Analysis of Structural Variants Previously Associated With ALS in Europeans Highlights Genomic Architectural Differences in Africans

Background And Objectives: Amyotrophic lateral sclerosis (ALS) is a degenerative condition of the brain and spinal cord in which protein-coding variants in known ALS disease genes explain a minority of sporadic cases. There is a growing interest in the role of noncoding structural variants (SVs) as ALS risk variants or genetic modifiers of ALS phenotype. In small European samples, specific short SV alleles in noncoding regulatory regions of , , and have been reported to be associated with ALS, and several groups have investigated the possible role of / gene copy numbers in ALS susceptibility and clinical severity.

Methods: Using short-read whole genome sequencing (WGS) data, we investigated putative ALS-susceptibility (3'UTR poly-T repeat), (intron 5 AAAC insertion) and (intron 3 CA repeat) alleles in African ancestry patients with ALS and described the architecture of the / gene region. South African cases with ALS (n = 114) were compared with ancestry-matched controls (n = 150), 1000 Genomes Project samples (n = 2,336), and H3Africa Genotyping Chip Project samples (n = 347).

Results: There was no association with previously reported poly-T repeat, AAAC insertion, and long CA alleles with ALS risk in South Africans ( > 0.2). Similarly, and gene copy numbers did not differ between South Africans with ALS and matched population controls ( > 0.9). Notably, 20% of the African samples in this study had no gene copies, which is a higher frequency than that reported in Europeans (approximately 7%).

Discussion: We did not replicate the reported association of , , and short SVs with ALS in a small South African sample. In addition, we found no link between and copy numbers and susceptibility to ALS in this South African sample, which is similar to the conclusion of a recent meta-analysis of European studies. However, the gene region findings in Africans replicate previous results from East and West Africa and highlight the importance of including diverse population groups in disease gene discovery efforts. The clinically relevant differences in the gene architecture between African and non-African populations may affect the effectiveness of targeted gene therapy for related diseases such as spinal muscular atrophy.