A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Abstract

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.

Intrathecal, Not Systemic Inflammation Is Correlated With Multiple Sclerosis Severity, Especially in Progressive Multiple Sclerosis

“…Furthermore, unbiased proteomic analysis of cerebrospinal fluid (CSF) biomarkers identified proteins that change with MS evolution (from early RRMS stage to late progressive MS stages), but none that could reproducibly differentiate PPMS and SPMS on a molecular level (3). These data are consistent with extensive genetic studies that also were unable to identify reproducible differences in MS susceptibility alleles between clinical subtypes of MS (4). The efficacy of B cell-depleting therapy (ocrelizumab) in both relapse-onset and PPMS clinical subgroups (5, 6) combined with clear and significant decline in efficacy on disability progression between young (<40 y) and older (≥40 y) relapse-onset MS patients (7), the genetic and proteomic results indicate that the MS disease process is largely overlapping, if not identical in all clinical MS subgroups and the main difference in the efficacy of current FDA-approved drugs on MS disability progression resides in the patient's age (1).…”

Reworking GWAS Data to Understand the Role of Nongenetic Factors in MS Etiopathogenesis

“…In MS pathogenesis, a great deal of evidence suggests the integration of the risk related to genetic predisposition with cell-type-specific epigenetic changes occurring in the immune system and in the brain in response to environmental stimuli [49][50][51]. A reworking of GWAS data, aimed at identifying the cellular type where the MS-associated variants might exert functional effects, was recently performed in an association study that analyzed a total of 47,351 cases and 68,284 healthy controls [38]. Taking into consideration the 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), the authors considered all the regulatory elements that could be affected by the presence of these variants in a cell-specific manner, and created a cell-specific protein network.…”

“…Taking into consideration the 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), the authors considered all the regulatory elements that could be affected by the presence of these variants in a cell-specific manner, and created a cell-specific protein network. This paradigmatic approach to decoding the disease risk in a cell/tissue specific context suggested MS-associated variants operative in CNS resident microglia as important contributors (besides those of peripheral immune cells) to disease development [11,38].…”

Large-Scale “OMICS” Studies to Explore the Physiopatholgy of HIV-1 Infection

“…Importantly, it is essential for data integration to perform all these cross-checks in a smart and automated manner. Finally, more sophisticated statistical approaches have recently emerged outside of the HIV field, such as the Bayesian method for data integration (Kichaev et al, 2014; Pickrell, 2014; Finucane et al, 2015; Yang et al, 2017; International Multiple Sclerosis Genetics Consortium, 2019). These new methods are yet to be implemented in the relatively small HIV/AIDS cohorts but might reveal novel underlying physiopathological mechanisms.…”