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

Bandrés‐Ciga, Sara; Ahmed, Sarah; Sabir, Marya S.; Blauwendraat, Cornelis; Adarmes‐Gómez, Astrid; Bernal‐Bernal, Inmaculada; Toribio, Marta Bonilla; Buiza‐Rueda, Dolores; Carrillo, Fátima; Carrión‐Claro, Mario; Gómez‐Garre, Pilar; Jesús, Silvia; Labrador‐Espinosa, Miguel A.; Macías, Daniel; Méndez‐del‐Barrio, Carlota; Periñán, María Teresa; Tejera‐Parrado, Cristina; Vargas‐González, Laura; Díez-Fairén, Mónica; Álvarez, Victoria; Tartari, Juan Pablo; Buongiorno, Maria Teresa; Aguilar, Miquel; Gorostidi, Ana; Bergareche, J; Mondragón, Elisabet; Ruíz‐Martínez, Javier; Dols‐Icardo, Oriol; Kulisevsky, Jaime; Marín‐Lahoz, Juan; Pagonabarraga, Javier; Pascual‐Sedano, Berta; Ezquerra, Mario; Cámara, Ana; Compta, Yaroslau; Fernández, Manel; Fernández‐Santiago, Rubén; Muñoz, Esteban; Tolosa, Eduard; Valldeoriola, Francesc; Rodríguez, A; Sierra, María; Menéndez-González, Manuel; Blázquez, Marta; García, Ciara; Martin, Esther Suarez-San; García‐Ruiz, Pedro J.; Martínez‐Castrillo, Juan Carlos; Vela-Desojo, Lydia; Ruz, Clara; Barrero, Francisco Javier; Escamilla-Sevilla, Francisco; Minguez-Castellanos, Adolfo; Cerdan, Debora; Tabernero, C; Heredia, Maria Jose Gómez; Errázquin, Francisco; Romero-Acebal, Manolo; Feliz, Cici; López‐Sendón, José; Mata, Marina; Torres, Irene Martínez; Kim, Jonggeol Jeffrey; Brooks, Janet; Sáez-Atiénzar, Sara; Gibbs, J. Raphael; Jorda, Rafael; Botía, Juan A.; Bonet-Ponce, Luis; Morrison, Karen E.; Clarke, Carl E; Tan, Manuela; Morris, Huw; Edsall, Connor; Hernandez, Dena G.; Simón‐Sánchez, Javier; Nalls, Mike A.; Scholz, Sonja W.; Jiménez‐Escrig, Adriano; Duarte, Jacinto; Vives, Francisco; Durán, Raquel; Hoenicka, Janet; Álvarez, Victoria; Infante, Jon; Martı́, Marı́a José; Clarimón, Jordi; Munáin, Adolfo López de; Pástor, Pau; Mir, Pablo; Singleton, Andrew B.

doi:10.1101/609016

Cited by 7 publications

(17 citation statements)

References 33 publications

(35 reference statements)

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“…Analyzing large case-control cohorts has paved the way for the discovery of genetic risk variants for PD (12). Nevertheless, heterogeneity across cohorts from different countries or even regions within countries may mask genetic associations specific to sub-populations (22, 23). We investigated environmental factors and the genetic architecture of PD in a PD case-control cohort selectively recruited from the southernmost region of Sweden.…”

Section: Resultsmentioning

confidence: 99%

“…Identifying regions of extended homozygosity can help identify rare recessive risk variants contributing to disease, and increased level of genomic homozygosity has been observed in PD patients with an early PD diagnosis compared to controls (48). It has also been observed that PD patients exhibit overall excess homozygosity in genes/loci previously associated with PD (22). We therefore investigated ROH in the entire study cohort as well as in a subset of PD patients with an early PD diagnosis (AAD < 50 years) and/or with a first-degree relative with PD (N=147).…”

Section: Resultsmentioning

confidence: 99%

“…It has previously been observed that PD patients with an early AAO have an increased rate of ROHs compared to controls (48) and that PD patients have longer ROHs both in regard to the total distance spanned by the segments and average segment size (22). We did not observe similar results in our Swedish PD cohort.…”

Section: Discussionmentioning

confidence: 99%

“…Long ROHs are also a signature of inbreeding and do not necessarily harbor disease-causing genetic variants. Since an overall excess of homozygosity has been observed in genes/loci previously associated with PD (22), we investigated ROHs in known mendelian PD genes, the nearest gene and the QTL nominated gene for the 90 risk loci from the latest GWAS-meta-analysis (12) as well as the nearest gene of our GWAS top-hit, PLPP4 . Enriched segments of homozygosity among PD patients were observed at 12 genes/loci respective 10 genes/loci for the subset group.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the need for a widened scope of PD genetic research on a global level, there is also a need of narrowed, regional studies, since heterogeneity across cohorts from different countries or regions may mask genetic associations specific to sub-populations (21). Population-specific GWAS of PD from different European countries have both replicated many of the variants identified from GWAS meta-analyses and identified novel candidate variants associated with PD or PD age at onset (AAO) that appear to be specific for the investigated population, highlighting the importance of regional studies (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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Insights on Genetic and Environmental Factors in Parkinson’s Disease from a regional Swedish Case-Control Cohort

Brolin

Bandrés‐Ciga

Blauwendraat

et al. 2021

Preprint

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BACKGROUND: Risk factors for Parkinson's disease (PD) can be more or less relevant to a population due to population-specific genetic architecture, local lifestyle habits, and environmental exposures. Therefore, it is essential to study PD at a local, regional, and continental scale in order to increase the knowledge on disease etiology. OBJECTIVE: We aimed to investigate the contribution of genetic and environmental factors to PD in a new Swedish case-control cohort. METHODS: PD patients (n=929) and matched population-based controls (n=935) from the southernmost county in Sweden were included in the cohort. Information on environmental exposures was obtained using questionnaires at inclusion. Genetic analyses included a genome-wide association study (GWAS), haplotype assessment, and a risk profile analysis using cumulative genetic risk scores. RESULTS: The cohort is a representative PD case-control cohort (64% men, mean age at diagnosis = 67 years, median Hoehn and Yahr score = 2.0), in which previously reported associations between PD and environmental factors, such as tobacco, could be confirmed. We describe the first GWAS of PD solely composed of PD patients from Sweden, and confirm associations to well-established risk alleles in SNCA. In addition, we identified a potential novel, population-specific PD risk variant in the PLPP4 locus (rs12771445) along with a risk haplotype in the region. CONCLUSIONS: This work provides an in-depth description of a new PD case-control cohort from southern Sweden in which we identified a potential novel PD risk locus, PLPP4. Replication studies are needed to determine whether the PLPP4 locus is associated with PD in Sweden, and on a global scale.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Insights on Genetic and Environmental Factors in Parkinson’s Disease from a regional Swedish Case-Control Cohort

Brolin

Bandrés‐Ciga

Blauwendraat

et al. 2021

Preprint

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Genome-wide epistasis analysis in Parkinson’s disease between populations with different genetic ancestry reveals significant variant-variant interactions

Cisterna-García

Bustos²,

Bandrés‐Ciga

et al. 2022

Preprint

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Genome-wide association studies (GWAS) have increased our understanding of Parkinson's disease (PD) genetics through the identification of common disease-associated variants. However, much of the heritability remains unaccounted for and we hypothesized that this could be partly explained by epistasis. Here, we developed a genome-wide non-exhaustive epistasis screening pipeline called Variant-variant interaction through variable thresholds (VARI3) and applied it to diverse PD GWAS cohorts. First, as a discovery cohort, we used 14 cohorts of European ancestry (14,671 cases and 17,667 controls) to identify candidate variant-variant interactions. Next, we replicated significant results in a cohort with a predominately Latino genetic ancestry (807 cases and 690 controls). We identified 14 significant epistatic signals in the discovery stage, with genes showing enrichment in PD-relevant ontologies and pathways. Next, we successfully replicated two of the 14 interactions, where the signals were located nearby SNCA and within MAPT and WNT3. Finally, we determined that the epistatic effect on PD of those variants was similar between populations. In brief, we identified several epistatic signals associated with PD and replicated associations despite differences in the genetic ancestry between cohorts. We also observed their biological relevance and effect on the phenotype using in silico analysis.

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Identification of a sex-specific genetic signature in dementia with Lewy bodies: a meta-analysis of genome-wide association studies

Gibbons

Rongve

Rojas

et al. 2022

Preprint

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Background: Genome-wide Association Studies (GWAS) have reshaped our understanding of the genetic bases of complex diseases in general and neurodegenerative diseases in particular. Despite being a common disorder, dementia with Lewy bodies (DLB), which, together with Parkinson's disease dementia (PDD), comprise the umbrella term Lewy body dementias (LBD), is far from being well-characterized genetically. This is primarily due to a lack of familial cases and difficulty recruiting large, deeply characterized cohorts, given the high rate of misdiagnosis. By performing the largest GWAS in DLB, we aimed to identify novel risk loci to gain a better understanding of this disease's pathobiology. Methods: Here, we conducted the largest meta-analysis of genome-wide association studies performed in LBD, using a total of 5,119 cases and 20,988 controls, from five independent datasets, aggregating all previously published DLB genome-wide association results to date, as well as two previously undescribed cohorts. Additionally, we performed a sex stratified GWAS using the discovery datasets. We updated the heritability estimates for DLB and, to fine map these estimates, we used local heritability analysis. We calculated genetic correlation estimates between DLB and a range of other diseases and traits to identify potential pleiotropy. We also performed gene-set analysis to identify genes with excess burden of rare variability and pathway analysis. Lastly, we used the UK Biobank data to perform a PheWas using individuals at the extremes of genetic risk for DLB. Findings: Between November 2018 and September 2022 we analyzed 8.6 million single nucleotide polymorphisms in 3293 DLB cases, 1826 LBD cases and 20,988 controls, as well as phenotypes from the UK Biobank dataset. Despite more than doubling the sample size from the previous GWAS in DLB, we did not identify significant loci in addition to those previously reported at GBA, SNCA, STX1B, and APOE. However, the sex-stratified analysis revealed that the GBA and SNCA signals are mainly driven by males, suggesting a sex-specific genetic architecture of disease. Using only clinical and neuropathologically diagnosed cases, we highlight four loci surpassing the significance threshold. Using the largest cohort of DLB we update our heritability estimates to 13% and fine map these results highlighting regions of the genome with high heritability but no genome-wide significant result so far. Interpretation: These data provide the most comprehensive analysis of genetic variability in DLB to date. The fact that no novel risk loci have been identified after doubling the cohort size indicates the potentially significant role of rare variants in the genetic architecture of DLB and stresses the urgent need for larger, well-characterized cohorts of this disease for genetic studies. The sex-stratified analysis shows that males and females have different signatures of genetic risk for DLB. These results have widespread implications for clinical practice and clinical trials' design in DLB.

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

Abstract: Background

Cited by 7 publications

References 33 publications

Insights on Genetic and Environmental Factors in Parkinson’s Disease from a regional Swedish Case-Control Cohort

Insights on Genetic and Environmental Factors in Parkinson’s Disease from a regional Swedish Case-Control Cohort

Genome-wide epistasis analysis in Parkinson’s disease between populations with different genetic ancestry reveals significant variant-variant interactions

Identification of a sex-specific genetic signature in dementia with Lewy bodies: a meta-analysis of genome-wide association studies

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