{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T06:09:30Z","timestamp":1760854170177,"version":"3.41.2"},"reference-count":121,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T00:00:00Z","timestamp":1610582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Genome-wide association studies (GWAS) and rare variant association studies (RVAS) are applied across many areas of complex disease to analyze variation in whole genomes of thousands of unrelated patients. These approaches are able to identify variants and\/or biological pathways which are associated with disease status and, in contrast to traditional linkage studies or candidate gene approaches, do so without requiring multigenerational affected families, prior hypotheses, or known genes of interest. However, the novel associations identified by these methods typically have lower effect sizes than those found in classical family studies. In the motor neuron disease amyotrophic lateral sclerosis (ALS), GWAS, and RVAS have been used to identify multiple disease-associated genes but have not yet resulted in novel therapeutic interventions. There is significant urgency within the ALS community to identify additional genetic markers of disease to uncover novel biological mechanisms, stratify genetic subgroups of disease, and drive drug development. Given the widespread and increasing application of genetic association studies of complex disease, it is important to recognize the strengths and limitations of these approaches. Here, we review ALS gene discovery via GWAS and RVAS.<\/jats:p>","DOI":"10.3389\/fnins.2020.603023","type":"journal-article","created":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T16:40:20Z","timestamp":1610642420000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Searching Far and Genome-Wide: The Relevance of Association Studies in Amyotrophic Lateral Sclerosis"],"prefix":"10.3389","volume":"14","author":[{"given":"Kelly A.","family":"Rich","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Roggenbuck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen J.","family":"Kolb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1126\/science.1156409","article-title":"Genetic mapping in human disease.","volume":"322","author":"Altshuler","year":"2008","journal-title":"Science (New York, N.Y.)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-015-0138-2","article-title":"Rare variant association studies: considerations, challenges and opportunities.","volume":"7","author":"Auer","year":"2015","journal-title":"Genome Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/ng.381","article-title":"Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.","volume":"41","author":"Barrett","year":"2009","journal-title":"Nat. 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