Multiple sclerosis (MS) is an inflammatory CNS disease with a substantial genetic component, originally mapped to only the human leukocyte antigen (HLA) region. In the last 5 years, a total of seven genome-wide association studies and one meta-analysis successfully identified 57 non-HLA susceptibility loci. Here, we merged nominal statistical evidence of association and physical evidence of interaction to conduct a protein-interaction-network-based pathway analysis (PINBPA) on two large genetic MS studies comprising a total of 15,317 cases and 29,529 controls. The distribution of nominally significant loci at the gene level matched the patterns of extended linkage disequilibrium in regions of interest. We found that products of genome-wide significantly associated genes are more likely to interact physically and belong to the same or related pathways. We next searched for subnetworks (modules) of genes (and their encoded proteins) enriched with nominally associated loci within each study and identified those modules in common between the two studies. We demonstrate that these modules are more likely to contain genes with bona fide susceptibility variants and, in addition, identify several high-confidence candidates (including BCL10, CD48, REL, TRAF3, and TEC). PINBPA is a powerful approach to gaining further insights into the biology of associated genes and to prioritizing candidates for subsequent genetic studies of complex traits.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in signi cant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults. To provide insight into the mechanisms determining progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our ndings in a further 9,805 cases. We identi ed a signi cant association with rs10191329 in the DYSF-ZNF638 locus (P=3.6×10-9), the risk allele shortening the median time to require a walking aid by up to 3.7 years. We also identi ed suggestive association with rs149097173 in the DNM3-PIGC locus (P=2.3×10-7) and signi cant enrichment for expression in CNS tissues. Mendelian randomization analyses indicated a protective role for higher educational attainment. In contrast to immune-driven susceptibility, these ndings indicate a key role of CNS resilience and neurocognitive reserve in determining outcome in MS.

the presence of α-synuclein aggregates in the retina of parkinson's disease patients has been associated with vision impairment. In this study we sought to determine the effects of α-synuclein overexpression on the survival and function of dopaminergic amacrine cells (DACs) in the retina. Adult mice were intravitreally injected with an adeno-associated viral (AAV) vector to overexpress human wild-type α-synuclein in the inner retina. Before and after systemic injections of levodopa (L-DOPA), retinal responses and visual acuity-driven behavior were measured by electroretinography (ERG) and a water maze task, respectively. Amacrine cells and ganglion cells were counted at different time points after the injection. α-synuclein overexpression led to an early loss of DACs associated with a decrease of light-adapted ERG responses and visual acuity that could be rescued by systemic injections of L-DOPA. The data show that α-synuclein overexpression affects dopamine neurons in the retina. The approach provides a novel accessible method to model the underlying mechanisms implicated in the pathogenesis of synucleinopathies and for testing novel treatments.

BackgroundAim of the study was to investigate whether menstrual cycle length may be considered as a surrogate measure of reproductive health, improving the accuracy of biochemical/sonographical ovarian reserve test in estimating the reproductive chances of women referred to ART.MethodsA retrospective-observational-study in Padua’ public tertiary level Centre was conducted. A total of 455 normo-ovulatory infertile women scheduled for their first fresh non-donor IVF/ICSI treatment. The mean menstrual cycle length (MCL) during the preceding 6 months was calculated by physicians on the basis of information contained in our electronic database (first day of menstrual cycle collected every month by telephonic communication by single patients). We evaluated the relations between MCL, ovarian response to stimulation protocol, oocytes fertilization ratio, ovarian sensitivity index (OSI) and pregnancy rate in different cohorts of patients according to the class of age and the estimated ovarian reserve.ResultsIn women younger than 35 years, MCL over 31 days may be associated with an increased risk of OHSS and with a good OSI. In women older than 35 years, and particularly than 40 years, MCL shortening may be considered as a marker of ovarian aging and may be associated with poor ovarian response, low OSI and reduced fertilization rate. When AMH serum value is lower than 1.1 ng/ml in patients older than 40 years, MCL may help Clinicians discriminate real from expected poor responders. Considering the pool of normoresponders, MCL was not correlated with pregnancy rate while a positive association was found with patients’ age.ConclusionsMCL diary is more predictive than chronological age in estimating ovarian biological age and response to COH and it is more predictive than AMH in discriminating expected from real poor responders. In women older than 35 years MCL shortening may be considered as a marker of ovarian aging while chronological age remains most accurate parameter in predicting pregnancy.