A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches

Abstract

Multiple sclerosis (MS) is a common complex neurodegenerative disease of the central nervous system. It develops with autoimmune inflammation and demyelination. Genome-wide association studies (GWASs) serve as a powerful tool for investigating the genetic architecture of MS and are generally used to identify the genetic factors of disease susceptibility, clinical phenotypes, and treatment response. This review considers the main achievements and challenges of using GWAS to identify the genes involved in MS. It also describes hypothesis-driven studies with extensive genome coverage of the selected regions, complementary to GWASs. To date, over 100 MS risk loci have been identified by the combination of both approaches; 40 of them were found in at least two GWASs and meet genome-wide significance threshold (p ≤ 5 × 10(-8)) in at least one GWAS, whereas the threshold for the rest of GWASs was set in our review at p < 1 × 10(-5). Yet, MS risk loci identified to date explain only a part of the total heritability, and the reasons of "missing heritability" are discussed. The functions of MS-associated genes are described briefly; the majority of them encode immune-response proteins involved in the main stages of MS pathogenesis.

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

“…Выявленная ассоциа-ция полиморфизмов TNFRSF1A и IL7RA с длитель-ностью ПР находится в соответствии c результатами исследования, проведенного на смешанной популя-ции европеоидов [22]. Показано [10], что носитель-ство аллелей риска генов TNFRSF1A и IL7RA ведет к увеличению количества растворимых изоформ ре-цепторов, которые, связываясь с соответствующими цитокинами, способны конкурентно ингибировать активацию сигнальных путей рецепторов цитоки-нов ФНО и ИЛ-7. Возможность прогнозировать индивидуальное клиническое течение РС в самом начале заболева-ния является важным фактором для стратегии веде-ния пациента.…”

“…Эти рецепторы являются важнейшими участниками сигнальных путей интерлейкина (ИЛ)-7, ИЛ-2 и фактора некроза опухолей (ФНО) и во многом определяют развитие и функционирование клеток иммунной системы. Ассоциация полиморф-ных вариантов этих генов с предрасположенностью к РС была выявлена в одном из обзоров GWAS [10] и подтверждена в нескольких популяциях [8,9,11]. В ряде исследований [8,9,12] была обнаружена ас-социация полиморфных вариантов генов, кодирую-щих рецепторы цитокинов, не только с риском РС, но и с рядом его клинических характеристик.…”

Genetic variation in the geneLRP2increases relapse risk in multiple sclerosis

“…Successes in identifying genetic risk factors for MS derive mainly from genome-wide association studies (GWAS), with the first published in 2007 3. However, most of the MS GWAS have thus far utilised a case–control design4: comparing genotype frequencies between persons with and without disease. This study design necessarily focuses on initiating events, rather than progression of MS, thus giving indications of disease ‘onset’ risk but not potential genetic drivers of subsequent disease severity.…”

Environmental control of autoimmune inflammation in the central nervous system

“…Today, over 100 genetic risk loci have been identified and include HLA alleles (HLA-DRB1*1501, DR3, DR4), cytokines, chemokines and their receptors (e. g. IL12A , IL2RA , IL7RA, CCR5, CXCR5 ), transcription factors (e. g. SOCS1, STAT3, IRF8, EOMES ), adhesion molecules (e. g. VCAM1 ), as well as micro-RNA genes (e. g. MIR1204 , MIR1205 , MIR1208 , MIR3686 ), clearly underlining both the importance of the immune system and the multi-factorial nature of MS pathogenesis 8,9 . Interestingly, genetic variants associated with Vitamin D metabolism ( CYP27B1 ) have been shown to increase the risk of MS as well 10 .…”