The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Immunoglobulin subclass profiles of anti-idiotypic antibodies to GAD65Ab differ between type 1 diabetes patients and healthy individuals.

Previously we reported the presence of anti-idiotypic antibodies (anti-Id) specific to autoantibodies against GAD65 (GAD65Ab) in healthy individuals while the activity of anti-Id directed to GAD65Ab in T1D patients was significantly lower. These anti-Id recognize the antigen binding site of GAD65Ab, thus preventing their binding to GAD65. Here we characterized the IgG subclass profile of these anti-Id (GAD65Ab-specific) and of the associated GAD65Ab themselves. The IgG subclass response of anti-Id in healthy individuals (n=16) was IgG3-dominated, while in T1D patients (n=8) IgG1 was the major IgG subclass. The GAD65Ab bound by anti-Id in both healthy individuals (n=38) and GAD65Ab-negative T1D patients (n=35) showed a predominant rank order of IgG1>IgG2>IgG4>IgG3. However, the frequency of GAD65Ab of the IgG4 subclass was significantly higher in T1D patients (p<0.05). We conclude that the IgG subclass profile of anti-Id (GAD65Ab-specific) in healthy individuals differs from that in T1D patients. These differences may provide insights in the development of these antibodies

Comparison of three assays for the detection of GAD65Ab-specific anti-idiotypic antibodies

Anti-idiotypic antibodies (anti-Id) to autoantibodies are present in several autoimmune diseases and are hypothesized to have regulatory function. Recently we reported the presence of anti-Id to a major type 1 diabetes-associated autoantibody (CAD65Ab) in sera of healthy individuals. Our current assay for the detection of GAD65Ab-specific anti-Id requires the initial removal of anti-Id from the sera using immobilized monoclonal GAD65Ab, followed by detection of the now exposed GAD65Ab. However, anti-Id in samples that are GAD65Ab-negative cannot be detected in this assay. Furthermore, we cannot distinguish between serum GAD65Ab and the monoclonal GAD65Ab used in the absorption of anti-Id. In this study we evaluated two novel detection assays for GAD65Ab-specific anti-Id. The biotin/streptavidin based absorption assay utilizes the strong interaction of biotin and streptavidin to prevent possible leakage of the immobilized antibody. Moreover, this assay format allows to identify the origin of the detected GAD65Ab. The ECL-based assay allows the direct detection of anti-Id independent of the presence of GAD65Ab. We analyzed new-onset type 1 diabetes patients (n = 133) and matched healthy controls (n = 178) for the presence of GAD65Ab-specific anti-Id using both new detection assays and the original absorption assay. We found that all three assays can distinguish between the type 1 diabetes cohort and the healthy control samples. The biotin/streptavidin assay allowed us to positively exclude the monoclonal GAD65Ab as the source of the detected GAD65Ab. While the original absorption assay showed the highest sensitivity and specificity, the ECL format showed the highest peak signal-to-noise ratio and excellent linear correlation, making this assay our first choice for quantification of anti-Id. (C) 2009 Elsevier B.V. All rights reserved

Sample information of the NHS cohort.

<p>Sample information of the NHS cohort.</p

GAD65Ab level in progressors and non-progressors.

<p>GAD65Ab levels at baseline and at diagnosis (or final sampling in non-progressors) are shown for progressors and non-progressors of the NHS cohort. GAD65Ab levels and median for each group are presented. Significant differences are indicated by the horizontal bar and asterix.</p