There are at least two main competing models that try to explain the genetic basis of human complex disease: rare alleles with moderate to high effect versus many variants with small effects. For the past seven years, genome-wide association studies (GWAS) have identified thousands of common single-nucleotide polymorphisms for a wide range of diseases including multiple sclerosis, Alzheimer’s, Parkinson’s and type 2 diabetes. Despite this success, GWAS have been limited in their lack of coverage of low frequency and rare variation. Evidence accumulates that multiple rare variants (copy number variants and mutations) are related to many complex human diseases, including schizophrenia and autism, but they have been notoriously difficult to study.
In addition, GWAS do not provide (sufficient) information about more complex types of variation like repeat expansions or structural variants. Next-generation sequencing technologies now make it possible to investigate the genome extensively, and provide an unprecedented opportunity to learn about the genetic basis of complex diseases like ALS, where the contribution of rare variants and more complex types of variants may be more relevant than that of common variation. Therefore, our research is focused on a combination of GWAS with a systematic (whole genome) sequencing of large cohorts of ALS patients and appropriate controls. For familial variants of ALS we perform whole genome sequencing of nuclear families.