Genome-Wide Copy Number Variation in Sporadic Amyotrophic Lateral Sclerosis in the Turkish Population: Deletion of EPHA3 Is a Possible Protective Factor

Abstract

The genome-wide presence of copy number variations (CNVs), which was shown to affect the expression and function of genes, has been recently suggested to confer risk for various human disorders, including Amyotrophic Lateral Sclerosis (ALS). We have performed a genome-wide CNV analysis using PennCNV tool and 733K GWAS data of 117 Turkish ALS patients and 109 matched healthy controls. Case-control association analyses have implicated the presence of both common (>5%) and rare (<5%) CNVs in the Turkish population. In the framework of this study, we identified several common and rare loci that may have an impact on ALS pathogenesis. None of the CNVs associated has been implicated in ALS before, but some have been reported in different types of cancers and autism. The most significant associations were shown for 41 kb and 15 kb intergenic heterozygous deletions (Chr11: 50,545,009–50,586,426 and Chr19: 20,860,930–20,875,787) both contributing to increased risk for ALS. CNVs in coding regions of the MAP4K3, HLA-B, EPHA3 and DPYD genes were detected however, after validation by Log R Ratio (LRR) values and TaqMan CNV genotyping, only EPHA3 deletion remained as a potential protective factor for ALS (p = 0.0065024). Based on the knowledge that EPHA4 has been previously shown to rescue SOD1 transgenic mice from ALS phenotype and prolongs survival, EPHA3 may be a promising candidate for therepuetic interventions.

Copy number variations (CNVs) - is there a biological difference between submicroscopic and microscopically visible ones?

“…It has to be admitted, that some potentially harmless MG-CNVs have already been linked in population studies to an enhanced or diminish susceptibility for special disorders or (age-related) diseases. However, mechanisms, therefore, are still not understood yet 14 .…”

Genome sequencing reveals a novel genetic mechanism underlying dihydropyrimidine dehydrogenase deficiency: A novel missense variant c.1700G>A and a large intragenic inversion in DPYD spanning intron 8 to intron 12

“…Previously, we showed that genomic deletions affecting DPYD occurred in 7% of pediatric patients with a complete DPD deficiency (van Kuilenburg et al., ). Genomic rearrangements in DPYD have also been observed in patients with ID (Willemsen et al., ), autism‐spectrum disorder (Carter et al., ; Prasad et al., ), syndromic obesity (D'Angelo, Moller Dos Santos, Alonso, & Koiffmann, ), and amyotrophic lateral sclerosis (Uyan et al., ). To date, no clear genotype–phenotype correlation has been established in patients with a DPD deficiency but it is noteworthy that patients with gross deletions in DPYD presented with a severe phenotype when compared with that observed in other DPD patients (van Kuilenburg et al., ).…”

Genetic causes of amyotrophic lateral sclerosis: New genetic analysis methodologies entailing new opportunities and challenges

“…In addition, there have been studies of copy number variation (Blauw et al, 2008; Cronin et al, 2008; Wain et al, 2009; Blauw et al, 2010; Uyan et al 2013), a study specifically focusing on homozygosity segments (Mok et al 2013), and a pooling GWAS combined with pathway analysis (Xie et al, 2014). …”

“…Similar to single nucleotide polymorphisms (SNPs), copy number variants are detected in healthy people. Several surveys have been performed in attempt to evaluate the involvement of copy number variants in ALS (Blauw et al, 2008; Cronin et al, 2008; Wain et al, 2009; Soichet et al, 2009; Blauw et al, 2010; Uyan et al 2013), while others investigated specific categories of copy number variants including de novo copy number variants (Pamphlett and Morahan, 2011a), somatic copy number variants (Pamphlett and Morahan, 2011b; Pamphlett and Morahan, 2011c), and copy number variants in ALS-discordant monozygotic twin pairs (Pamphlett and Morahan, 2011c). Although many copy number variants that were specific to patients with ALS were detected, common copy number variants were not significantly associated to ALS in these studies.…”

“…Conflicting results have been obtained for SMN2 , a homologe of SMN1 (Lee et al, 2012a; Corcia et al, 2012). Finally, a recent study pointed out that deletion of EPHA3 might be a protective factor (Uyan et al, 2013). Taken together, these data indicate that the role of copy number variants in ALS has not been fully resolved and is worth exploring further, possibly with the help of newer genome-wide technologies.…”