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Neurobiol Aging. 2018 Oct;70:325.e1-325.e5. doi: 10.1016/j.neurobiolaging.2018.05.008. Epub 2018 May 14.

Pooled-DNA target sequencing of Parkinson genes reveals novel phenotypic associations in Spanish population.

Author information

1
Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain; Movement Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
2
Department of Medicine, School of Medicine, Washington University, St. Louis, MO, USA.
3
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain; Division of Neurosciences, Neurogenetics Laboratory, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain; Department of Neurology and Neurosurgery, Hospital Universitario de Burgos, Burgos, Spain.
4
Department of Neurology, Veterans Affairs Puget Sound Health Care System, University of Washington School of Medicine, Seattle, WA, USA.
5
Department of Neurology, University of Washington School of Medicine, St. Louis, MO, USA; Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, USA.
6
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain; Division of Neurosciences, Neurogenetics Laboratory, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.
7
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
8
Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain; Movement Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain.
9
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain; Centre for Integrative Neurosciences AC (CINAC), Hospital HM Puerta del Sur, Fundación Hospitales de Madrid, Madrid, Spain; CEU San Pablo University, Campus de Moncloa, Madrid, Spain.
10
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain; Department of Neurology, University Hospital Donostia, Neuroscience Unit BioDonostia Research Institute, San Sebastian, Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
11
Clinic for Nervous Disorders, Service of Neurology, Son Espases University Hospital, Palma de Mallorca, Spain.
12
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain; Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain; Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
13
Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain; Movement Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: pastorpau@gmail.com.

Abstract

Eighteen loci and several susceptibility genes have been related to Parkinson's disease (PD). However, most studies focus on single genes in small PD series. Our aim was to establish the genetic background of a large Spanish PD sample. Pooled-DNA target sequencing of 7 major PD genes (SNCA, PARK2, PINK1, DJ-1, LRRK2, GBA, and MAPT) was performed in 562 PD cases. Forty-four variants were found among 114 individuals (20.28%, p<0.05). Among these variants, 30 were found in Mendelian genes (68.18%) and 14 in PD susceptibility genes (31.82%). Seven novel variants were identified. Interestingly, most variants were found in PARK2 and PINK1 genes, whereas SNCA and DJ-1 variants were rare. Validated variants were also genotyped in Spanish healthy controls (n = 597). Carriers of heterozygous PARK2 variants presented earlier disease onset and showed dementia more frequently. PD subjects carrying 2 variants at different genes (1.42%) had an earlier age of onset and a predominantly akinetic-rigid PD phenotype (55.6%, p < 0.05), suggesting that the accumulation of genetic risk variants could modify PD phenotype.

KEYWORDS:

GBA; LRRK2; MAPT; PARK2; PINK1

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