Genetic report abstractGenome-wide assessment of Parkinson's disease in a Southern Spanish population
Introduction
Over the last several years, genetic investigation of Parkinson's disease (PD) has successfully identified many disease-causing mutations (Bonifati et al., 2003, Kitada et al., 1998, Paisán-Ruíz et al., 2004, Polymeropoulos et al., 1997, Valente et al., 2004, Vilariño-Güell et al., 2011, Zimprich et al., 2004, Zimprich et al., 2011) providing considerable insight into the molecular mechanisms underlying the etiology and pathogenesis of this multifactorial and complex disease.
Importantly, Genome Wide Association (GWA) studies (Edwards et al., 2010, Hernandez et al., 2012, Pihlstrøm et al., 2013, Saad et al., 2011, Satake et al., 2009, Simón-Sánchez et al., 2009, Simón-Sánchez et al., 2011) and large scale meta-analyses (Do et al., 2011, International Parkinson's Disease Genomics Consortium (IPDGC) and Wellcome Trust Case Control Consortium 2 (WTCCC2), 2011, Lill et al., 2012, Nalls et al., 2014, International Parkinson Disease Genomics Consortium et al., 2011; Pankratz et al., 2012) have been applied to identify and replicate risk loci that fit the common disease, common variant hypothesis in PD (Reich and Lander, 2001). Despite the significant number of novel risk loci identified so far, only a small portion of the heritable component for PD has been explained, suggesting there is a substantial unknown genetic component to be discovered (Keller et al., 2012). The polygenic nature of the illness and the hypothetically large number of loci involved with risk variants of small effect size make analysis of the genetic contribution to disease phenotype particularly difficult.
It has been widely suggested that studies in populations with limited genetic heterogeneity are valuable for studying the genetic basis of disease (Hernandez et al., 2012). Moreover, replication studies in independent populations are absolutely necessary to test the robustness of such association reports. Andalusia, given its geographical location on the southernmost region of Spain, represents a cross-link between Europe and Africa. The interactions and interbreeding across the Mediterranean Sea and North Africa have contributed to shape a genetic profile, which to date has been poorly studied in the context of PD genetics. Motivated by these considerations, we set out to study the genetic architecture of PD in this population by performing GWAS.
The purpose of this project was to identify novel putative candidate loci associated with PD and to investigate whether single nucleotide polymorphisms (SNPs) previously identified as risk variants contribute to PD risk in the Southern Spanish population. Furthermore, we use genetic risk profiling to aggregate risk across the previously established risk loci. In the same way, we aim to understand whether this genetic risk is associated with age at disease onset. We also attempt to identify recessive founder variants by exploring runs of homozygosity enriched in cases and explore whether disease-associated rare variants are present in our cohort. Finally, we estimate PD heritability attributable to genetic variation assessed by our genotyping platform and evaluate the role of copy number variants (CNVs) as risk factors for PD in these subjects.
Section snippets
Methods
We included a group of 240 PD patients treated at the Movement Disorders Unit of the Service of Neurology in both Hospital Clínico San Cecilio and Hospital Virgen de las Nieves of Granada (Spain). PD was diagnosed at least by 2 experienced neurologists in the field of movement disorders following the criteria of the UK PD Society Brain Bank (Gelb et al., 1999). Our control group was comprised of 192 healthy individuals with no signs or symptoms of parkinsonism who were extensively assessed to
Results
Descriptive statistics of the Spanish cohort are summarized in Table 1. Visualization of the top 2 genetic PCs of our Spanish samples shows them to be similar overall to HapMap European populations (Figure S1).
Our GWA failed to detect any genetic variant significant at p < 5e−8 (Fig. 1). Although we did not show any association signal with PD at this stringent p-value, we managed to marginally replicate association on the basis of a nominal uncorrected p-value < 0.05 with the following loci
Discussion
Here, we describe what is to our knowledge the first GWAS for PD in a Spanish cohort, and the second in a Southern European population (Kara et al., 2014). Although we are aware that the sample size itself is a limitation, it comprised most PD cases from the province of Granada. Therefore, one of the strengths of this study is that no potential problems of population stratification are expected as the sample comes from a relatively homogeneous ancestry background.
Our results suggest that there
Disclosure statement
No pharmaceutical entity has collaborated in this study, and no financial purpose exists.
Acknowledgements
The authors are grateful to the participants in this study without whom this work would not have been possible. Sara Bandrés Ciga and Timothy Ryan Price contributed equally to this work. Andrew Singleton, Michael Nalls, Dena Hernández, Raquel Durán, and Francisco Vives contributed to study concept, design, revision, and critique. Sampath Arepalli and Sara Bandrés Ciga contributed for execution of the laboratory work. Timothy Ryan Price, Sara Bandrés Ciga, Alberto Rivera, and Jing-Hui Ding
References (45)
- et al.
Analysis of the genetic variability in Parkinson's disease from Southern Spain
Neurobiol. Aging
(2016) - et al.
Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data
Lancet Neurol.
(2006) - et al.
Assessment of Parkinson's disease risk loci in Greece
Neurobiol. Aging
(2014) - et al.
Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease
Am. J. Hum. Genet.
(2008) - et al.
Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies
Am. J. Hum. Genet.
(2012) - et al.
NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases
Neurobiol. Aging
(2015) - et al.
Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study
Lancet Neurol.
(2015) - et al.
Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease
Neuron
(2004) - et al.
Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease
Neurobiol. Aging
(2013) - et al.
PLINK: a tool set for whole-genome association and population-based linkage analyses
Am. J. Hum. Genet.
(2007)
On the allelic spectrum of human disease
Trends Genet.
Genome-wide linkage analysis of a Parkinsonian-pyramidal syndrome pedigree by 500 K SNP arrays
Am. J. Hum. Genet.
VPS35 mutations in Parkinson disease
Am. J. Hum. Genet.
GCTA: a tool for genome-wide complex trait analysis
Am. J. Hum. Genet.
A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease
Am. J. Hum. Genet.
Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology
Neuron
Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism
Science
Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease
PLoS Genet.
The glucocerobrosidase E326K variant predisposes to Parkinson’s disease, but does not cause Gaucher's disease
Mov. Disord.
Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease
Ann. Hum. Genet.
Polygenic risk of Parkinson disease is correlated with disease age at onset
Ann. Neurol.
Diagnostic criteria for Parkinson disease
Arch. Neurol.
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These authors contributed equally to this work.