Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy

The genetic basis of variation in the rate of disease progression of primary tauopathies has not been determined. In two independent progressive supranuclear palsy cohorts, we show that common variation at the LRRK2 locus determines survival from motor symptom onset to death, possibly through regulation of gene expression. This links together genetic risk in alpha-synuclein and tau disorders, and suggests that modulation of proteostasis and neuro-inflammation by LRRK2 inhibitors may have a therapeutic role across disorders.

[1]  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.

[2]  W. Oertel,et al.  How to apply the movement disorder society criteria for diagnosis of progressive supranuclear palsy , 2019, Movement disorders : official journal of the Movement Disorder Society.

[3]  D. Hernandez,et al.  Genetic risk of Parkinson disease and progression: , 2019, Neurology. Genetics.

[4]  Prashant S. Emani,et al.  Comprehensive functional genomic resource and integrative model for the human brain , 2018, Science.

[5]  M. Feany,et al.  Lrrk promotes tau neurotoxicity through dysregulation of actin and mitochondrial dynamics , 2018, PLoS biology.

[6]  Sina A. Gharib,et al.  Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis , 2018, bioRxiv.

[7]  J. Hardy,et al.  Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype , 2018, bioRxiv.

[8]  Luca Passamonti,et al.  [11C]PK11195 binding in Alzheimer disease and progressive supranuclear palsy , 2018, Neurology.

[9]  D. Alessi,et al.  LRRK2 kinase in Parkinson's disease , 2018, Science.

[10]  D. Posthuma,et al.  Functional mapping and annotation of genetic associations with FUMA , 2017, Nature Communications.

[11]  Sonja W. Scholz,et al.  NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases , 2017, Neurobiology of Aging.

[12]  D. Dickson,et al.  Study of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration , 2017, Movement disorders : official journal of the Movement Disorder Society.

[13]  E. Gerhardt,et al.  LRRK2 Promotes Tau Accumulation, Aggregation and Release , 2015, Molecular Neurobiology.

[14]  David C. Wilson,et al.  Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease , 2016, Nature Genetics.

[15]  J. Rowe,et al.  Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes , 2016, Neurology.

[16]  Guixiang Xu,et al.  Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. , 2015, Brain : a journal of neurology.

[17]  Carson C Chow,et al.  Second-generation PLINK: rising to the challenge of larger and richer datasets , 2014, GigaScience.

[18]  B. Ghetti,et al.  Brain homogenates from human tauopathies induce tau inclusions in mouse brain , 2013, Proceedings of the National Academy of Sciences.

[19]  G. Abecasis,et al.  Detecting and estimating contamination of human DNA samples in sequencing and array-based genotype data. , 2012, American journal of human genetics.

[20]  P. Visscher,et al.  Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits , 2012, Nature Genetics.

[21]  D. Standaert,et al.  LRRK2 Inhibition Attenuates Microglial Inflammatory Responses , 2012, The Journal of Neuroscience.

[22]  Andrew J. Lees,et al.  Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy , 2011, Nature Genetics.

[23]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[24]  A. Morris,et al.  Data quality control in genetic case-control association studies , 2010, Nature Protocols.

[25]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[26]  Tetsuaki Arai,et al.  LRRK2 Expression in Normal and Pathologic Human Brain and in Human Cell Lines , 2006, Journal of neuropathology and experimental neurology.

[27]  Alexander Gerhard,et al.  In vivo imaging of microglial activation with [11C](R)‐PK11195 PET in progressive supranuclear palsy , 2006, Movement disorders : official journal of the Movement Disorder Society.

[28]  S. Tsuji,et al.  A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2–q13.1 , 2002, Annals of neurology.

[29]  M. Islam,et al.  G2019S LRRK2 enhances the neuronal transmission of tau in the mouse brain , 2018, Human molecular genetics.