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

Díez-Fairén, Mónica; Benitez, Bruno A.; Ortega‐Cubero, Sara; Lorenzo‐Betancor, Oswaldo; Cruchaga, Carlos; Lorenzo, Elena; Samaranch, Lluı́s; Cárcel, María; Obeso, José A.; Rodriguez-Oroz, María C.; Aguilar, Miquel; Coria, F; Pastor, María A.; Pástor, Pau

doi:10.1016/j.neurobiolaging.2018.05.008

Cited by 6 publications

(4 citation statements)

References 22 publications

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“…Here, we assessed the overall cumulative contribution of common SNPs on disease risk and age at onset. Our PRS derived model for disease risk and age at onset showed expected trends comparable to previous literature 12,13,33 .…”

Section: Discussionsupporting

confidence: 87%

The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight

Bandrés‐Ciga

Ahmed

Sabir

et al. 2019

Preprint

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Section: Discussionsupporting

confidence: 87%

The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight

Bandrés‐Ciga

Ahmed

Sabir

et al. 2019

Preprint

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“…We assume that there are a considerable number of variants that impact risk for disease outside the limits of what can be accurately detected with a genotyping platform. This could explain the lower observed frequency of certain well‐established pathogenic variants and exonic rearrangements when comparing other sequencing studies previously performed in the Spanish population …”

Section: Discussionmentioning

confidence: 77%

“…This could explain the lower observed frequency of certain well-established pathogenic variants and exonic rearrangements when comparing other sequencing studies previously performed in the Spanish population. 44,45 We have applied a state-of-the-art ML approach in an effort to predict disease status. Our results show that genetic data are not sufficient to accurately predict disease status in a clinical setting by itself when used alone, although this may change in the future when combining genetic with other biomarker data.…”

Section: Discussionmentioning

confidence: 99%

The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population‐Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight

Bandrés‐Ciga¹,

Ahmed²,

Sabir³

et al. 2019

Movement Disorders

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Background The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. Objectives To perform the largest PD genome‐wide association study restricted to a single country. Methods We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population‐specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease‐associated loci, heritability estimates, genetic correlations, and burden analyses. Results We identified a novel population‐specific genome‐wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome‐wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA‐DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non‐Spanish origin. Seventeen PD‐related genes showed functional consequence by two‐sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. Conclusions Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine‐mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society

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“…Demographic characteristics of some of those cohorts have been published previously. 22-24 PPMI is a prospective study with ongoing recruitment. CSF samples were obtained at baseline (N=510), six months (N=385), and yearly after enrolment (N 1stYear =428, N 2ndYear =404 and N 3rdYear =320).…”

Section: Methodsmentioning

confidence: 99%

Genome-wide association, Mendelian Randomization and polygenic risk score studies converge on a role of β−amyloid and APOE locus in Parkinson disease

Ibáñez¹,

Bahena²,

Yang³

et al. 2020

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Alpha-Synuclein (a-Syn) is the main protein component of Lewy bodies (LB), the pathological hallmark of Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of a-Syn are not currently used as a clinical biomarker but may be a proxy for pathological a-Syn accumulation in the brain. Therefore, identifying genetic modifiers of CSF a-Syn levels could provide insights into the underlying molecular mechanisms leading to PD. However, genetic modifiers of CSF a-Syn levels remain unknown. CSF levels of amyloid beta1-42 (Ab42), total tau (t-tau), and phosphorylated tau181 (p-tau181) are standard biomarkers for the diagnosis of Alzheimer disease (AD); its use as quantitative traits in genetic studies have provided novel insights into AD pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in PD has not been conducted. Here, genome-wide association studies (GWAS) were performed using CSF biomarker levels as quantitative traits in four PD cases and control cohorts (combined N=1,960). CSF biomarker (a-Syn, Ab42, t-tau, and p-tau181) levels were significantly lower in PD cases compared with controls. An SNP, proxy for APOE e4, was associated with CSF Ab42 levels (effect=-0.5, p=9.2x10-19). Several genome-wide suggestive loci associated with CSF a-Syn, t-tau, or p-tau181 were found. Polygenic risk scores (PRS) were constructed using the latest PD risk meta-analysis (49,731 PD cases and 784,343 controls) and the largest CSF biomarkers GWAS (N=3,146). PRS calculated using META-PD were associated with PD status in the four cohorts included in the present study (p= 2.2x10-16). A highly significant correlation (Nagelkerke pseudo-R2 =2.29%; p=2.5x10-11) of the genomic architecture between CSF Ab42 and PD risk was also found. Higher PRS scores were associated with lower CSF Ab42 levels (p=7.3x10-04). Two-sample Mendelian Randomization (MR) approach revealed that CSF Ab42 plays a role in PD risk (p=1.4x10-05) and age at onset (p=7.6x10-06), an effect mainly mediated by variants in the APOE locus. Subsequently, the APOE e4 allele was associated with significantly lower levels of CSF Ab42 (p=3.8x10-06), higher mean cortical binding potentials (cortical binding of Pittsburgh compound B PET) (p=5.8x10-08) and higher Braak Ab; score (p=4.4x10-04) in PD participants. Together these results from high-throughput and hypothesis-free approaches (GWAS, PRS and MR) converge on a genetic link between PD with CSF Ab42 and APOE.

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

Cited by 6 publications

References 22 publications

The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight

The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight

The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population‐Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight

Genome-wide association, Mendelian Randomization and polygenic risk score studies converge on a role of β−amyloid and APOE locus in Parkinson disease

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