Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis

• Published in: European journal of human genetics : EJHG Vol. 26; no. 10; pp. 1537 - 1546
• Main Authors: Wouter Van Rheenen, Pulit, Sara L, Dekker, Annelot M, Ahmad Al Khleifat, Brands, William J, Iacoangeli, Alfredo, Kenna, Kevin P, Kavak, Ersen, Kooyman, Maarten, McLaughlin, Russell L, Middelkoop, Bas, Moisse, Matthieu, Schellevis, Raymond D, Shatunov, Aleksey, Sproviero, William, Tazelaar, Gijs H P, Rick A A Van der Spek, Perry T C Van Doormaal, Van Eijk, Kristel R, Joke Van Vugt, Basak, A Nazli, Blair, Ian P, Glass, Jonathan D, Hardiman, Orla, Hide, Winston, Landers, John E, Mora, Jesus S, Morrison, Karen E, Newhouse, Stephen, Robberecht, Wim, Shaw, Christopher E, Shaw, Pamela J, Philip Van Damme, Van Es, Michael A, Wray, Naomi R, Al-Chalabi, Ammar, Leonard H Van den Berg, Veldink, Jan H
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.10.2018; Springer International Publishing
• Subjects: Alleles; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Data processing; Female; Gene Frequency; Genetic diversity; Genetic Predisposition to Disease; Genetic Variation - genetics; Genome, Human - genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Humans; Male; Netherlands; Nucleotide sequence; Polymorphism, Single Nucleotide; Whole Genome Sequencing; Netherlands
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/s41431-018-0177-4

The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility to disease. We have therefore begun Project MinE, an international collaboration that seeks to analyze whole-genome sequence data of at least 15 000 ALS patients and 7500 controls. Here, we report on the design of Project MinE and pilot analyses of successfully sequenced 1169 ALS patients and 608 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public datasets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests.