Replication of TCF4 through Association and Linkage Studies in Late-Onset Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33×10−35; ADD: P = 7.48×10−30; REC: P = 5.27×10−6). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies

Linkage and association analysis of chromosome 19q13 in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune neurological disorder with a complex etiology. Sibling risk, twin, and adoption studies have demonstrated that genes play a vital role in susceptibility to MS. Numerous association and linkage studies have implicated the major histocompatibility complex (MHC) as one component of the genetic etiology, but additional loci remain to be identified. Genomic screens have suggested over 50 regions that might harbor these genes, but there has been little agreement between studies. The one region suggested by all four screens resides within chromosome 19q13. Allelic associations with several markers in this region have also been described. This region has now been examined in detail in an expanded dataset of MS families from the United States. Genetic linkage and association were tested with multiple markers in this region using both parametric and non-parametric analyses. Additional support for an MS susceptibility locus was observed, primarily in families with the MS-associated HLA-DR2 allele. While consistent, this effect appears to be modest with a maximum λS=1.47, probably representing no more than 10% of the overall genetic effect in MS

Multiple susceptibility loci for multiple sclerosis

Multiple sclerosis (MS) is a common and frequently disabling autoimmune disorder mediated by autoaggressive T cells and autoantibodies that target central nervous system myelin. While numerous studies have demonstrated a strong genetic component to MS, it has been difficult to identify the specific genes involved. Several genomic screens have been undertaken to locate such genes, but have not provided consistent gene localization, except for the MHC on chromosome 6p21 and a locus on chromosome 19q13. To determine which of the original genomic locations presented in the US genome screen could be replicated, a more detailed analysis of additional families was performed. The results, derived from a population of 266 affected individuals belonging to 98 multiplex families, continue to support linkage to chromosomes 6p21, 6q27, and 19q13 with LOD scores>3.0, and suggest that regions on chromosomes 12q23-24 and 16p13 may also harbor susceptibility loci for MS. Analysis taking into account the known HLA-DR2 association identified two additional potential linkage regions on chromosomes 7q21-22 and 13q33-34. These regions can now be targeted for detailed study to identify the underlying MS susceptibility genes

Association of Polymorphisms in the Apolipoprotein E Region with Susceptibility to and Progression of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, with a complex etiology that includes a strong genetic component. The contribution of the major histocompatibility complex (MHC) has been established in numerous genetic linkage and association studies. In addition to the MHC, the chromosome 19q13 region surrounding the apolipoprotein E (APOE) gene has shown consistent evidence of involvement in MS when family-based analyses were conducted. Furthermore, several clinical reports have suggested that the APOE-4 allele may be associated with more-severe disease and faster progression of disability. To thoroughly examine the role of APOE in MS, we genotyped its functional alleles, as well as seven single-nucleotide polymorphisms (SNPs) located primarily within 13 kb of APOE, in a data set of 398 families. Using family-based association analysis, we found statistically significant evidence that an SNP haplotype near APOE is associated with MS susceptibility (P=.005). An analysis of disease progression in 614 patients with MS from 379 families indicated that APOE-4 carriers are more likely to be affected with severe disease (P=.03), whereas a higher proportion of APOE-2 carriers exhibit a mild disease course (P=.02)

Comparison of genotype frequencies between Duke dataset and dataset used in Baratz et al. (2010), and between male and female in Duke dataset for rs613872.

<p>*<b>N: total sample size.</b></p><p>**<b>Heterozygous frequencies are elevated in all datasets and are highlighted in bold.</b></p

Plot of the top multipoint linkage peak on chromosome 18.

<p>SNP markers are plotted along the x-axis by their deCODE map position, and the LOD/HLOD scores for each marker are plotted along the y-axis. The results of the FASTLINK/HOMOG dominant two-point analysis are indicated with black circles, and the results of the MERLIN dominant multipoint analysis are indicated with a black line. The SNP rs4941043 is the peak marker from the two-point analysis (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0018044#pone-0018044-t003" target="_blank"><b>Table 3</b></a>). The location of the <i>FCD2</i> peak (Sundin <i>et al.</i>, 2006) and the most significantly associated SNP, rs613872, from the FECD GWAS performed by Baratz <i>et al.</i> (2010) are indicated by arrows. The location of the <i>TCF4</i> gene is also indicated for reference. 2PT, two-point results; MPT, multipoint results; cM, centiMorgans; LOD, logarithm of the odds; HLOD, heterogeneity logarithm of the odds.</p

Results of the multipoint linkage analysis using MERLIN.

<p>Note: All linkage regions with a LOD score >1.5 at the peak marker in at least one of the multipoint analyses, nonparametric (NPL), dominant (DOM), or recessive (REC), are presented. The upper and lower bounds of each linkage peak interval presented were selected based on covering all markers with a LOD or HLOD score within one LOD score unit of the peak marker's LOD score. The peak LOD scores are indicated with <b>bold text</b>. Chr, chromosome; SNP, single nucleotide polymorphism; LOD, logarithm of the odds; HLOD, heterogeneity logarithm of the odds.</p

Worldwide distribution of the minor (risk) allele, G, of rs613872 in <i>TCF4.</i>

<p>Data from the Human Genome Diversity Project, available online through the UCSC genome browser at <a href="http://genome.ucsc.edu/" target="_blank">http://genome.ucsc.edu/</a>. Note the higher prevalence of the risk allele in sample populations from Europe, the Middle East, and Southern Asia and the absence of the risk allele in sample populations from Africa, Eastern Asia, and Central and South America.</p