Elsevier

Neurobiology of Aging

Volume 45, September 2016, Pages 213.e3-213.e9
Neurobiology of Aging

Genetic report abstract
Genome-wide assessment of Parkinson's disease in a Southern Spanish population

https://doi.org/10.1016/j.neurobiolaging.2016.06.001Get rights and content

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.

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

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