A Bayesian approach to Mendelian randomization with multiple pleiotropic variants.

We propose a Bayesian approach to Mendelian randomization (MR), where instruments are allowed to exert pleiotropic (i.e. not mediated by the exposure) effects on the outcome. By having these effects represented in the model by unknown parameters, and by imposing a shrinkage prior distribution that assumes an unspecified subset of the effects to be zero, we obtain a proper posterior distribution for the causal effect of interest. This posterior can be sampled via Markov chain Monte Carlo methods of inference to obtain point and interval estimates. The model priors require a minimal input from the user. We explore the performance of our method by means of a simulation experiment. Our results show that the method is reasonably robust to the presence of directional pleiotropy and moderate correlation between the instruments. One section of the article elaborates the model to deal with two exposures, and illustrates the possibility of using MR to estimate direct and indirect effects in this situation. A main objective of the article is to create a basis for developments in MR that exploit the potential offered by a Bayesian approach to the problem, in relation with the possibility of incorporating external information in the prior, handling multiple sources of uncertainty, and flexibly elaborating the basic model

Mendelian Randomization with Incomplete Exposure Data: a Bayesian Approach

We expand Mendelian Randomization (MR) methodology to deal with randomly missing data on either the exposure or the outcome variable, and furthermore with data from nonindependent individuals (eg components of a family). Our method rests on the Bayesian MR framework proposed by Berzuini et al (2018), which we apply in a study of multiplex Multiple Sclerosis (MS) Sardinian families to characterise the role of certain plasma proteins in MS causation. The method is robust to presence of pleiotropic effects in an unknown number of instruments, and is able to incorporate inter-individual kinship information. Introduction of missing data allows us to overcome the bias introduced by the (reverse) effect of treatment (in MS cases) on level of protein. From a substantive point of view, our study results confirm recent suspicion that an increase in circulating IL12A and STAT4 protein levels does not cause an increase in MS risk, as originally believed, suggesting that these two proteins may not be suitable drug targets for MS

Acid sensing ion channel 2: A new potential player in the pathophysiology of multiple sclerosis

Acid-sensing ion channels (ASICs) are proton-gated channels involved in multiple biological functions such as: pain modulation, mechanosensation, neurotransmission, and neurodegeneration. Earlier, we described the genetic association, within the Nuoro population, between Multiple Sclerosis (MS) and rs28936, located in ASIC2 3′UTR. Here we investigated the potential involvement of ASIC2 in MS inflammatory process. We induced experimental autoimmune encephalomyelitis (EAE) in wild-type (WT), knockout Asic1 −/− and Asic2 −/− mice and observed a significant reduction of clinical score in Asic1 −/− mice and a significant reduction in the clinical score in Asic2 −/− mice in a limited time window (i.e., at days 20–23 after immunization). Immunohistochemistry confirmed the reduction in adaptive immune cell infiltrates in the spinal cord of EAE Asic1 −/− mice. Analysis of mechanical allodynia, showed a significant higher pain threshold in Asic2 −/− mice under physiological conditions, before immunization, as compared to WT mice and Asic1 −/−. A significant reduction in pain threshold was observed in all three strains of mice after immunization. More importantly, analysis of human autoptic brain tissue in MS and control samples showed an increase of ASIC2 mRNA in MS samples. Subsequently, in vitro luciferase reporter gene assays, showed that ASIC2 expression is under possible miRNA regulation, in a rs28936 allele-specific manner. Taken together, these findings suggest a potential role of ASIC2 in the pathophysiology of MS

Short and Long Term Variation in Ultraviolet Radiation and Multiple Sclerosis

We examined the role of ultraviolet radiation (UVR) in persons diagnosed with multiple sclerosis (MS) in four different populations, Italians, Danish, White and African Americans. We tested whether variation in UVR as determined by seasons (short term variation) and solar cycles (long term variation) is related to MS birth month and to survival as measured by lifespan. Cases were selected from three Italian MS Case Registries (2,737); from the United States National Center for Health Statistics (56,020); and from the Danish Multiple Sclerosis registry (15,900). Chi-square tests were used to study the pattern of month of birth distribution in patients with MS comparing with general population data. T-tests were employed to study solar cycles association with lifespan. A surplus of births was observed in June for White Americans. A decrease of births in October and November, though not significant after multiple testing correction, was observed in the three populations. In White American with MS overall, males and females, we found that solar cycle is associated with lifespan. We found that season and solar cycles have some role in MS susceptibility and life duration. However, this is an exploratory analysis and further work is needed to discern the association

Association between the ACCN1 Gene and Multiple Sclerosis in Central East Sardinia

Multiple genome screens have been performed to identify regions in linkage or association with Multiple Sclerosis (MS, OMIM 126200), but little overlap has been found among them. This may be, in part, due to a low statistical power to detect small genetic effects and to genetic heterogeneity within and among the studied populations. Motivated by these considerations, we studied a very special population, namely that of Nuoro, Sardinia, Italy. This is an isolated, old, and genetically homogeneous population with high prevalence of MS. Our study sample includes both nuclear families and unrelated cases and controls. A multi-stage study design was adopted. In the first stage, microsatellites were typed in the 17q11.2 region, previously independently found to be in linkage with MS. One significant association was found at microsatellite D17S798. Next, a bioinformatic screening of the region surrounding this marker highlighted an interesting candidate MS susceptibility gene: the Amiloride-sensitive Cation Channel Neuronal 1 (ACCN1) gene. In the second stage of the study, we resequenced the exons and the 3′ untranslated (UTR) region of ACCN1, and investigated the MS association of Single Nucleotide Polymorphisms (SNPs) identified in that region. For this purpose, we developed a method of analysis where complete, phase-solved, posterior-weighted haplotype assignments are imputed for each study individual from incomplete, multi-locus, genotyping data. The imputed assignments provide an input to a number of proposed procedures for testing association at a microsatellite level or of a sequence of SNPs. These include a Mantel-Haenszel type test based on expected frequencies of pseudocase/pseudocontrol haplotypes, as well as permutation based tests, including a combination of permutation and weighted logistic regression analysis. Application of these methods allowed us to find a significant association between MS and the SNP rs28936 located in the 3′ UTR segment of ACCN1 with p = 0.0004 (p = 0.002, after adjusting for multiple testing). This result is in tune with several recent experimental findings which suggest that ACCN1 may play an important role in the pathogenesis of MS

Association between Protective and Deleterious HLA Alleles with Multiple Sclerosis in Central East Sardinia

The human leukocyte antigen (HLA) complex on chromosome 6p21 has been unambiguously associated with multiple sclerosis (MS). The complex features of the HLA region, especially its high genic content, extreme polymorphism, and extensive linkage disequilibrium, has prevented to resolve the nature of HLA association in MS. We performed a family based association study on the isolated population of the Nuoro province (Sardinia) to clarify the role of HLA genes in MS. The main stage of our study involved an analysis of the ancestral haplotypes A2Cw7B58DR2DQ1 and A30Cw5B18DR3DQ2. On the basis of a multiplicative model, the effect of the first haplotype is protective with an odds ratio (OR) = 0.27 (95% confidence interval CI 0.13–0.57), while that of the second is deleterious, OR 1.78 (95% CI 1.26–2.50). We found both class I (A, Cw, B) and class II (DR, DQ) loci to have an effect on MS susceptibility, but we saw that they act independently from each other. We also performed an exploratory analysis on a set of 796 SNPs in the same HLA region. Our study supports the claim that Class I and Class II loci act independently on MS susceptibility and this has a biological explanation. Also, the analysis of SNPs suggests that there are other HLA genes involved in MS, but replication is needed. This opens up new perspective on the study of MS

Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

Janna Saarela on työryhmien jäsen.Peer reviewe

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Multiple sclerosis is a complex neurological disease, with 3c20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFN\u3b3 biology, and NF\u3baB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS. In a large multi-cohort study, unexplained heritability for multiple sclerosis is detected in low-frequency coding variants that are missed by GWAS analyses, further underscoring the role of immune genes in MS pathology

A common biological basis of obesity and nicotine addiction

J. Kaprio ja J. Tuomilehto työryhmien jäseniä (yht. 281).Peer reviewe