A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease

Plagnol, Vincent; Nalls, Mike A.; Brás, José; Hernandez, Dena G.; Sharma, Manu; Sheerin, Una Marie; Saad, Mohamad; Simón‐Sánchez, Javier; Schulte, Claudia; Lesage, Suzanne; Sveinbjörnsdóttir, Sigurlaug; Amouyel, Philippe; Arepalli, Sampath; Barker, Roger A.; Bellinguez, C.; Ben‐Shlomo, Yoav; Berendse, H.W.; Berg, Daniela; Bhatia, Kailash P.; Bie, Rob M.A. de; Biffi, Alessandro; Bloem, B.R.; Bochdanovits, Zoltán; Bonin, Michael; Brockmann, Kathrin; Brooks, Janet; Burn, David; Charlesworth, Gavin; Chen, Honglei; Chinnery, Patrick F.; Chong, Siow‐Ann; Clarke, Carl E; Cookson, Mark; Cooper, Jane; Corvol, Jean‐Christophe; Counsell, Carl; Damier, Philippe; Jf, Dartigues; Deloukas, Panos; Deuschl, Günther; Dexter, David T.; Dijk, Karin D. van; Dillman, Allissa; Durif, F.; Dürr, Alexandra; Edkins, Sarah; Evans, Jonathan; Foltynie, Thomas; Freeman, Colin; Gao, Jianjun; Gardner, Michelle; Gibbs, J. Raphael; Goate, Alison; Gray, Emma; Guerreiro, Rita; Gústafsson, Ómar; Harris, Curtis C.; Hellenthal, Garrett; Hilten, Jacobus J. van; Hofman, Albert; Hollenbeck, Albert R.; Holton, Janice L.; Hu, Ming; Huang, Xuemei; Huber, Heiko; Hudson, Gavin; Hunt, Sarah; Huttenlocher, Johanna; Illig, Thomas; Jónsson, Pálmi V.; Langford, Cordelia; Lees, Andrew J.; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; McNeill, Alisdair; Moorby, Catriona D.; Moore, Matthew; Morris, Huw; Morrison, Karen; Mudanohwo, Ese; O’Sullivan, Sean S.; Pearson, John F.; Pearson, Richard; Perlmutter, Joel S.; Pétursson, Hannes; Pirinen, Matti; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Révész, Tamás; Rieß, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Sawcer, Stephen; Heutink, Peter; Wood, Nicholas W.

doi:10.1371/journal.pgen.1002142

Cited by 247 publications

(131 citation statements)

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“…That being acknowledged, an association at the BCL7C/ STX1B locus has been previously reported for Parkinson’s disease. 29,32 The top Parkinson’s disease-associated variants at this locus were rs14235 (synonymous; located at BCKDK ) and rs4889603 (intronic; located at SETD1A ). The top SNP identified in dementia with Lewy bodies at this locus (rs897984) shows the same direction of association seen in Parkinson’s disease (OR 0·93, 95% CI 0·90–0·96), a Parkinson’s disease meta-analysis p value of 1·34 × 10 −5 (data from PDgene), and strong linkage disequilibrium with both Parkinson’s disease hits ( R 2 =0·28–0·32; correlation p values<0·0001).…”

Section: Discussionmentioning

confidence: 99%

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Guerreiro

Ross

Kun‐Rodrigues

et al. 2018

The Lancet Neurology

207

240

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Summary Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson’s disease, and Alzheimer’s disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14–2·70; p=1·05 × 10−48), SNCA (rs7681440; OR 0·73, 0·66–0·81; p=6·39 × 10−10), and GBA (rs35749011; OR 2·55, 1·88–3·46; p=1·78 × 10−9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27–1·79; p=2·32 × 10−6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.

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Section: Discussionmentioning

confidence: 99%

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Guerreiro

Ross

Kun‐Rodrigues

et al. 2018

The Lancet Neurology

207

240

View full text Add to dashboard Cite

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“…Of these 16, all but 3 (rs4073221, rs10906923, and rs9468199) were also nominally associated in the NeuroX study (one-sided P < 0.05). A genetic risk score 8,18,19 defined by these 16 loci, in addition to the previously reported loci, had a non-negligible ability to predict PD case status (area under the curve, 0.6518; 95% CI, 0.6419–0.6616). This represents a significant improvement over the predictive power of risk scores defined by previously reported loci alone ( P = 6 × 10 −8 ) (Supplementary Note 1).…”

mentioning

confidence: 82%

A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

Chang¹,

et al. 2017

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Common variant genome-wide association studies (GWASs) have, to date, identified >24 risk loci for Parkinson’s disease (PD). To discover additional loci, we carried out a GWAS comparing 6,476 PD cases with 302,042 controls, followed by a meta-analysis with a recent study of over 13,000 PD cases and 95,000 controls at 9,830 overlapping variants. We then tested 35 loci (P < 1 × 10−6) in a replication cohort of 5,851 cases and 5,866 controls. We identified 17 novel risk loci (P < 5 × 10−8) in a joint analysis of 26,035 cases and 403,190 controls. We used a neurocentric strategy to assign candidate risk genes to the loci. We identified protein-altering or cis–expression quantitative trait locus (cis-eQTL) variants in linkage disequilibrium with the index variant in 29 of the 41 PD loci. These results indicate a key role for autophagy and lysosomal biology in PD risk, and suggest potential new drug targets for PD.

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“…Genome-wide association studies (GWAS) have led to breakthroughs in investigating the genetic susceptibility to PD [5,6,7]. Recently, 5 new variants were identified as PD-susceptible genes ( ACMSD, STK39, MCCC1/LAMP3, SYT11 , and CCDC62/HIP1R ) in a GWAS meta-analysis by the International Parkinson's Disease Genomics Consortium (IPDGC) [8].…”

Section: Introductionmentioning

confidence: 99%

<b><i>CCDC62</i></b> Variant rs12817488 Is Associated with the Risk of Parkinson's Disease in a Han Chinese Population

Liu¹,

Zhou²,

Cheng³

et al. 2013

Eur Neurol

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It has been recently proposed by a genome-wide association study (GWAS) meta-analysis that the CCDC62 variant rs12817488 is a new risk locus associated with Parkinson's disease (PD). In this study, we aimed to investigate the association between rs12817488 and PD in a Chinese cohort. A total of 341 PD patients and 423 matched controls were recruited in Eastern China. Our results showed that the A allele of rs12817488 was significantly associated with an aggravated risk of PD (p = 0.006) and represented a major allele in contrast to a minor one in Caucasians. Genotype distributions also differed between PD patients and controls (p = 0.011 for AA/AG/GG). Further analysis showed that the association of rs12817488 with PD only existed in females. We also investigated the protein level of CCDC62 in peripheral blood mononuclear cells from 41 AA or GG carriers and found an apparently higher expression in PD patients carrying the AA genotype. A potential interaction was found between two estrogen-related loci, i.e. rs12817488/CCDC62 and rs2697962/PRDM2, particularly in the female stratum. In conclusion, our study demonstrated for the first time a significant association between the rs12817488 polymorphism and PD predisposition in a Chinese population with gender variations and provides new insight regarding the variant's protein expression and estrogen-related genetic interaction.

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A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease

Cited by 247 publications

References 34 publications

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

<b><i>CCDC62</i></b> Variant rs12817488 Is Associated with the Risk of Parkinson's Disease in a Han Chinese Population

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