Genetics and Epigenetics of Amyotrophic Lateral Sclerosis in Mongolia, Egypt, Germany and China

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Amyotrophic lateral sclerosis (ALS) is a common (lifetime risk ~1/400) and rapidly progressing neurodegenerative disease affecting primary motoneurons of the motor cortex, brain stem and spinal cord. Associated denervation of skeletal muscles results in muscular atrophy, paralysis and death by respiratory failure. Roughly 5-10% of ALS patients report a family history of the disease (fALS) and about 2/3 thereof are explained by mutations in one of more than two dozen protein-coding ALS genes. The remaining patients are considered sporadic (sALS) with polygenic and/or environmental causality. Genetics of ALS is not uniform across different ethnic groups and/or geographical regions. For example, the most frequent cause of fALS in populations of European ancestry, a hexanucleotide repeat expansion in C9ORF72, is very rare in patients of Chinese origin and result from distinct mutational founder events. Additionally, epigenetic mechanisms, e.g. DNA methylation, are genetically linked to ALS, and changes are evident in the CNS but also extra-CNS tissue such as blood samples. Considering that roughly 1/3 of fALS and most sALS patients are still unexplained, and our knowledge of ALS (epi)genetics is mainly derived from patients with European ancestry, we propose to search for novel genic causes in understudied non-European populations, and to define robust epigenetic profiles of ALS. Therefore, we plan whole-genome-sequencing of 250 ALS patients and available relatives from Mongolia and Egypt. Identification of candidate variants, especially recessive traits, variations in non-coding regions and structural variants will be supported by total RNA sequencing from blood samples monitoring functional consequences, and by targeted co-segregation analyses. Furthermore, we plan Infinium Methylation EPIC arrays from blood samples of 100 fALS patients and controls from Mongolia, Egypt and Germany. Increasing the variance of genetic backgrounds and environmental factors may help discriminating primary disease-associated epigenetic changes from secondary alterations and/or possible confounders. Candidate variants and robust epigenetic changes will be further confirmed/explored by targeted approaches in independent replication cohorts of German and Chinese fALS and sALS patients. Considering that current biomarkers for ALS, i.e. different types of neurofilaments in plasma and/or cerebrospinal fluid, are restricted to the symptomatic phase of the disease, putative epigenetic findings will also be validated in a cohort of German presymptomatic mutation carriers and tested for biomarker potential. Additionally, post-mortem CNS tissue will be analyzed to test conservation of changes from blood samples in relevant tissues, providing insights into putatively novel disease mechanisms.