For complex disease genetics, collaboration drives progress

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Science  27 Mar 2015:
Vol. 347, Issue 6229, pp. 1422-1423
DOI: 10.1126/science.aaa9838

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A principal tool in the development of etiology-based therapies is the identification of the genetic determinants of disease. The logic of this approach rests on the expectation that knowledge of the genetic variants underlying disease will enhance our understanding of the molecular pathogenesis of disease and reveal viable points for therapeutic intervention. Because of the general adoption of this paradigm, genetics has been a dominant force in disease investigation over the past 25 years. Success in this area has come in waves, each driven by new methods and technology. Linkage (identifying segments of the genome that are associated with given traits), positional sequencing (sequencing specific candidate genes based on their location), genome-wide association (examining genetic variants in a genome-wide manner across individuals for association with a trait), and family-based next-generation sequencing have each produced startling new phases of genetic discovery. The study by Cirulli et al. (1), reported on page 1436 of this issue, marks an early success in another phase of gene discovery: the application of exome sequencing in large case-control cohorts to identify genetic factors involved in complex disease. This is one of the first successes in this area and provides insights into amyotrophic lateral sclerosis (ALS), as well as broader lessons for disease gene discovery.