1. Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis
- Author
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Vural, Atay (ORCID 0000-0003-3222-874X & YÖK ID 182369); Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Ahmad Al, Khleifat; Alfredo, Iacoangeli; Joke J F A van, Vugt; Harry, Bowles; Matthieu, Moisse; Ramona A J, Zwamborn; Rick A A van, der Spek; Aleksey, Shatunov; Johnathan, Cooper-Knock; Simon, Topp; Ross, Byrne; Cinzia, Gellera; Victoria, Lopez; Ashley R, Jones; Sarah, Opie-Martin; Yolanda, Campos; Wouter van, Rheenen; Brendan, Kenna; Kristel R Van, Eijk; Kevin, Kenna; Markus, Weber; Bradley, Smith; Isabella, Fogh; Vincenzo, Silani; Karen E., Morrison; Richard, Dobson; Michael A van, Es; Russell L., McLaughlin; Patrick, Vourc’h; Adriano, Chio; Philippe, Corcia; Mamede, de Carvalho; Marc, Gotkine; Monica, P Panades; Jesus ,S Mora; Pamela, J Shaw; John, E Landers; Jonathan, D Glass; Christopher, E Shaw; Orla, Hardiman; Wim, Robberecht; Philip Van, Damme; Leonard H van, den Berg; Jan, H Veldink; Ammar, Al-Chalabi, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Vural, Atay (ORCID 0000-0003-3222-874X & YÖK ID 182369); Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Ahmad Al, Khleifat; Alfredo, Iacoangeli; Joke J F A van, Vugt; Harry, Bowles; Matthieu, Moisse; Ramona A J, Zwamborn; Rick A A van, der Spek; Aleksey, Shatunov; Johnathan, Cooper-Knock; Simon, Topp; Ross, Byrne; Cinzia, Gellera; Victoria, Lopez; Ashley R, Jones; Sarah, Opie-Martin; Yolanda, Campos; Wouter van, Rheenen; Brendan, Kenna; Kristel R Van, Eijk; Kevin, Kenna; Markus, Weber; Bradley, Smith; Isabella, Fogh; Vincenzo, Silani; Karen E., Morrison; Richard, Dobson; Michael A van, Es; Russell L., McLaughlin; Patrick, Vourc’h; Adriano, Chio; Philippe, Corcia; Mamede, de Carvalho; Marc, Gotkine; Monica, P Panades; Jesus ,S Mora; Pamela, J Shaw; John, E Landers; Jonathan, D Glass; Christopher, E Shaw; Orla, Hardiman; Wim, Robberecht; Philip Van, Damme; Leonard H van, den Berg; Jan, H Veldink; Ammar, Al-Chalabi, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine
- Abstract
There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype., Motor Neurone Disease Association (MNDA); Wellcome Trust; Medical Research Council; University of Manchester Centre for Integrated Genomic Medical Research (CIGMR); National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South London at King's College Hospital NHS Foundation Trust; Dementia Biomedical Research Unit; Maudsley Biomedical Research Centre; King's Health Partners (Guy's and St Thomas' NHS Foundation Trust, King's College Hospital NHS Foundation Trust, King's College London and South London and Maudsley NHS Foundation Trust; Guy's and St Thomas' Charity; Health Data Research UK (HDR UK); ALS Association Milton Safenowitz Research Fellowship; European Research Council (ERC); EU Joint Programme-Neurodegenerative Disease Research (JPND); European Community's Health Seventh Framework Programme (FP7/2007-2013); European Union (EU); Horizon 2020; H2020-PHC-2014-two-stage; PPP Allowance; KU Leuven Opening the Future Fund; ALS Liga Belgie; Science Foundation Ireland; Project MinE; American ALS Association; National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS)
- Published
- 2022