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

Konstantinos Mitropoulos, Eleni Merkouri Papadima, Georgia Xiromerisiou, Angeliki Balasopoulou, Kyriaki Charalampidou, Vasiliki Galani, Krystallia Vassiliki Zafeiri, Efthymios Dardiotis, Styliani Ralli, Georgia Deretzi, Anne John, Kyriaki Kydonopoulou, Elpida Papadopoulou, Alba Di Pardo, Fulya Akcimen, Annalisa Loizedda, Valerija Dobriĉić, Ivana Novaković, Vladimir S. Kostic, Clint MizziBrock A. Peters, Nazli Basak, Sandro Orrù, Evangelos Kiskinis, David N. Cooper, Spyridon Gerou, Radoje Drmanac, Marina Bartsakoulia, Evangelia Eirini Tsermpini, Georgios M. Hadjigeorgiou, Bassam R. Ali, Theodora Katsila, George P. Patrinos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background: 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. 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). Results: Whole-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 diseaseassociated 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. Conclusions: To 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.

Original languageEnglish (US)
Article number30
JournalHuman genomics
Volume11
Issue number1
DOIs
StatePublished - Mar 4 2017

Keywords

  • FTO gene
  • Founder population
  • Genomic variants
  • Sporadic amyotrophic lateral sclerosis
  • Whole-genome sequencing

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery

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