Cellular Adhesion Gene SELP Is Associated with Rheumatoid Arthritis and Displays Differential Allelic Expression.

In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p<10-6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1 = 0.004; p2 = 0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA

Genetic risk variants for dyslexia on chromosome 18 in a German cohort

Dyslexia is characterized by impaired reading and spelling. The disorder has a prevalence of about 5% in Germany, and a strong hereditary component. Several loci are thought to be involved in the development of dyslexia. Scerri et al. identified eight potential dyslexia-associated single nucleotide polymorphisms (SNPs) in seven genes on chromosome 18 in an English-speaking population. Here, we present an association analysis that explores the relevance of these SNPs in a German population comprising 388 dyslexia cases and 364 control cases. In case–control analysis, three nominal SNP associations were replicated. The major alleles of NEDD4L-rs12606138 and NEDD4L-rs8094327 were risk associated [odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.0–1.7, P-value = 0.017 and OR = 1.39, 95% CI = 1.1–1.7, P-value = 0.007, respectively], and both SNPs were in strong linkage disequilibrium (r2 = 0.95). For MYO5B-rs555879, the minor allele was risk associated (OR = 1.31, 95% CI = 1.1–1.6, P-value = 0.011). The combined analysis of SNP sets using set enrichment analysis revealed a study-wide significant association for three SNPs with susceptibility for dyslexia. In summary, our results substantiate genetic markers in NEDD4L and MYO5B as risk factors for dyslexia and provide first evidence that the relevance of these markers is not restricted to the English language

Imaging genetics of FOXP2 in dyslexia

Dyslexia is a developmental disorder characterised by extensive difficulties in the acquisition of reading or spelling. Genetic influence is estimated at 50-70%. However, the link between genetic variants and phenotypic deficits is largely unknown. Our aim was to investigate a role of genetic variants of FOXP2, a prominent speech and language gene, in dyslexia using imaging genetics. This technique combines functional magnetic resonance imaging (fMRI) and genetics to investigate relevance of genetic variants on brain activation. To our knowledge, this represents the first usage of fMRI-based imaging genetics in dyslexia. In an initial case/control study (n = 245) for prioritisation of FOXP2 polymorphisms for later use in imaging genetics, nine SNPs were selected. A non-synonymously coding mutation involved in verbal dyspraxia was also investigated. SNP rs12533005 showed nominally significant association with dyslexia (genotype GG odds ratio recessive model = 2.1 (95% confidence interval 1.1-3.9), P = 0.016). A correlated SNP was associated with altered expression of FOXP2 in vivo in human hippocampal tissue. Therefore, influence of the rs12533005-G risk variant on brain activity was studied. fMRI revealed a significant main effect for the factor 'genetic risk' in a temporo-parietal area involved in phonological processing as well as a significant interaction effect between the factors 'disorder' and 'genetic risk' in activation of inferior frontal brain areas. Hence, our data may hint at a role of FOXP2 genetic variants in dyslexia-specific brain activation and demonstrate use of imaging genetics in dyslexia research