Evaluating rare variants in complex disorders using next-generation sequencing

Abstract

Determining the genetic architecture of liability for complex neuropsychiatric disorders like autism spectrum disorders and schizophrenia poses a tremendous challenge for contemporary biomedical research. Here we discuss how genetic studies first tested, and rejected, the hypothesis that common variants with large effects account for the prevalence of these disorders. We then explore how the discovery of structural variation has contributed to our understanding of the etiology of these disorders. The rise of fast and inexpensive oligonucleotide sequencing and methods of targeted enrichment and their influence on the search for rare genetic variation contributing to complex neuropsychiatric disorders is the next focus of our article. Finally, we consider the technical challenges and future prospects for the use of next-generation sequencing to reveal the complex genetic architecture of complex neuropsychiatric disorders in both research and the clinical settings.

Figure 1

Summary of single nucleotide variant (SNV) and insertion/deletion (indel) variation discovered at the FMR1 and AFF2 loci in males with autism spectrum disorder. The frequency of SNVs and indels (minor alleles) in cases is plotted against their level of evolutionary conservation. Population genetic theory predicts, and empirical data has now confirmed, that most genetic variation is rare. The observation of evolutionary conservation between species at a given site in the human genomes implies that genetic variation at this site is deleterious to individual fitness and is therefore rapidly removed from the human population. Hence, it follows that disease-causing mutations are expected to be enriched among the class of rare variants found at highly evolutionary conserved sites in the human genome. Most common variation has already been discovered and exists in public databases like dbSNP (blue; circles and diamonds). In contrast, most of the rare variation at both loci was not contained in public databases (red; circles and diamonds).