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 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.

Fig. 1

Consortium design. Consortium structure including funding agencies, research groups, the Project MinE general assembly, sub-projects, and data management. Each research group obtains funding using uniform grant proposals shared between the research groups. DNA samples are provided to the sequencing providers via the Project MinE general assembly. Samples are sequenced, and data is centrally stored (the size of the data for the first 1,935 samples is indicated in parentheses; the full dataset for N = 22,500 samples will be ~1.7 petabytes). External data can also be contributed to and integrated into the dataset. Different research groups, including external groups, collaborate to work on specific projects. ALS amyotrophic lateral sclerosis, WGS whole-genome sequencing

Fig. 2

Population structure by principal component and IBD analysis. a Birthplaces of cases and controls for individuals born in The Netherlands. b The first two principal components reflect the geographical distribution of samples. c–e Relation between birthplace distance between pairs of individuals and shared IBD segments 1–2 cM (c), 2–7 cM (d) and 7–15 cM (e). PC principal component, MAF minor allele frequency, IBD identity by descent, km kilometer, cM centimorgan

Fig. 3

Allele frequency distribution and comparison to existing datasets. The majority of rare variants (<1%) were not found in public datasets such as the Genome of the Netherlands and the 1000 Genomes Project phase 1. In contrast, almost all common alleles (>10%) were found in these datasets. GoNL Genome of the Netherlands, 1000GP 1000 Genomes Project