Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 26, Issue 10, Pages 1537-1546Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41431-018-0177-4
Keywords
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Funding
- European Community's Health Seventh Framework Programme (FP7)
- ALS Foundation Netherlands
- IWT (Project MinE)
- Belgian ALS liga (Project MinE)
- National Lottery
- Interuniversity Attraction Poles (IUAP) program of the Belgian Federal Science Policy Office [P7/16]
- Fund for Scientific Research Vlaanderen (FWO-Vlaanderen)
- MND Association [957-799]
- Science Foundation Ireland [15/SPP/3244]
- Health Research Board
- Charity Research Motor Neurone
- Spanish ALS Research Foundation FUNDELA
- Suna and Inan Kirac Foundation
- Bogazici University
- National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London
- NIHR University College London Hospitals Biomedical Research Centre
- Farr Institute of Health Informatics Research at UCL Partners
- Medical Research Council
- Arthritis Research UK
- British Heart Foundation
- Cancer Research UK
- Chief Scientist Office
- Economic and Social Research Council
- Engineering and Physical Sciences Research Council
- National Institute for Health Research
- National Institute for Social Care and Health Research
- Wellcome Trust [MR/K006584/1]
- US National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) [R01NS073873]
- American ALS Association
- Motor Neurone Disease Research Institute of Australia
- National Health and Medical Research Council of Australia
- MRC [MR/R024804/1] Funding Source: UKRI
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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.
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