Application of next-generation sequencing technologies in Neurology

Abstract

Genetic risk factors that underlie many rare and common neurological diseases remain poorly understood because of the multi-factorial and heterogeneous nature of these disorders. Although genome-wide association studies (GWAS) have successfully uncovered numerous susceptibility genes for these diseases, odds ratios associated with risk alleles are generally low and account for only a small proportion of estimated heritability. These results implicated that there are rare (present in <5% of the population) but not causative variants exist in the pathogenesis of these diseases, which usually have large effect size and cannot be captured by GWAS. With the decreasing cost of next-generation sequencing (NGS) technologies, whole-genome sequencing (WGS) and whole-exome sequencing (WES) have enabled the rapid identification of rare variants with large effect size, which made huge progress in understanding the basis of many Mendelian neurological conditions as well as complex neurological diseases. In this article, recent NGS-based studies that aimed to investigate genetic causes for neurological diseases, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, stroke, amyotrophic lateral sclerosis and spinocerebellar ataxias, have been reviewed. In addition, we also discuss the future directions of NGS applications in this article.

Keywords: Next-generation sequencing (NGS); genetics; neurological diseases; whole-exome sequencing (WES); whole-genome sequencing (WGS).

Figure 1

Simplified workflows for NGS. (A) Sample preparation. Genomic DNA is extracted from lymphocyte and is broken up into short fragment (~350 bp); (B) sequencing and data analysis. Sequence adaptors are added to each fragment, which allow each fragment to be hybridized to the flowcell where the sequencing occurs. WES proceeds by hybridizing the fragments to probes that are complimentary to all the exons in the genome, which are then captured while the remaining DNA is washed away. WGS does not need extra steps following the addition of sequence adaptors and the library is ready to be sequenced at that point. After receiving the results of WES or WGS, millions of short sequence reads are accurately mapped to a reference genome sequence, and variants within the genome are identified. NGS, next-generation sequencing; WES, whole-exome sequencing; WGS, whole-genome sequencing.