title: Assessment of common variability and expression quantitative trait loci for genome-wide associations for progressive supranuclear palsy.
abstract: Progressive supranuclear palsy is a rare parkinsonian disorder with characteristic neurofibrillary pathology consisting of hyperphosphorylated tau protein. Common variation defining the microtubule associated protein tau gene (MAPT) H1 haplotype strongly contributes to disease risk. A recent genome-wide association study (GWAS) revealed 3 novel risk loci on chromosomes 1, 2, and 3 that primarily implicate STX6, EIF2AK3, and MOBP, respectively. Genetic associations, however, rarely lead to direct identification of the relevant functional allele. More often, they are in linkage disequilibrium with the causative polymorphism(s) that could be a coding change or affect gene expression regulatory motifs. To identify any such changes, we sequenced all coding exons of those genes directly implicated by the associations in progressive supranuclear palsy cases and analyzed regional gene expression data from control brains to identify expression quantitative trait loci within 1 Mb of the risk loci. Although we did not find any coding variants underlying the associations, GWAS-associated single-nucleotide polymorphisms at these loci are in complete linkage disequilibrium with haplotypes that completely overlap with the respective genes. Although implication of EIF2AK3 and MOBP could not be fully assessed, we show that the GWAS single-nucleotide polymorphism rs1411478 (STX6) is a strong expression quantitative trait locus with significantly lower expression of STX6 in white matter in carriers of the risk allele.
authors: Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors: Raffaele
authors: R
authors: Ferrari
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors: Mina
authors: M
authors: Ryten
authors: Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors: Roberto
authors: R
authors: Simone
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors: Daniah
authors: D
authors: Trabzuni
authors: Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors: Nayia
authors: N
authors: Nicolaou
authors: Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors: Naiya
authors: N
authors: Nicolaou
authors: Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors: Geshanthi
authors: G
authors: Hondhamuni
authors: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, London, UK.
authors: Adaikalavan
authors: A
authors: Ramasamy
authors: Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors: Jana
authors: J
authors: Vandrovcova
authors: Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, London, UK.
authors: Michael E
authors: ME
authors: Weale
authors: Reta Lila Weston Institute, UCL Institute of Neurology, London, UK.
authors: Andrew J
authors: AJ
authors: Lees
authors: Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors: Parastoo
authors: P
authors: Momeni
authors: Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors: John
authors: J
authors: Hardy
authors: Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address: r.desilva@ucl.ac.uk.
authors: Rohan
authors: R
authors: de Silva
mesh_terms: D002877:Chromosomes, Human / Q000235:genetics; D005091:Exons / Q000235:genetics; D015870:Gene Expression / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D009185:Myelin Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D050765:Qa-SNARE Proteins / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012306:Risk; D013494:Supranuclear Palsy, Progressive / Q000235:genetics*; D019892:eIF-2 Kinase / Q000235:genetics; D016875:tau Proteins / Q000235:genetics
chemical_list: C054369:MAPT protein, human; C560487:MOBP protein, human; D009185:Myelin Proteins; D050765:Qa-SNARE Proteins; D016875:tau Proteins; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase
keywords: GWAS; Haplotype; Linkage disequilibrium; Missense variant; PSP; Quantitative trait loci; Sequencing