Abstract
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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal neurodegenerative disease [1]
Genetic risk factors have been extensively studied in familial ALS cases, and this effort has led to the identification of highly penetrant causal variants, including variants residing in SOD1 [4], TARBP [5], FUS [6], and C9orf72 [7, 8]
After Quality control (QC), 1,169 unrelated Dutch-ancestry cases and 608 ancestrally-matched controls were available for analysis
Summary
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal neurodegenerative disease [1]. Twin studies estimate the heritability of ALS to be ~60%, suggesting a strong genetic component contributing to disease risk [2], and approximately 10–15% of patients have a clear family history of disease [3]. In so-called sporadic ALS cases, who have no known family history of disease and comprise the majority of all cases, only a small number of other common genetic risk loci have been identified. Among these loci are the ATXN2 CAG repeat expansion.
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