title: Genome-wide assessment of Parkinson's disease in a Southern Spanish population.
abstract: Here, we set out to study the genetic architecture of Parkinson's disease (PD) through a Genome-Wide Association Study in a Southern Spanish population. About 240 PD cases and 192 controls were genotyped on the NeuroX array. We estimated genetic variation associated with PD risk and age at onset (AAO). Risk profile analyses for PD and AAO were performed using a weighted genetic risk score. Total heritability was estimated by genome-wide complex trait analysis. Rare variants were screened with single-variant and burden tests. We also screened for variation in known PD genes. Finally, we explored runs of homozygosity and structural genomic variations. We replicate PD association (uncorrected p-value < 0.05) at the following loci: ACMSD/TMEM163, MAPT, STK39, MIR4697, and SREBF/RAI1. Subjects in the highest genetic risk score quintile showed significantly increased risk of PD versus the lowest quintile (odds ratio = 3.6, p-value < 4e(-7)), but no significant difference in AAO. We found evidence of runs of homozygosity in 2 PD-associated regions: one intersecting the HLA-DQB1 gene in 6 patients and 1 control; and another intersecting the GBA-SYT11 gene in PD case. The GBA N370S and the LRRK2 G2019S variants were found in 8 and 7 cases, respectively, replicating previous work. A structural variant was found in 1 case in the PARK2 gene locus. This current work represents a comprehensive assessment at a genome-wide level characterizing a novel population in PD genetics.
authors.affiliation: Department of Physiology and Institute of Neurosciences Federico Olóriz, Centro de Investigaciones Biomedicas (CIBM), University of Granada, Granada, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Bandrés-Ciga
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
authors.forename: Timothy Ryan
authors.initials: TR
authors.lastname: Price
authors.affiliation: Movement Disorders Unit, University Hospital San Cecilio, Granada, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Barrero
authors.affiliation: Movement Disorders Unit, Department of Neurology, Instituto de Investigación Biosanitaria (IBS), University Hospital Virgen de las Nieves, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Escamilla-Sevilla
authors.affiliation: Movement Disorders Unit, University Hospital San Cecilio, Granada, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Pelegrina
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
authors.forename: Sampath
authors.initials: S
authors.lastname: Arepalli
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
authors.forename: Dena
authors.initials: D
authors.lastname: Hernández
authors.affiliation: Department of Psychiatry and Institute of Neurosciences Federico Olóriz, Centro de Investigaciones Biomedicas (CIBM), University of Granada, Granada, Spain; CIBER en Salud Mental (CIBERSAM), University of Granada, Granada, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Gutiérrez
authors.affiliation: Department of Psychiatry and Institute of Neurosciences Federico Olóriz, Centro de Investigaciones Biomedicas (CIBM), University of Granada, Granada, Spain; CIBER en Salud Mental (CIBERSAM), University of Granada, Granada, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cervilla
authors.affiliation: Department of Psychiatry and Institute of Neurosciences Federico Olóriz, Centro de Investigaciones Biomedicas (CIBM), University of Granada, Granada, Spain; CIBER en Salud Mental (CIBERSAM), University of Granada, Granada, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Rivera
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rivera
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
authors.forename: Jing-Hui
authors.initials: JH
authors.lastname: Ding
authors.affiliation: Department of Physiology and Institute of Neurosciences Federico Olóriz, Centro de Investigaciones Biomedicas (CIBM), University of Granada, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Vives
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Nalls
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: Department of Physiology and Institute of Neurosciences Federico Olóriz, Centro de Investigaciones Biomedicas (CIBM), University of Granada, Granada, Spain. Electronic address: rduran@ugr.es.
authors.forename: Raquel
authors.initials: R
authors.lastname: Durán
mesh_terms: D017668:Age of Onset; D000368:Aged; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005962:Glucosylceramidase / Q000235:genetics; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D012306:Risk; D013030:Spain / Q000453:epidemiology; D050857:Synaptotagmins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; C494265:SYT11 protein, human; D050857:Synaptotagmins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D005962:Glucosylceramidase
keywords: GWAS; Genetics; Parkinson's disease; Southern Spain