title: Genome-wide association study of behavioural and psychiatric features in human prion disease.
abstract: Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves.
authors.affiliation: 1] MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK [2] NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, UK.
authors.forename: A G B
authors.initials: AG
authors.lastname: Thompson
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Uphill
authors.affiliation: 1] MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK [2] NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Lowe
authors.affiliation: 1] MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK [2] NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, UK.
authors.forename: M-C
authors.initials: MC
authors.lastname: Porter
authors.affiliation: 1] MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK [2] NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Lukic
authors.affiliation: 1] MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK [2] NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Carswell
authors.affiliation: 1] MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK [2] NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Rudge
authors.affiliation: NHS Highland Mental Health Services, Argyll and Bute Hospital, Lochgilphead, Argyll, UK.
authors.forename: A
authors.initials: A
authors.lastname: MacKay
authors.affiliation: 1] MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK [2] NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Collinge
authors.affiliation: 1] MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK [2] NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Mead
mesh_terms: D017487:Ankyrins / Q000235:genetics; D060565:Argonaute Proteins / Q000235:genetics; D001714:Bipolar Disorder / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D015331:Cohort Studies; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics* / Q000523:psychology; D003702:Delusions / Q000235:genetics / Q000523:psychology; D003863:Depression / Q000235:genetics / Q000523:psychology; D003865:Major Depressive Disorder / Q000235:genetics; D055106:Genome-Wide Association Study; D006212:Hallucinations / Q000235:genetics / Q000523:psychology; D006801:Humans; D019964:Mood Disorders / Q000235:genetics* / Q000523:psychology; D009419:Nerve Tissue Proteins / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017096:Prion Diseases / Q000235:genetics / Q000523:psychology; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics; D011618:Psychotic Disorders / Q000235:genetics* / Q000523:psychology; D016601:RNA-Binding Proteins; D012559:Schizophrenia / Q000235:genetics; D006113:United Kingdom
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins; D060565:Argonaute Proteins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C556795:PIWIL4 protein, human; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D016601:RNA-Binding Proteins; C118958:SNCAIP protein, human; C492429:AGK protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor)