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.
Highlights
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a neurodegenerative disorder that affects the upper and lower motor neurons in the motor cortex, brain stem, and spinal cord [20]
Whole-genome sequencing analysis of Greek sporadic ALS (sALS) patients reveals a positive association with FTO and TBC1D1 variants Our next-generation sequencing-based genomics approach yielded a total of 174 Single nucleotide polymorphisms (SNPs) that were found only in the sALS patients studied; these were variously intergenic (n = 144), intronic (n = 23), and/or were present in upstream (n = 2), downstream (n = 1), and 3′UTR (n = 2) regions or non-coding RNAs (n = 2)
We found that four FTO intronic variants, rs2892469 (C>T) and rs1861869 (G>C), rs17217144 (C>T), and rs7186521 (A>G), reached statistical significance (p = 0.033, p = 0.07, p = 0.002, and p < 0.001, respectively), when Greek sALS patients were compared to their healthy counterparts
Summary
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a neurodegenerative disorder that affects the upper and lower motor neurons in the motor cortex, brain stem, and spinal cord [20]. 90–95% of ALS patients suffer from a sporadic form of ALS (sALS), which has both an environmental etiology and a likely strong genetic component [23]. The remaining 5–10% of ALS patients exhibit a clear genetic etiology for the disease, known as familial ALS (fALS). Genomic variants in the SOD1 gene have been shown to lead to fALS, with an autosomal dominant mode of inheritance. More than 170 different SOD1 genomic variants have been reported, affecting ~ 13% of fALS and ~ 1% of sALS patients [40]. Amyotrophic 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. 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)
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