Mapping the genomic basis for neurodegenerative disease

This study seeks to identify and characterise genomic factors relevant to amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's and related disorders of the neurodegenerative spectrum. Our study will integrate data from ADSP with additional genetic datasets, most notably 22,500 whole genome sequences generated by project MinE (www.projectmine.com), as well as secondary genetic datasets generated by project MinE collaborators or obtained through public repositories. The combining of datasets is necessary to achieve the statistical power required for this work.
Our study will analyze genetic factors as both single variants and in aggregated variant sets in order to identify variants, genes and biological networks of disease relevance. Statistical methods will include techniques standard to the field such as GWAS, heritability analyses, gene and pathway level association testing and related methods utilized previously by our group (van Rheenen, Nat Genet, 2016; Kenna, Nat Genet 2016; McLaughlin Nat. Commun, 2017), as well as novel methods currently under development. The phenotypic end-point studied in all primary analyses will be disease risk, however the study will also investigate genetic correlation across disease states and test for variants that modify patient phenotype (survival, age at onset, motor impairment, cognitive impairment, behavioural impairment etc). Standard data quality control measures will be implemented to prevent spurious association signals, these include appropriate corrections for data quality, genetic relatedness, sample outliers and batch effects. Consent type and other Data Use Limitations for each study will be fully respected in all analyses. The resulting dataset does not create additional risks to the participants. All data will be anonymised and stored in a secure location with strictly controlled access restrictions as per dbGAP recommended best practices. All methods and research findings generated by this study will be published and made available to the wider research community.

This study will combine genetic datasets from ADSP with whole genome sequencing of patients diagnosed with amyotrophic lateral sclerosis, frontotemporal dementia and related neurodegenerative disorders. Integrating these large datasets provides an unprecedented opportunity to screen for genetic factors that cause disease, as well as for genetic factors that modify the symptoms or progression of disease across individual patients. Our work has the potential to provide critical new insights into neurodegenerative disease and to guide the development of new treatments.