Multipoint LOD scores (a, b) and information content (%) (c, d) for the MS and the SNPs chromosome 3 (a, c) and chromosome 5 (b, d) regions for the affected-only strategy (MLB-binary) and the affected and unaffected strategy (MLB-categorical)

<p><b>Copyright information:</b></p><p>Taken from "Inclusion of unaffected sibs increases power in model-free linkage analysis of a behavioral trait"</p><p></p><p>BMC Genetics 2005;6(Suppl 1):S22-S22.</p><p>Published online 30 Dec 2005</p><p>PMCID:PMC1866764.</p><p></p> The vertical lines on the x-axes of 1 c and 1 d are for the MS (black) and SNPs (gray) marker position. LOD and information content are provided at positions corresponding to MS and SNPs

Table_1_CDG: An Online Server for Detecting Biologically Closest Disease-Causing Genes and its Application to Primary Immunodeficiency.XLSX

<p>High-throughput genomic technologies yield about 20,000 variants in the protein-coding exome of each individual. A commonly used approach to select candidate disease-causing variants is to test whether the associated gene has been previously reported to be disease-causing. In the absence of known disease-causing genes, it can be challenging to associate candidate genes with specific genetic diseases. To facilitate the discovery of novel gene-disease associations, we determined the putative biologically closest known genes and their associated diseases for 13,005 human genes not currently reported to be disease-associated. We used these data to construct the closest disease-causing genes (CDG) server, which can be used to infer the closest genes with an associated disease for a user-defined list of genes or diseases. We demonstrate the utility of the CDG server in five immunodeficiency patient exomes across different diseases and modes of inheritance, where CDG dramatically reduced the number of candidate genes to be evaluated. This resource will be a considerable asset for ascertaining the potential relevance of genetic variants found in patient exomes to specific diseases of interest. The CDG database and online server are freely available to non-commercial users at: http://lab.rockefeller.edu/casanova/CDG.</p

SNPs genotyped in the IL28B genomic region and their association with spontaneous clearance.

<p>A. The top panel shows the IL28B genomic region bounded by rs958039 and rs576832, its position on chromosome 19 (39,730,301–39,759,282 base pairs), and the respective positions of the genotyped SNPs. The bottom panel shows the frequencies of the minor allele for each SNP in the European and Egyptian populations. European frequencies are estimated from the CEU data from Hapmap and the 1000 Genomes project. Egyptian frequencies are estimated from the population from the overall sample studied here and separately for the two groups of individuals (HCV clearance and HCV persistence). Odds ratio for HCV clearance (OR) and 95% confidence intervals (CI 95%), together with P-values for univariate tests with the additive genetic model are also shown for each SNP. B. Proportion of spontaneous clearance as a function of genotype at SNPs rs12979860 and rs8103142.</p

Data_Sheet_1_CDG: An Online Server for Detecting Biologically Closest Disease-Causing Genes and its Application to Primary Immunodeficiency.PDF

<p>High-throughput genomic technologies yield about 20,000 variants in the protein-coding exome of each individual. A commonly used approach to select candidate disease-causing variants is to test whether the associated gene has been previously reported to be disease-causing. In the absence of known disease-causing genes, it can be challenging to associate candidate genes with specific genetic diseases. To facilitate the discovery of novel gene-disease associations, we determined the putative biologically closest known genes and their associated diseases for 13,005 human genes not currently reported to be disease-associated. We used these data to construct the closest disease-causing genes (CDG) server, which can be used to infer the closest genes with an associated disease for a user-defined list of genes or diseases. We demonstrate the utility of the CDG server in five immunodeficiency patient exomes across different diseases and modes of inheritance, where CDG dramatically reduced the number of candidate genes to be evaluated. This resource will be a considerable asset for ascertaining the potential relevance of genetic variants found in patient exomes to specific diseases of interest. The CDG database and online server are freely available to non-commercial users at: http://lab.rockefeller.edu/casanova/CDG.</p

Family based sample and study design.

<p>Two sets of families were employed: those with T1R-affected offspring and those with leprosy but T1R-free offspring. The T1R-affected subset comprised 229 offspring belonging to 221 families while the T1R-free subset comprised 229 offspring in 209 families. Offspring were matched by clinical leprosy subtype in the two family sets. In a first analysis stage, the transmission disequilibrium test (TDT) was used to estimate significance of association of <i>LRRK2</i> variants with disease in each subset. In a second stage, a formal heterogeneity test was performed to identify <i>LRRK2</i> variants preferentially associated with T1R.</p

LRRK2 variants preferentially associated with T1R.

<p>LRRK2 variants preferentially associated with T1R.</p

Host versus pathogen control of <i>LRRK2</i> expression levels.

<p><i>LRRK2</i> expression levels for 53 unrelated subjects are indicated on the y-axis and stratified according to rs2404580 genotypes on the x-axis. The left panel represents baseline expression while the right panel indicates gene expression levels following stimulation with <i>M</i>. <i>leprae</i> antigen.</p

Multivariate analysis of <i>LRRK2</i> variants with T1R

<p>Multivariate analysis of <i>LRRK2</i> variants with T1R</p

Proposed mechanism for LRRK2 in T1R.

<p>The LRRK2 M2397T amino acid substitution affects protein turnover. The methionine variant of LRRK2 displays a half-life of approximately 8 hours while the half-life of the threonine variant is 18 hours [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004412#pntd.0004412.ref034" target="_blank">34</a>]. LRRK2 arrests the NFAT transcription factor in the cytoplasm through a complex mechanism mediated by Ca²⁺ [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004412#pntd.0004412.ref036" target="_blank">36</a>]. This prevents NFAT to migrate to the nucleus and trigger the expression of pro-inflammatory cytokines [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004412#pntd.0004412.ref035" target="_blank">35</a>]. The M2397 allele is in tight linkage disequilibrium with alleles of SNPs that promote an increase in <i>LRRK2</i> expression creating a compensatory mechanism to counterbalance the shorter LRRK2-M2397 half-life. This compensatory mechanism is abrogated in the presence of <i>M</i>. <i>leprae</i> antigen. Hence, the effect of the M2397T amino acid substitution is most pronounced in the presence of <i>M</i>. <i>leprae</i> antigen.</p

Haplotype analysis of independent signal of association with T1R.

<p>Haplotype analysis of independent signal of association with T1R.</p