A replication study of GWAS-genetic risk variants associated with Parkinson’s disease in a Spanish population

Abstract Parkinson’s disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson’s disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson’s disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson’s disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson’s disease cases, 13 431 Parkinson’s disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson’s disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson’s disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson’s disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson’s disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

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AB0017 Association study of genetic risk variants for psoriasis in a large cohort of psoriatic arthritis, psoriasis and controls of the spanish population and association with relevant clinical subphenotypes

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2012-eular.17 ◽

2013 ◽

Vol 71 (Suppl 3) ◽

pp. 638.4-638

Author(s):

J.D. Cañete ◽

J.M. Hernanz ◽

E. Fonseca ◽

C. Ferrandiz ◽

P. Unamuno ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Association Study ◽

Genetic Risk ◽

Large Cohort ◽

Spanish Population ◽

Risk Variants ◽

Genetic Risk Variants

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Genome-Wide Association Study Meta-Analysis for Parkinson’s Disease Motor Subtypes

10.1101/2020.06.26.174276 ◽

2020 ◽

Author(s):

Isabel Alfradique-Dunham ◽

Rami Al-Ouran ◽

Rainer von Coelln ◽

Cornelis Blauwendraat ◽

Emily Hill ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Association Study ◽

Essential Tremor ◽

Genetic Risk ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Risk Variants ◽

Genome Wide

AbstractOBJECTIVETo discover genetic determinants of Parkinson disease (PD) motor subtypes, including Tremor Dominant (TD) and Postural Instability/Gait Difficulty (PIGD) forms.METHODSIn 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining two complementary outcome traits derived from the Unified Parkinson’s Disease Rating Scale (UPDRS), including dichotomous motor subtype (TD vs. PIGD) or a continuous tremor / PIGD score ratio. Logistic or linear regression models were adjusted for sex, age of onset, disease duration, and 5 ancestry principal components, followed by meta-analysis.RESULTSAmong 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199347, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ß = −0.04, 95% CI = −0.07, 0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6×10−7), which harbors an independent risk allele for essential tremor.CONCLUSIONSMultiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.

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Unexpected opposing biological effect of genetic risk factors for Parkinson’s disease

10.1101/702340 ◽

2019 ◽

Author(s):

Marcus Keatinge ◽

Matthew E. Gegg ◽

Lisa Watson ◽

Heather Mortiboys ◽

Nan Li ◽

...

Keyword(s):

Risk Factors ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Genetic Risk ◽

Biological Effect ◽

Disease Risk ◽

Genetic Risk Factors ◽

Additive Effect ◽

Neuronal Function ◽

Risk Variants

AbstractThe additive effect of genetic risk variants on overall disease risk is a plausible but frequently unproven hypothesis. To test this hypothesis, we assessed the biological effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) deficiency. Variants in both glucocerebrosidase1 (GBA1) and sphingomyelinase (SMPD1) are genetic risk factors for Parkinson’s disease. Unexpectedly, ASM deficiency resulted in normalized behaviour and prolonged survival in gba1−/−;smpd1−/− double-mutant zebrafish compared to gba1−/−. RNAseq-based pathway analysis confirmed a profound rescue of neuronal function and intracellular homeostasis. We identified complete reciprocal rescue of mitochondrial respiratory chain function and abolished lipid membrane oxidation in gba1−/−;smpd1−/− compared to gba1−/− or smpd1−/− as the underlying rescue mechanism. Complementing in vitro experiments demonstrated an unexpected reduction of α-synuclein levels in human cell lines with combined GCase and ASM deficiency. Our study highlights the importance of functional validation for any putative interactions between genetic risk factors and their overall effect on disease-relevant mechanisms rather than readily assuming an additive effect.SummaryThe additive effect of genetic risk variants on disease risk is a popular but typically unproven hypothesis. We investigated this hypothesis mechanistically for Parkinson’s disease risk factors and provide evidence of an unexpected rescue effect on neuronal function and survival.

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