ATXN2 and its neighbouring gene SH2B3 are associated with increased ALS risk in the Turkish population

Expansions of the polyglutamine (polyQ) domain (≥34) in Ataxin-2 (ATXN2) are the primary cause of spinocerebellar ataxia type 2 (SCA2). Recent studies reported that intermediate-length (27–33) expansions increase the risk of Amyotrophic Lateral Sclerosis (ALS) in 1–4% of cases in diverse populations. This study investigates the Turkish population with respect to ALS risk, genotyping 158 sporadic, 78 familial patients and 420 neurologically healthy controls. We re-assessed the effect of ATXN2 expansions and extended the analysis for the first time to cover the ATXN2 locus with 18 Single Nucleotide Polymorphisms (SNPs) and their haplotypes. In accordance with other studies, our results confirmed that 31–32 polyQ repeats in the ATXN2 gene are associated with risk of developing ALS in 1.7% of the Turkish ALS cohort (p = 0.0172). Additionally, a significant association of a 136 kb haplotype block across the ATXN2 and SH2B3 genes was found in 19.4% of a subset of our ALS cohort and in 10.1% of the controls (p = 0.0057, OR: 2.23). ATXN2 and SH2B3 encode proteins that both interact with growth receptor tyrosine kinases. Our novel observations suggest that genotyping of SNPs at this locus may be useful for the study of ALS risk in a high percentage of individuals and that ATXN2 and SH2B3 variants may interact in modulating the disease pathway

Distribution of ATXN2 repeat sizes, represented as polyQ triplet numbers.

<p>Turkish ALS patients are represented in red and healthy controls in blue bars; numbers of the individuals having the relevant alleles are shown on the top of each bar.</p

CNV call validation via LRR values.

<p>LRR values of controls and individuals with CNV for particular SNPs were extracted to check CNV calls of PennCNV tool. Average LRR values of each SNP for both groups were calculated and plotted. Consecutive SNPs in chromosome position line do not demonstrate the exact distance. The CNVs detected by PennCNV were shown by black bars. (a) Loss of an intergenic region on chromosome 11 between rs1916207 and rs554110 (chr11: 50,545,009–50,586,426), (b) gain of MAP4K3 gene between rs12151392 and rs2373530 (chr2: 39,372,016–39,428,488), (c) homozygous loss of HLA-B gene between rs9295976 and rs28367708 (chr6: 31,389,749–31,393,270), (d) loss of EPHA3 gene between rs2063589 and rs870899 (chr3: 89,485,137–89,499,861) (NCBI37/hg19).</p

Distribution of LRR values of controls and individuals with CNV at SNP level.

<p>LRRs of all individuals were extracted and plotted. “<i>Cont</i>” indicates control individuals and “<i>CNV</i>” indicates individuals with a CNV. “*” indicates the significance level between controls and CNV. 4 SNPs, including one upstream, one downstream and two within the CNV region, were selected and LRRs were plotted for (a) intergenic reigon on chromosome 11, (b) MAP4K3 gene, (c) HLA-B gene and (d) EPHA3 gene.</p

Association results of CNVs observed in analysis with p<0.05 (Fisher’s Exact Test).

<p>loss* Homozygous deletion.</p

Characteristics of CNV calls.

<p>Characteristics of CNV calls.</p

Summary Statistics of CNV screening in 115 ALS patients and 106 controls.

<p>Summary Statistics of CNV screening in 115 ALS patients and 106 controls.</p