped with one or more genes, some of which are involved in pathways suspected in the pathogenesis of PD, or are rare. This study shows that PD brain CNVs can be detected, and raises the possibility that brain-situated mutations could underlie some cases of PD. A method of undertaking a definitive study of brain somatic mutations in PD, using massively parallel sequencing and multiple tissues, is suggested.
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Encéfalo/patología , Variaciones en el Número de Copia de ADN , Mutación , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Multiple sclerosis (MS) is a highly debilitating immune mediated disorder of the central nervous system and represents a substantial burden to the developed world. Despite the recent advances in MS research, which risk factors are implicated and how they contribute to MS pathogenesis is largely unknown. However, in line with older studies investigating the genetic and geographical epidemiology of this complex disease, more recent studies have highlighted how MS arises from a combination of genetic susceptibility and environmental exposures acting from gestation to early adulthood. Vitamin D deficiency, season of birth, Epstein Barr virus infection, and smoking behaviour are strongly implicated and able to influence genetic predisposition to MS. Furthermore, these factors appear to act synergistically and the risk of MS in individuals exposed to more than one factor combines multiplicatively. Current evidence suggests that a large part of MS could be prevented and understanding how and when during life risk factors act will ultimately aid the development of prevention strategies.
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Esclerosis Múltiple/epidemiología , Adolescente , Adulto , Niño , Infecciones por Virus de Epstein-Barr/fisiopatología , Predisposición Genética a la Enfermedad , Humanos , Esclerosis Múltiple/etiología , Esclerosis Múltiple/genética , Esclerosis Múltiple/prevención & control , Factores de Riesgo , Estaciones del Año , Fumar/efectos adversos , Deficiencia de Vitamina D/fisiopatologíaRESUMEN
More than 50 genomic regions have now been shown to influence the risk of multiple sclerosis (MS). However, the mechanisms of action, and the cell types in which these associated variants act at the molecular level remain largely unknown. This is especially true for associated regions containing no known genes. Given the evidence for a role for B cells in MS, we hypothesized that MS associated genomic regions co-localized with regions which are functionally active in B cells. We used publicly available data on 1) MS associated regions and single nucleotide polymorphisms (SNPs) and 2) chromatin profiling in B cells as well as three additional cell types thought to be unrelated to MS (hepatocytes, fibroblasts and keratinocytes). Genomic intervals and SNPs were tested for overlap using the Genomic Hyperbrowser. We found that MS associated regions are significantly enriched in strong enhancer, active promoter and strong transcribed regions (pâ=â0.00005) and that this overlap is significantly higher in B cells than control cells. In addition, MS associated SNPs also land in active promoter (pâ=â0.00005) and enhancer regions more than expected by chance (strong enhancer pâ=â0.0006; weak enhancer pâ=â0.00005). These results confirm the important role of the immune system and specifically B cells in MS and suggest that MS risk variants exert a gene regulatory role. Previous studies assessing MS risk variants in T cells may be missing important effects in B cells. Similar analyses in other immunological cell types relevant to MS and functional studies are necessary to fully elucidate how genes contribute to MS pathogenesis.
Asunto(s)
Linfocitos B/metabolismo , Esclerosis Múltiple/genética , Línea Celular , Línea Celular Tumoral , Células Cultivadas , Cromatina/metabolismo , Inmunoprecipitación de Cromatina , Elementos de Facilitación Genéticos , Variación Genética , Genética , Genómica , Humanos , Sistema Inmunológico , Modelos Genéticos , Método de Montecarlo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Transcripción GenéticaRESUMEN
There is general consensus that season of birth influences the risk of developing psychiatric conditions later in life. We aimed to investigate whether the risk of schizophrenia (SC), bipolar affective disorder (BAD) and recurrent depressive disorder (RDD) is influenced by month of birth in England to a similar extent as other countries using the largest cohort of English patients collected to date (n = 57,971). When cases were compared to the general English population (n = 29,183,034) all diseases showed a seasonal distribution of births (SC p = 2.48E-05; BAD p = 0.019; RDD p = 0.015). This data has implications for future strategies of disease prevention.
Asunto(s)
Trastorno Bipolar/epidemiología , Trastorno Depresivo/epidemiología , Parto , Esquizofrenia/epidemiología , Estaciones del Año , Estudios de Cohortes , Inglaterra/epidemiología , Femenino , Humanos , Masculino , EmbarazoRESUMEN
OBJECTIVE: To identify rare variants contributing to multiple sclerosis (MS) susceptibility in a family we have previously reported with up to 15 individuals affected across 4 generations. METHODS: We performed exome sequencing in a subset of affected individuals to identify novel variants contributing to MS risk within this unique family. The candidate variant was genotyped in a validation cohort of 2,104 MS trio families. RESULTS: Four family members with MS were sequenced and 21,583 variants were found to be shared among these individuals. Refining the variants to those with 1) a predicted loss of function and 2) present within regions of modest haplotype sharing identified 1 novel mutation (rs55762744) in the tyrosine kinase 2 (TYK2) gene. A different polymorphism within this gene has been shown to be protective in genome-wide association studies. In contrast, the TYK2 variant identified here is a novel, missense mutation and was found to be present in 10/14 (72%) cases and 28/60 (47%) of the unaffected family members. Genotyping additional 2,104 trio families showed the variant to be transmitted preferentially from heterozygous parents (transmitted 16: not transmitted 5; χ(2) = 5.76, p = 0.016). CONCLUSIONS: Rs55762744 is a rare variant of modest effect on MS risk affecting a subset of patients (0.8%). Within this pedigree, rs55762744 is common and appears to be a modifier of modest risk effect. Exome sequencing is a quick and cost-effective method and we show here the utility of sequencing a few cases from a single, unique family to identify a novel variant. The sequencing of additional family members or other families may help identify other variants important in MS.
Asunto(s)
Exoma/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Esclerosis Múltiple/genética , TYK2 Quinasa/genética , Adolescente , Adulto , Secuencia de Bases , Distribución de Chi-Cuadrado , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Ligamiento Genético , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
A loss of function mutation in the TRESK K2P potassium channel (KCNK18), has recently been linked with typical familial migraine with aura. We now report the functional characterisation of additional TRESK channel missense variants identified in unrelated patients. Several variants either had no apparent functional effect, or they caused a reduction in channel activity. However, the C110R variant was found to cause a complete loss of TRESK function, yet is present in both sporadic migraine and control cohorts, and no variation in KCNK18 copy number was found. Thus despite the previously identified association between loss of TRESK channel activity and migraine in a large multigenerational pedigree, this finding indicates that a single non-functional TRESK variant is not alone sufficient to cause typical migraine and highlights the genetic complexity of this disorder.
RESUMEN
Chromosomal copy number association studies in patients with amyotrophic lateral sclerosis (ALS) using blood DNA have so far been inconclusive. We employed genome-wide screening to look for copy number imbalances (CNIs) between blood and hair DNA from three ALS-discordant monozygotic twin pairs and two phenotypically normal monozygotic twin pairs. Genome-wide chromosomal copy number was estimated using AffyMetrix 6.0 GeneChips. CNIs were sought both between twin pairs and between blood and hair DNA from the same individuals. Two blood CNIs were found in one ALS-discordant twin pair. In another ALS-discordant twin pair, seven hair CNIs were detected. CNIs were also found between blood and hair in three individuals. Imbalances in blood copy number appear to be rare in monozygotic twin pairs, but hair may harbour more CNIs than blood. Copy number differences between blood and hair from the same individuals appear to be common. Since brain and hair share a common ectodermal origin, hair may be a more suitable tissue than blood to estimate somatic copy number variation in the brain.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Variaciones en el Número de Copia de ADN/genética , Cabello/metabolismo , Adulto , Anciano , Desequilibrio Alélico/genética , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/patología , Proteínas de Unión al ADN/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Superóxido Dismutasa/genética , Superóxido Dismutasa-1 , Gemelos Monocigóticos/genéticaRESUMEN
Rare de novo genetic variants have been detected in a number of diseases using case-parent trios. So far, trio studies have largely been confined to early-onset diseases where parent DNA samples are readily available. To test the feasibility of finding rare de novo variants in a typical late-onset neurodegenerative disease, we compared genome-wide copy number variants (CNVs) between patients with sporadic amyotrophic lateral sclerosis (SALS) and their unaffected parents. DNA from 12 SALS patients and their 24 parents was analysed for CNVs using AffyMetrix SNP 6.0 microarrays and Partek software. De novo CNVs (present in patients but not their parents) considered likely candidates for SALS were those that overlapped with CNS-related genes, were rare, or were found in multiple patients. All SALS patients had de novo CNVs. In 11 patients, 37 de novo CNVs fulfilled one or more criteria for a candidate region. Eleven de novo CNVs overlapped with genes, some of which are in pathways suspected in the pathogenesis of SALS. In conclusion, this pilot study shows that trios can be used to look for rare de novo genetic variants in patients with late adult-onset neurodegenerative disease. The results suggest that further studies of this nature with larger numbers of trios are warranted, but it is unusual to find surviving parents of offspring who have a late-onset neurodegenerative disease. An international collaborative effort will therefore be needed to collect sufficient numbers of such trios to reliably detect de novo mutations underlying these diseases.