Genetic sequencing technology is advancing at a considerable pace, and learning how to effectively harness the power of whole-genome sequencing will provide information of unparalleled depth and detail. Van Rheenen et al. used whole-genome sequencing data on 1246 ALS cases and 615 controls to dramatically improve the sensitivity of genetic screening to enable detection of low-frequency variants by imputation. An impressive 8.7 million SNPs were genotyped in 7763 ALS cases and 4669 controls, and by combining with genotyping data from 41 other genetic studies of ALS, a meta-analysis was performed on a total of 12,577 ALS cases and 23,475 controls. The study reports three new independent loci that associate with ALS risk with genome-wide significance: C27orf2, MOBP and SCFD1, which were all replicated in subsequent analysis of 2579 ALS cases and 2767 controls. Three previously associated loci were also replicated: C9orf72, SARM1 and UNC13A.
The authors go on to report fine mapping and functional data that begin to explain how the newly discovered variants confer risk to ALS. Fine mapping of C27orf2 in 2562 ALS cases and 1138 controls demonstrated an excess of loss-of-function mutations, suggesting pathology is caused by reduced protein product of C27orf2. Also, publicly available gene expression data from human brain were used to search for SNPs at the risk loci that correlate with expression of nearby genes. This analysis revealed that the variants at SARM1 and UNC13A appear to, at least partly, influence function by controlling expression of the genes POLDIP2 and KCNN1, respectively.
Finally, the study proceeded to analyse the genetic architecture of ALS by estimating the proportion of heritability explained by low versus high frequency variants. When compared with schizophrenia, a classical polygenic disorder dominated by common variants, the genetic risk for ALS appears to be dominated by a large number of rare variants that each confer substantial risk.
Comment This powerful study identifies three new loci that confer risk to ALS and provides some initial information on the possible pathogenic mechanisms. This is by far the largest genetic study in ALS to date and goes some way to resolving a fundamental question about the genetic architecture of ALS. Complementary to this work is a study published in the same edition of Nature Genetics by Kenna et al. who report discovery of a new gene implicated in familial ALS by exome sequencing. As a substantial proportion of the heritability of ALS is conferred by a large number of rare variants, each conferring relatively high risk to disease, future genetic studies of ALS must ensure that rare variants are captured. Such a genetic architecture implies that clinicians will have a key role in establishing genotype–phenotype correlations, which will help determine how genetic factors contribute to clinical heterogeneity.
Van Rheenen W et al. (2016) Nature Genetics 48(9):1043–1046.