Association of protein kinase C alpha (PRKCA) gene with multiple sclerosis in a UK population

Barton, Anne; Woolmore, John; Ward, Daniel; Eyre, Steve; Hinks, Anne; Ollier, William; Strange, R. C.; Fryer, Anthony A.; John, Sujit; Hawkins, Clive; Worthington, Jane

doi:10.1093/brain/awh193

Cited by 38 publications

(28 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The curves are clearly converging to the limiting value of a that would be achieved if m ¼ 0. The dashed line in Figure 3 corresponds to m ¼ 0.005, which is at the high end of the range of m (0.0001-0.005) estimated in recent, large, SNP genotyping studies (Gabriel et al 2002;Kennedy et al 2003;Barton et al 2004;Hao et al 2004;Mitra et al 2004). Throughout the rest of this study, we assume m ¼ 0.005.…”

Section: Resultsmentioning

confidence: 95%

The Power of Single-Nucleotide Polymorphisms for Large-Scale Parentage Inference

2006

View full text Add to dashboard Cite

Likelihood-based parentage inference depends on the distribution of a likelihood-ratio statistic, which, in most cases of interest, cannot be exactly determined, but only approximated by Monte Carlo simulation. We provide importance-sampling algorithms for efficiently approximating very small tail probabilities in the distribution of the likelihood-ratio statistic. These importance-sampling methods allow the estimation of small false-positive rates and hence permit likelihood-based inference of parentage in large studies involving a great number of potential parents and many potential offspring. We investigate the performance of these importance-sampling algorithms in the context of parentage inference using single-nucleotide polymorphism (SNP) data and find that they may accelerate the computation of tail probabilities .1 millionfold. We subsequently use the importance-sampling algorithms to calculate the power available with SNPs for largescale parentage studies, paying particular attention to the effect of genotyping errors and the occurrence of related individuals among the members of the putative mother-father-offspring trios. These simulations show that 60-100 SNPs may allow accurate pedigree reconstruction, even in situations involving thousands of potential mothers, fathers, and offspring. In addition, we compare the power of exclusion-based parentage inference to that of the likelihood-based method. Likelihood-based inference is much more powerful under many conditions; exclusion-based inference would require 40% more SNP loci to achieve the same accuracy as the likelihood-based approach in one common scenario. Our results demonstrate that SNPs are a powerful tool for parentage inference in large managed and/or natural populations.

show abstract

Section: Resultsmentioning

confidence: 95%

The Power of Single-Nucleotide Polymorphisms for Large-Scale Parentage Inference

2006

View full text Add to dashboard Cite

show abstract

“…FLT3LG treatment was reported to delay diabetes onset in the NOD mouse model of autoimmune diabetes (41). Protein kinase C (PRKCA), also shown in our list, is associated with multiple sclerosis (42), which is known to be initiated by a misdirected immune response against myelin autoantigens (43). In addition, our list includes the molecules associated with T1DM-related pathophysiology in pancreatic b-cells (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 98%

Identification of Novel Autoantibodies in Type 1 Diabetic Patients Using a High-Density Protein Microarray

et al. 2014

View full text Add to dashboard Cite

Autoantibodies can facilitate diagnostic and therapeutic means for type 1 diabetes (T1DM). We profiled autoantibodies from serum samples of 16 T1DM patients, 16 type 2 diabetic (T2DM) patients, and 27 healthy control subjects with normal glucose tolerance (NGT) by using protein microarrays containing 9,480 proteins. Two novel autoantibodies, anti-EEF1A1 and anti-UBE2L3, were selected from microarrays followed by immunofluorescence staining of pancreas. We then tested the validity of the candidates by ELISA in two independent test cohorts: 1) 95 adults with T1DM, 49 with T2DM, 11 with latent autoimmune diabetes in adults (LADA), 20 with Graves disease, and 66 with NGT and 2) 33 children with T1DM and 34 healthy children. Concentrations of these autoantibodies were significantly higher in T1DM patients than in NGT and T2DM subjects (P < 0.01), which was also confirmed in the test cohort of children (P < 0.05). Prevalence of anti-EEF1A1 and anti-UBE2L3 antibodies was 29.5% and 35.8% in T1DM, respectively. Of note, 40.9% of T1DM patients who lack anti-GAD antibodies (GADA) had anti-EEF1A1 and/or anti-UBE2L3 antibodies. These were also detected in patients with fulminant T1DM but not LADA. Our approach identified autoantibodies that can provide a new dimension of information indicative of T1DM independent of GADA and new insights into diagnosis and classification of T1DM.Type 1 diabetes (T1DM) results from immune-mediated pancreatic b-cell destruction. Several autoantibodies, such as GAD65 antibody (GADA) (1), islet cell antibody (ICA) (2), protein tyrosine phosphatase antibody (IA-2 antibodies [IA-2A]) (3), and zinc transporter antibody (ZnT8A) (4), were identified and used for diagnosis and prediction of T1DM.However, the nature and mechanism of b-cell destruction in humans seem to be variable, which results in a broad spectrum of T1DM spanning from fulminant T1DM (5) to latent autoimmune diabetes in adults (LADA) (6). Fulminant T1DM is a rapidly progressing form of T1DM without evidence of autoimmunity, whereas LADA is autoimmune diabetes not requiring insulin at diagnosis. In most cases of LADA, which account for 10% of incident cases of diabetes in adults, b-cell function is severely impaired within 6 years, leading to insulin dependency (6). Fulminant T1DM is an important subtype of T1DM in Asian adults (7), accounting for 15%-20% of T1DM with ketosis or ketoacidosis in Japan (5). Moreover, T1DM in adults often lacks evidence of autoimmunity. The prevalence of autoantibodies associated with T1DM declines as the onset age increases, especially in the case of IA-2A (8) and ZnT8A

show abstract

“…Failure to obtain replication in follow-up samples could reflect differences in linkage disequilibrium structure at this locus across Europe, as has been alluded to in earlier studies 57,58 or the result may be a false-positive. However, our finding of gene-wide significant evidence for association at PRKCA, taken together with the fact that the SNPs genotyped in this study detect 57% of even the HapMap CEU-defined common genetic variation at PRKCA, suggests that that further fine-scale association mapping of this locus is required.…”

Section: Meta-analysismentioning

confidence: 96%

Evidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha

et al. 2009

View full text Add to dashboard Cite

We earlier reported a genome-wide significant linkage to schizophrenia at chromosome 17 that was identified in a single pedigree (C702) consisting of six affected, male siblings with DSM-IV schizophrenia and prominent mood symptoms. In this study, we adopted several approaches in an attempt to map the putative disease locus. First, mapping the source of linkage to chromosome 17 in pedigree C702. We refined the linkage region in family C702 to a 21-marker segment spanning 11.7 Mb at 17q23-q24 by genotyping a total of 50 microsatellites across chromosome 17 in the pedigree. Analysis of data from 1028 single nucleotide polymorphisms (SNPs) across the refined linkage region identified a single region of homozygosity present in pedigree C702 but not in 2938 UK controls. This spanned B432 kb of the gene encoding protein kinase C, alpha (PRKCA), the encoded protein of which has been implicated in the pathogenesis of psychiatric disorders. Analysis of pedigree C702 by oligonucleotide-array comparative genome hybridization excluded the possibility that this region of homozygosity was because of a deletion. Mutation screening of PRKCA identified a rare, four-marker haplotype (C-HAP) in the 3 0 untranslated region of the gene, which was present in the homozygous state in all six affected members of pedigree C702. No other homozygotes were observed in genotype data for a total of 6597 unrelated Europeans (case N = 1755, control N = 3580 and parents of probands N = 1262). Second, association analysis of C702 alleles at PRKCA. The low-frequency haplotype (C-HAP) showed a trend for association in a study of unrelated schizophrenia cases and controls from the UK (661 cases, 2824 controls, P = 0.078 and odd ratio (OR) = 1.9) and significant evidence for association when the sample was expanded to include cases with bipolar (N = 710) and schizoaffective disorder (N = 50) (psychosis sample: 1421 cases, 2824 controls, P = 0.037 and OR = 1.9). Given that all the affected members of C702 are male, we also undertook sex-specific analyses. This revealed that the association was strongest in males for both schizophrenia (446 male cases, 1421 male controls, P = 0.008 and OR = 3.9) and in the broader psychosis group (730 male cases, 1421 male controls, P = 0.008 and OR = 3.6). Analysis of C-HAP in follow-up samples from Ireland and Bulgaria revealed no evidence for association in either the whole sample or in males alone, and meta-analysis of all male psychosis samples yielded no significant evidence of association (969 male cases, 1939 male controls, 311 male probands P = 0.304 and OR = 1.4). Third, association mapping of the pedigree C702 linkage region. Independent of pedigree C702, genotype data from the Affymetrix 500k GeneChip set were available for 476 patients with schizophrenia and 2938 controls from the United Kingdom. SNPs in PRKCA showed evidence for association with schizophrenia that achieved gene-wide significance (P = 0.027). Moreover, the same SNP was the most significantly associated marker out of the 1028 SNPs genotyped...

show abstract

Association of protein kinase C alpha (PRKCA) gene with multiple sclerosis in a UK population

Cited by 38 publications

References 19 publications

The Power of Single-Nucleotide Polymorphisms for Large-Scale Parentage Inference

The Power of Single-Nucleotide Polymorphisms for Large-Scale Parentage Inference

Identification of Novel Autoantibodies in Type 1 Diabetic Patients Using a High-Density Protein Microarray

Evidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha

Contact Info

Product

Resources

About