Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease Evidence From the COURAGE-PD Consortium

Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identi fi ed SNCA and TMEM175 loci on chromosome (Chr) 4 with a signi fi cant in fl uence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed fi ndings in worldwide populations. A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics eQTL = expression quantitative trait locus; GTEx = Genotype-Tissue Expression; GWAS = genome-wide association studies; IPDGC = International Parkinson Disease Genomics Consortium; LD = linkage disequilibrium (LD); PD = Parkinson disease; PRS = polygenic risk score; QQ = quantile-quantile; SNV = single-nucleotide variation; UKBEC = UK Brain Expression Consortium.

D. Hernandez | A. Singleton | P. May | C. Blauwendraat | M. Farrer | E. Tolosa | A. Deutschländer | B. Bloem | N. Pedersen | D. Krainc | P. Lichtner | N. Hattori | A. Brice | E. Rogaeva | P. Pástor | S. Lesage | J. Corvol | J. Ferreira | M. Toft | T. Gasser | E. Valente | K. Wirdefeldt | S. Bardien | A. Elbaz | S. Kõks | C. Schulte | K. Brockmann | C. Clarke | K. Morrison | L. Stefanis | Rejko Kruger | P. Taba | M. Diez-Fairen | M. Ezquerra | Connor Edsall | W. Pirker | S. Chung | G. Hadjigeorgiou | Z. Landoulsi | Y. Kim | J. Carr | J. Aasly | C. Ferrarese | A. Puschmann | G. Pezzoli | A. Zimprich | A. Quattrone | Clara Hellberg | C. Ran | A. C. Belin | G. Mellick | L. Guedes | A. Zecchinelli | M. Chartier-Harlin | B. V. D. Warrenburg | K. Nishioka | L. Brighina | E. Mutez | L. Straniero | L. Pavelka | D. Bobbili | G. Annesi | H. Matsuo | L. Pihlstrøm | Y. Kawamura | Lena F. Burbulla | E. Dardiotis | A. A. Sreelatha | M. Gagliardi | A. Simitsi | S. Petrucci | P. Sugier | Felix Bartusch | A. Lang | Océane Mohamed | Milena Radivojkov-Blagojević | Berta Portugal | Maximilian Hanussek | Jens Krüger | Cloé Domenighetti | Sandeep Grover | PhD Patrick May | M. Tan | PhD Zied Landoulsi | MSc Claudia Schulte | Md Phd | PhD SandeepGrover | Ashwin Ashok | MTech Kumar Sreelatha | MD Lasse Pihlstrom | PhD Clo´eDomenighetti | PhD Pierre-Emmanuel Sugier | MSc Jens Kru Milena Radivojkov-Blagojevic | PhD Peter Lichtner | MSc Oc´eane Mohamed | PhD Berta Portugal | PhD Dheeraj Bobbili | PhD Connor Edsall | MSc Felix Bartusch | MSc Maximilian Hanussek | PhD Jens Kr¨uger | PhD Dena G. Hernandez | PhD Cornelis Blauwendraat | PhD George D. Mellick | MD Alexander Zimprich | MD Walter Pirker | Msc Manuela Tan | PhD Ekaterina Rogaeva | MD Anthony Lang | MD Sulev Koks | Suzanne Lesage PhD | Alexis Brice PhD | MD Jean-Christophe Corvol | PhD Marie-Christine Chartier-Harlin | Eugenie Mutez PhD | Kathrin Brockmann PhD | MD Angela B. Deutschl¨ander | G. M. Md | E. Md | MD Leonidas Stefanis | Athina Maria Simitsi PhD | Enza Maria Valente PhD | PhD Simona Petrucci | Letizia Straniero PhD | Anna Zecchinelli PhD | G. Md | MD Laura Brighina | Carlo Ferrarese PhD | Grazia Annesi PhD | Andrea Quattrone PhD | MD Monica Gagliardi | Lena F. Burbulla PhD | Hirotaka Matsuo PhD | Yusuke Kawamura PhD | MD Nobutaka Hattori | Kenya Nishioka PhD | Sun Ju Chung PhD | Yun Joong Kim PhD | PhD Lukas Pavelka | Bart P.C. van de Warrenburg Md | Bastiaan R. Bloem PhD | PhD Andrew B. Singleton | Jan Aasly PhD | M. Md | Leonor Correia Guedes PhD | PhD Joaquim J. Ferreira | Soraya Bardien PhD | Jonathan Phd | Eduardo Tolosa PhD | PhD Mario Ezquerra | Karin Wirdefeldt MSc | PhD Nancy L. Pedersen | Caroline Ran PhD | Andrea C. Belin PhD | Andreas Puschmann PhD | PhD Clara Hellberg | C. E. Md | K. E. Md | D. Md | Matt J. Farrer PhD | PhD Rejko Kruger | A. Md | Thomas Gasser PhD | MD Manu Sharma

[1]  Houeto Jean-Luc.  [Parkinson's disease]. , 2022, La Revue du praticien.

[2]  Wei Song,et al.  Genetic Modifiers of Age at Onset for Parkinson's Disease in Asians: A Genome‐Wide Association Study , 2021, Movement disorders : official journal of the Movement Disorder Society.

[3]  P. May,et al.  Replication of a Novel Parkinson's Locus in a European Ancestry Population , 2021, Movement disorders : official journal of the Movement Disorder Society.

[4]  Michaël E. Belloy,et al.  Common X‐Chromosome Variants Are Associated with Parkinson Disease Risk , 2020, medRxiv.

[5]  S. Fahn,et al.  Targeted sequencing of Parkinson's disease loci genes highlights SYT11, FGF20 and other associations , 2020, medRxiv.

[6]  M. Nalls,et al.  Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study. , 2020, JAMA neurology.

[7]  Sonja W. Scholz,et al.  Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies , 2019, The Lancet Neurology.

[8]  Yanbo Zhang,et al.  Association between alpha-synuclein (SNCA) rs11931074 variability and susceptibility to Parkinson’s disease: an updated meta-analysis of 41,811 patients , 2019, Neurological Sciences.

[9]  Sonja W. Scholz,et al.  Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia , 2019, bioRxiv.

[10]  Wei Q. Deng,et al.  Analytical strategies to include the X‐chromosome in variance heterogeneity analyses: Evidence for trait‐specific polygenic variance structure , 2019, Genetic epidemiology.

[11]  Sonja W. Scholz,et al.  Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms , 2019, Movement disorders : official journal of the Movement Disorder Society.

[12]  L. Tang,et al.  The association between CD157/BST1 polymorphisms and the susceptibility of Parkinson’s disease: a meta-analysis , 2019, Neuropsychiatric disease and treatment.

[13]  Yuting Shen,et al.  BST1 rs4698412 allelic variant increases the risk of gait or balance deficits in patients with Parkinson’s disease , 2019, CNS neuroscience & therapeutics.

[14]  A. Funaro,et al.  CD157: From immunoregulatory protein to potential therapeutic target. , 2019, Immunology letters.

[15]  Timothy Shin Heng Mak,et al.  Tutorial: a guide to performing polygenic risk score analyses , 2018, bioRxiv.

[16]  T. Postmus.  Genetics of Parkinson's disease , 2018 .

[17]  M. Nalls,et al.  A comprehensive analysis of SNCA‐related genetic risk in sporadic parkinson disease , 2018, Annals of neurology.

[18]  M. Nalls,et al.  A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci , 2017, Nature Genetics.

[19]  K. Ishihara,et al.  An immunohistochemical, enzymatic, and behavioral study of CD157/BST-1 as a neuroregulator , 2017, BMC Neuroscience.

[20]  K. Ishihara,et al.  Selegiline Ameliorates Depression-Like Behavior in Mice Lacking the CD157/BST1 Gene, a Risk Factor for Parkinson’s Disease , 2017, Front. Behav. Neurosci..

[21]  Dawn M. Toolan,et al.  TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation , 2017, Proceedings of the National Academy of Sciences.

[22]  Yonatan Stelzer,et al.  Parkinson-associated risk variant in enhancer element produces subtle effect on target gene expression , 2016, Nature.

[23]  Xiaowei Zhan,et al.  RVTESTS: an efficient and comprehensive tool for rare variant association analysis using sequence data , 2016, Bioinform..

[24]  G. Kempermann.  Faculty Opinions recommendation of Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. , 2015 .

[25]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[26]  A. Singleton,et al.  Genetic variability in the regulation of gene expression in ten regions of the human brain , 2014, Nature Neuroscience.

[27]  Chuong B. Do,et al.  Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease , 2014, Nature Genetics.

[28]  Makoto Sato,et al.  Anxiety- and depression-like behavior in mice lacking the CD157/BST1 gene, a risk factor for Parkinson's disease , 2014, Front. Behav. Neurosci..

[29]  M. Daly,et al.  LD Score regression distinguishes confounding from polygenicity in genome-wide association studies , 2014, Nature Genetics.

[30]  F. Malavasi,et al.  CD38 and CD157: A long journey from activation markers to multifunctional molecules , 2013, Cytometry. Part B, Clinical cytometry.

[31]  J. Ioannidis,et al.  Large-scale replication and heterogeneity in Parkinson disease genetic loci , 2012, Neurology.

[32]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[33]  Yusuke Nakamura,et al.  Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease , 2009, Nature Genetics.

[34]  T. Seike,et al.  CD38 is critical for social behaviour by regulating oxytocin secretion , 2007, Nature.

[35]  A. Guse,et al.  Regulation of calcium signalling by adenine-based second messengers. , 2007, Biochemical Society transactions.

[36]  W James Gauderman,et al.  Sample size requirements for matched case‐control studies of gene–environment interaction , 2002, Statistics in medicine.

[37]  J. Inazawa,et al.  BST-1, a surface molecule of bone marrow stromal cell lines that facilitates pre-B-cell growth. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[38]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[39]  W. Haenszel,et al.  Statistical aspects of the analysis of data from retrospective studies of disease. , 1959, Journal of the National Cancer Institute.

[40]  Makoto Sato,et al.  Anxiety-and depression-like behavior in mice lacking the CD 157 / BST 1 gene , a risk factor for Parkinson ’ s disease , 2014 .

[41]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.