RESUMEN
BACKGROUND: It remains unclear whether disease course in multiple sclerosis (MS) is influenced by genetic polymorphisms. Here, we aimed to identify genetic variants associated with benign and aggressive disease courses in MS patients. METHODS: MS patients were classified into benign and aggressive phenotypes according to clinical criteria. We performed exome sequencing in a discovery cohort, which included 20 MS patients, 10 with benign and 10 with aggressive disease course, and genotyping in 2 independent validation cohorts. The first validation cohort encompassed 194 MS patients, 107 with benign and 87 with aggressive phenotypes. The second validation cohort comprised 257 patients, of whom 224 patients had benign phenotypes and 33 aggressive disease courses. Brain immunohistochemistries were performed using disease course associated genes antibodies. RESULTS: By means of single-nucleotide polymorphism (SNP) detection and comparison of allele frequencies between patients with benign and aggressive phenotypes, a total of 16 SNPs were selected for validation from the exome sequencing data in the discovery cohort. Meta-analysis of genotyping results in two validation cohorts revealed two polymorphisms, rs28469012 and rs10894768, significantly associated with disease course. SNP rs28469012 is located in CPXM2 (carboxypeptidase X, M14 family, member 2) and was associated with aggressive disease course (uncorrected p value < 0.05). SNP rs10894768, which is positioned in IGSF9B (immunoglobulin superfamily member 9B) was associated with benign phenotype (uncorrected p value < 0.05). In addition, a trend for association with benign phenotype was observed for a third SNP, rs10423927, in NLRP9 (NLR family pyrin domain containing 9). Brain immunohistochemistries in chronic active lesions from MS patients revealed expression of IGSF9B in astrocytes and macrophages/microglial cells, and expression of CPXM2 and NLRP9 restricted to brain macrophages/microglia. CONCLUSIONS: Genetic variants located in CPXM2, IGSF9B, and NLRP9 have the potential to modulate disease course in MS patients and may be used as disease activity biomarkers to identify patients with divergent disease courses. Altogether, the reported results from this study support the influence of genetic factors in MS disease course and may help to better understand the complex molecular mechanisms underlying disease pathogenesis.
Asunto(s)
Secuenciación del Exoma/métodos , Predisposición Genética a la Enfermedad/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/fisiopatología , Polimorfismo de Nucleótido Simple/genética , Encéfalo/metabolismo , Carboxipeptidasas A/genética , Carboxipeptidasas A/metabolismo , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Inmunoglobulinas/genética , Inmunoglobulinas/metabolismo , Masculino , Esclerosis Múltiple/patología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , ARN MensajeroRESUMEN
BACKGROUND: The many attempts that have been made to identify genes for bipolar disorder (BD) have met with limited success, which may reflect an inadequacy of diagnosis as an informative and biologically relevant phenotype for genetic studies. Here we have explored aspects of personality as quantitative phenotypes for bipolar disorder through the use of the Temperament and Character Inventory (TCI), which assesses personality in seven dimensions. Four temperament dimensions are assessed: novelty seeking (NS), harm avoidance (HA), reward dependence (RD), and persistence (PS). Three character dimensions are also included: self-directedness (SD), cooperativeness (CO), and self-transcendence (ST). METHODS: We compared personality scores between diagnostic groups and assessed heritability in a sample of 101 families collected for genetic studies of BD. A genome-wide SNP linkage analysis was then performed in the subset of 51 families for which genetic data was available. RESULTS: Significant group differences were observed between BD subjects, their first-degree relatives, and independent controls for all but RD and PS, and all but HA and RD were found to be significantly heritable in this sample. Linkage analysis of the heritable dimensions produced several suggestive linkage peaks for NS (chromosomes 7q21 and 10p15), PS (chromosomes 6q16, 12p13, and 19p13), and SD (chromosomes 4q35, 8q24, and 18q12). LIMITATIONS: The relatively small size of our linkage sample likely limited our ability to reach genome-wide significance in this study. CONCLUSIONS: While not genome-wide significant, these results suggest that aspects of personality may prove useful in the identification of genes underlying BD susceptibility.
Asunto(s)
Trastorno Bipolar/genética , Trastorno Bipolar/psicología , Personalidad/genética , Adulto , Trastorno Depresivo Mayor/genética , Endofenotipos , Familia , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Inventario de Personalidad , Polimorfismo de Nucleótido Simple , TemperamentoRESUMEN
The few loci associated with multiple sclerosis (MS) are all related to immune function. We report a GWA study identifying a new locus replicated in 2,679 cases and 3,125 controls. An rs10492972[C] variant located in the KIF1B gene was associated with MS with an odds ratio of 1.35 (P = 2.5 x 10(-10)). KIF1B is a neuronally expressed gene plausibly implicated in the irreversible axonal loss characterizing MS in the long term.
Asunto(s)
Predisposición Genética a la Enfermedad , Cinesinas/genética , Esclerosis Múltiple/genética , Estudios de Casos y Controles , Estudio de Asociación del Genoma Completo , IntronesRESUMEN
Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. HLA-DRB1*14 and DRB1*11 bearing haplotypes protect against MS and DRB1*01 and DRB1*10 interact with DRB1*15 to reduce risk of the disease. Recent work in other autoimmune diseases such as rheumatoid arthritis has suggested that maternal non-transmitted protective alleles can also confer disease resistance. In this investigation of 7093 individuals from 1432 MS families, we have analysed the transmission of HLA-DRB1*14,*11,*10 and *01 haplotypes, stratified by sex of parent. No significant transmission differences between mothers and fathers were found, suggesting that non-inherited resistance alleles do not appear to play a role in MS.
Asunto(s)
Alelos , Salud de la Familia , Antígenos HLA-DR/genética , Esclerosis Múltiple/genética , Padres , Femenino , Genotipo , Humanos , Patrón de Herencia , Masculino , Esclerosis Múltiple/epidemiologíaRESUMEN
Using population-based data, the authors identified 24 MS index cases whose parents were related. Twenty-two had 67 sibs of whom 6 also had MS, yielding a recurrence risk of approximately 9%, significantly higher than for sibs of MS index cases from nonconsanguineous parents. These findings support the concept that multiple interacting genes increase the risk of MS.
