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

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

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.

1018-4813
1-10
Pulit, Sara L.
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Dekker, Annelot M.
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Al Khleifat, Ahmad
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Brands, William J.
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Iacoangeli, Alfredo
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Schellevis, Raymond D.
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Shatunov, Aleksey
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Sproviero, William
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Tazelaar, Gijs H.P.
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van der Spek, Rick A.A.
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van Doormaal, Perry T.C.
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van Eijk, Kristel R.
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van Vugt, Joke
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Glass, Jonathan D.
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Hardiman, Orla
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Hide, Winston
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Landers, John E.
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Al-Chalabi, Ammar
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van Den Berg, Leonard H.
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Hardiman, Orla
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Hide, Winston
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Landers, John E.
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Mora, Jesus S.
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Morrison, Karen E.
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Newhouse, Stephen
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Robberecht, Wim
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Shaw, Christopher E.
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Shaw, Pamela J.
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van Damme, Philip
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van Es, Michael A.
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Wray, Naomi R.
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Al-Chalabi, Ammar
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van Den Berg, Leonard H.
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Veldink, Jan H.
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Pulit, Sara L., Dekker, Annelot M., Al Khleifat, Ahmad, 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., van der Spek, Rick A.A., van Doormaal, Perry T.C., van Eijk, Kristel R., van Vugt, Joke, 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., van Damme, Philip, van Es, Michael A., Wray, Naomi R., Al-Chalabi, Ammar, van Den Berg, Leonard H. and Veldink, Jan H. (2018) Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis. European Journal of Human Genetics, 1-10. (doi:10.1038/s41431-018-0177-4).

Record type: Article

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.

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s41431-018-0177-4 - Version of Record
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More information

Accepted/In Press date: 26 April 2018
e-pub ahead of print date: 28 June 2018

Identifiers

Local EPrints ID: 422710
URI: http://eprints.soton.ac.uk/id/eprint/422710
ISSN: 1018-4813
PURE UUID: ceb295df-1ed8-4d60-b879-7f9b131369c7
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

Catalogue record

Date deposited: 31 Jul 2018 16:30
Last modified: 07 Oct 2020 02:09

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Contributors

Author: Sara L. Pulit
Author: Annelot M. Dekker
Author: Ahmad Al Khleifat
Author: William J. Brands
Author: Alfredo Iacoangeli
Author: Kevin P. Kenna
Author: Ersen Kavak
Author: Maarten Kooyman
Author: Russell L. McLaughlin
Author: Bas Middelkoop
Author: Matthieu Moisse
Author: Raymond D. Schellevis
Author: Aleksey Shatunov
Author: William Sproviero
Author: Gijs H.P. Tazelaar
Author: Rick A.A. van der Spek
Author: Perry T.C. van Doormaal
Author: Kristel R. van Eijk
Author: Joke van Vugt
Author: A. Nazli Basak
Author: Ian P. Blair
Author: Jonathan D. Glass
Author: Orla Hardiman
Author: Winston Hide
Author: John E. Landers
Author: Jesus S. Mora
Author: Karen E. Morrison ORCID iD
Author: Stephen Newhouse
Author: Wim Robberecht
Author: Christopher E. Shaw
Author: Pamela J. Shaw
Author: Philip van Damme
Author: Michael A. van Es
Author: Naomi R. Wray
Author: Ammar Al-Chalabi
Author: Leonard H. van Den Berg
Author: Jan H. Veldink

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