Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients

Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS).ResultsWhole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific disease-associated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question.ConclusionsTo our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance.Electronic supplementary materialThe online version of this article (10.1186/s40246-017-0126-2) contains supplementary material, which is available to authorized users.

Fat Mass and Obesity Associated (FTO) Protein Ekspresyonunun Neden Olduğu SH-SY5Y Hücrelerinin Proteomunda Meydana Gelen Değişiklikler, FTO Proteininin Çok Yönlü Özellikleri Ortaya Çıkarır

“…[12][13][14][15] Further research elucidated more about the physiological role of FTO and revealed that FTO is not only associated with obesity but also with a seemingly unrelated disorder, neurodegeneration. [16][17][18][19][20][21] However, so far no direct link was provided regarding the mechanism for the effect of FTO on neuronal degeneration. In this study, we choose to study the effect of expressing the WT and the mutant FTO expressions on the soluble proteome of SH-SY5Y cells.…”

New Insights on the Role of N6-Methyladenosine RNA Methylation in the Physiology and Pathology of the Nervous System

“…Evidence of m 6 A involvement in the pathogenesis of ALS is also emerging. In addition to its wide expression in brain, FTO has been shown to be highly expressed in lower motor neurons ( Mitropoulos et al, 2017 ). Whole-genome sequencing analysis of Greek patients with sporadic ALS revealed a positive association between FTO gene variants and the disease ( Mitropoulos et al, 2017 ).…”

“…In addition to its wide expression in brain, FTO has been shown to be highly expressed in lower motor neurons ( Mitropoulos et al, 2017 ). Whole-genome sequencing analysis of Greek patients with sporadic ALS revealed a positive association between FTO gene variants and the disease ( Mitropoulos et al, 2017 ). Moreover, a targeted gene sequencing of RBPs in ALS patients identified rare deleterious polymorphisms at a significantly higher rate than control in the RBM15 gene and in its paralog RMB15B ( Cooper-Knock et al, 2017 ).…”

Roadmap for Establishing Large-Scale Genomic Medicine Initiatives in Low- and Middle-Income Countries

“…In particular, the project aims to analyze (1) a large number of healthy donors of Hellenic origin, to determine the allelic architecture of the population, especially pharmacogenomic variants; (2) cohorts of patients suffering from rare multifactorial genetic diseases, such as amyotrophic lateral sclerosis, celiac disease, multiple sclerosis, etc., to identify their underlying genetic etiology; and (3) cohorts of patients suffering from monogenic diseases, such as cystic fibrosis and b-thalassemia, to identify genetic modifiers of the final clinical phenotype. So far, using this approach, a genomic locus was found to be associated with sporadic ALS in Greek patients via whole-genome sequencing 11 as well as a genomic locus associated with pediatric celiac disease in Greek patients. 12 Also, we have demonstrated the utility of whole-genome sequencing analysis in pharmacogenomics, using a Greek family as a paradigm.…”