RESUMO
A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10-7, 4.3 × 10-9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.
RESUMO
BACKGROUND: Reduced peripapillary retinal nerve fiber layer (pRNFL) and combined ganglion cell and inner plexiform layer (GCIP) thicknesses as measured by optical coherence tomography (OCT) have been observed in multiple sclerosis (MS) patients. The purpose was to determine the most associative OCT measure to level of cognitive and physical disability in MS. METHODS: Data were collected from 546 MS patients and 175 healthy controls (HCs). We compared the average pRNFL, temporal pRNFL (T-pRNFL), overall inner ganglion cell/inner plexiform layer (GCIP), and the overall ganglion cell complex (GCC) including macular RNFL and GCIP thicknesses measurements in differentiating MS subtypes from HCs. The association between OCT measures, Expanded Disability Status Scale (EDSS), and Symbol Digit Modalities Test (SDMT) were assessed using generalized estimating equations models. RESULTS: Both peripapillary and macular OCT measurements could differentiate all MS subtypes from HCs. The SDMT score was significantly associated with reduced thickness of all OCT measures, mostly in average pRNFL (0.14 µm, P = 0.001) and T-pRNFL (0.17 µm, P < 0.001). The EDSS score was significantly associated with reduced inner retinal layer thickness. The largest reduction was seen in T-pRNFL (-1.52 µm, P < 0.001) and inner GCC (-1.78 µm, P < 0.001). CONCLUSION: The T-pRNFL is highly sensitive and associated with level of both cognitive and physical disability.
