RESUMEN
Genome-wide association studies (GWAS) have identified over 100 loci containing single nucleotide variants (SNVs) that influence the risk of developing multiple sclerosis (MS). Most of these loci lie in non-coding regulatory regions of the genome that are active in immune cells and are therefore thought to modify risk by altering the expression of key immune genes. To explore this hypothesis we screened genes flanking MS-associated variants for evidence of allele specific expression (ASE) by quantifying the transcription of coding variants in linkage disequilibrium with MS-associated SNVs. In total, we were able to identify and successfully analyse 200 such coding variants (from 112 genes) in both CD4+ and CD8+ T cells from 106 MS patients and 105 controls. Fifty-six of these coding variants (from 43 genes) showed statistically significant evidence of ASE in one or both cell types. In the Lck interacting transmembrane adaptor 1 gene (LIME1), for example, we were able to show that in both cell types, the MS-associated variant rs2256814 increased the expression of some transcripts while simultaneously reducing the expression of other transcripts. In CD4+ cells from an additional independent set of 96 cases and 93 controls we were able to replicate the effect of this SNV on the balance of alternate LIME1 transcripts using qPCR (p = 5 × 10-24). Our data thus indicate that some of the MS-associated SNVs identified by GWAS likely exert their effects on risk by distorting the balance of alternate transcripts rather than by changing the overall level of gene expression.
Asunto(s)
Alelos , Esclerosis Múltiple/genética , ARN Mensajero/genética , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Adulto , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Sistemas de Lectura Abierta , Polimorfismo Genético , ARN Mensajero/metabolismoRESUMEN
Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
Asunto(s)
Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Mapeo Cromosómico , Frecuencia de los Genes , Sitios Genéticos , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
BACKGROUND: The environmental influence of sun exposure and vitamin D in particular and its implication with multiple sclerosis (MS) has recently received considerable attention. Current evidence based on genetic and epidemiological studies indicate that vitamin D is implicated in the aetiology of this disease. METHODS: We examined two common variants in the vitamin D receptor (VDR) gene in 1153 trio families and 726 cases and 604 controls. We also examined epistatic interactions between the VDR SNPs rs731236 and rs2228570 with the tagging single nucleotide polymorphism (SNP) rs3135388 for the HLA-DRB*1501 locus containing a highly conserved vitamin D responsive element within its promoter region. RESULTS: We found weak evidence for an association between the rs731236C allele and MS, while there was no direct association with rs2228570. When examining the interaction between the VDR gene variations and the DRB1*1501 tagging SNP a more complex relationship was observed. Although the interaction was not statistically significant, there appeared to be a trend of increasing risk of MS in participants who were homozygous for the HLA-DRB1*1501 allele in association with the more active form of the VDR (Fok1). CONCLUSION: We have identified weak evidence of an association between a common variation within the VDR gene and MS, in the largest study reported to date of this candidate gene. There appears to be a relationship between polymorphisms in the VDR and the risk of MS, which is potentially modified by HLA-DRB1*1501.
Asunto(s)
Epistasis Genética/genética , Predisposición Genética a la Enfermedad/genética , Cadenas HLA-DRB1/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Receptores de Calcitriol/genética , Adulto , Femenino , Genotipo , Humanos , Masculino , Oportunidad Relativa , Factores de RiesgoRESUMEN
OBJECTIVE: The core pathology of Parkinson's disease (PD) is a loss of the dopaminergic neurons in the nigro-striatal pathway, but this is only part of a more widespread pathological process, the nature of which is unknown. Recent data suggest a possible role for inflammation in this disease process. The Human Leucocyte Antigen (HLA) region is one of the most important genetic susceptibility factors in many immune-mediated diseases but has not been extensively investigated in PD. METHODS: The authors typed the HLA class II loci HLA-DRB1 and -DQB1 in 528 patients with Parkinson's disease and 3430 controls from the UK. RESULTS: The authors observed an association of HLA-DRB1 with susceptibility to Parkinson's disease. In particular, HLA-DRB1*03 was more common in patients compared with controls. CONCLUSIONS: These data suggest a possible role of the HLA region in susceptibility to Parkinson's disease and as such are consistent with other evidence supporting the role of an inflammatory process in the cellular loss in Parkinson's disease, especially of the nigral dopaminergic neurons.
Asunto(s)
Antígenos HLA/genética , Enfermedad de Parkinson/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Cohortes , Susceptibilidad a Enfermedades , Femenino , Genes MHC Clase II/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Prueba de Histocompatibilidad , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Reino Unido/epidemiologíaRESUMEN
In a recent genome-wide association study (GWAS) based on 12,374 non-synonymous single nucleotide polymorphisms we identified a number of candidate multiple sclerosis susceptibility genes. Here, we describe the extended analysis of 17 of these loci undertaken using an additional 4234 patients, 2983 controls and 2053 trio families. In the final analysis combining all available data, we found that evidence for association was substantially increased for one of the 17 loci, rs34536443 from the tyrosine kinase 2 (TYK2) gene (P=2.7 x 10(-6), odds ratio=1.32 (1.17-1.47)). This single nucleotide polymorphism results in an amino acid substitution (proline to alanine) in the kinase domain of TYK2, which is predicted to influence the levels of phosphorylation and therefore activity of the protein and so is likely to have a functional role in multiple sclerosis.