Genome-wide association study of severity in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Several lines of evidence support a strong role for genetic factors influencing both disease susceptibility and clinical outcome in MS. Identification of genetic variants that distinguish particular disease subgroups and/or predict a severe clinical outcome is critical to further our understanding of disease mechanisms and guide development of effective therapeutic approaches. We studied 1470 MS cases and performed a genome-wide association study of more than 2.5 million single-nucleotide polymorphisms to identify loci influencing disease severity, measured using the MS severity score (MSSS), a measure of clinical disability. Of note, no single result achieved genome-wide significance. Furthermore, variants within previously confirmed MS susceptibility loci do not appear to influence severity. Although bioinformatic analyses highlight certain pathways that are over-represented in our results, we conclude that the genetic architecture of disease severity is likely polygenic and comprised of modest effects, similar to what has been described for MS susceptibility, to date. However, a role for major effects of rare variants cannot be excluded. Importantly, our results also show the MSSS, when considered as a binary or continuous phenotype variable is by comparison a stable outcome.

Genome‐wide association studies of multiple sclerosis

“…This clinical course is unpredictable, and no tools for prognosis currently exist. Several studies have explored the genetic basis of clinical course, age of onset and severity, although no genome‐wide significant associations have been discovered 36, 37, 43, 74, 75, 76, 77. Whether more detailed disease parameters are more prone to error measurement, systematic differences across centres or simply not heritable remains to be determined, but a recent study showing that clinical scores can be predictive across centres suggests that lack of heritability is not the issue 78…”

Association analysis of cytokine receptors’ genes polymorphisms with clinical features of multiple sclerosis

“…Генетические исследования, проведенные с по-мощью полногеномного поиска ассоциаций (genome-wide association study -GWAS) с клиническим течением РС [6,7], не дали совпадающих результа-тов, что делает актуальным поиск генетических ва-риантов, ассоциированных с клиническими фено-типами РС, с использованием генов-кандидатов. При этом особый интерес представляет анализ воз-можного участия генов, связанных с предрасполо-женностью к РС и модификацией его клинического течения [8,9].…”

Interleukin 17 gene polymorphism is associated with anti-aquaporin 4 antibody-positive neuromyelitis optica in the Southern Han Chinese — A case control study

“…Individuals with an HLA-DRB1*1501 genotype are generally recognized as having the strongest risk of MS in Western populations [4]. In contrast, we have demonstrated an association of DPB1*0501, but not of DRB1*1501, with NMO in the Southern Han Chinese, indicating a difference from Western populations [5].…”

“…Unbiased genome-wide association studies in MS have mapped associated genetic variations among Western populations [4,7,19]. The genetic factors in NMO are less well studied.…”