Project MinE: study design and pilot analyses of a large-scale whole genome sequencing study in amyotrophic lateral sclerosis
Abstract
The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility of disease. We have therefore begun Project MinE, an international collaboration that seeks to analyse whole-genome sequence data of at least 15,000 ALS patients and 7,500 controls. Here, we report on the design of Project MinE and pilot analyses of newly whole-genome sequenced 1,264 ALS patients and 611 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 data sets. 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.
Subject Area
- Biochemistry (11573)
- Bioengineering (8623)
- Bioinformatics (28874)
- Biophysics (14805)
- Cancer Biology (11944)
- Cell Biology (17170)
- Clinical Trials (138)
- Developmental Biology (9306)
- Ecology (14022)
- Epidemiology (2067)
- Evolutionary Biology (18129)
- Genetics (12148)
- Genomics (16619)
- Immunology (11709)
- Microbiology (27697)
- Molecular Biology (11392)
- Neuroscience (60106)
- Paleontology (447)
- Pathology (1849)
- Pharmacology and Toxicology (3184)
- Physiology (4878)
- Plant Biology (10279)
- Synthetic Biology (2849)
- Systems Biology (7291)
- Zoology (1619)