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Genome‐wide survey of copy number variants finds MAPT duplications in progressive supranuclear palsy
Author(s) -
Chen Zhongbo,
Chen Jason A.,
Shatunov Aleksey,
Jones Ashley R.,
Kravitz Stephanie N.,
Huang Alden Y.,
Lawrence Lauren,
Lowe Jennifer K.,
Lewis Cathryn M.,
Payan Christine A. M.,
Lieb Wolfgang,
Franke Andre,
Deloukas Panagiotis,
Amouyel Philippe,
Tzourio Christophe,
Dartigues JeanFrançois,
Ludolph Albert,
Bensimon Gilbert,
Leigh P. Nigel,
Bronstein Jeff M.,
Coppola Giovanni,
Geschwind Daniel H.,
AlChalabi Ammar
Publication year - 2019
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.27702
Subject(s) - progressive supranuclear palsy , copy number variation , genetics , haplotype , gene duplication , biology , genetic heterogeneity , population , single nucleotide polymorphism , genotype , medicine , gene , genome , atrophy , environmental health , phenotype
Background Progressive supranuclear palsy is a neurodegenerative tauopathy manifesting clinically as a progressive akinetic‐rigid syndrome. In this study, we sought to identify genetic variants influencing PSP susceptibility through a genome‐wide association analysis of a cohort of well‐characterized patients who had participated in the Neuroprotection and Natural History in Parkinson Plus Syndromes and Blood Brain Barrier in Parkinson Plus Syndromes studies. Methods We genotyped single‐nucleotide polymorphisms in 283 PSP cases from the United Kingdom, Germany, and France and compared these with genotypes from 4472 controls. Copy number variants were identified from genotyping data. Results We observed associations on chromosome 17 within or close to the MAPT gene and explored the genetic architecture at this locus. We confirmed the previously reported association of rs1768208 in the MOBP gene ( P = 3.29 × 10 ‐13 ) and rs1411478 in STX6 ( P = 3.45 × 10 ‐10 ). The population‐attributable risk from the MAPT , MOBP , and STX6 single‐nucleotide polymorphisms was found to be 0.37, 0.26, and 0.08, respectively. In addition, we found 2 instances of copy number variants spanning the MAPT gene in patients with PSP. These copy number variants include tau but few other genes within the chromosome 17 haplotype region, providing additional support for the direct pathogenicity of MAPT in PSP. Conclusions Clinicians should also be aware of MAPT duplication as a possible genetic cause of PSP, especially in patients presenting with young age at onset. © 2019 International Parkinson and Movement Disorder Society