Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease

By M. Nalls, N. Pankratz, Christina M. Lill, Chuong B. Do, D. Hernandez, M. Saad, A. Destefano, E. Kara, J. Bras, Manu Sharma and 37 more. Nature Genetics, 2014

1,858 citations recorded by the source corpus.

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10−16). We also show six risk loci associated with proximal gene expression or DNA methylation.

Subfields: Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/888c71cc805574e54764c037363062034260e8c9

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Citations in the corpus

Developmental regulation of human cortex transcription and its clinical relevance at base resolution (2014, neutral): “…with neurodevelopment including brain-(Alzheimer's disease, AD, and Parkinson's disease, PD) and non-brain-related disorders (type 2 diabetes, T2D, see Methods), and identified significant overlap with the age-related DERs and PD 29 , marginal overlap with AD 30 , and no overlap with T2D 31 .”
Analysis of shared heritability in common disorders of the brain (2018, neutral): “Generally, this occurs via the combination of many common variants—examples include Alzheimer’s disease (18), bipolar disorder (19), migraine (20), Parkinson’s disease (21), and schizophrenia (22)—each with a small individual effect.”
Structures of α-Synuclein Filaments from Multiple System Atrophy (2020, background): “Sequence variation in the regulatory region of SNCA is associated with increased expression of α-synuclein and heightened risk of developing idiopathic Parkinson’s disease (14), which accounts for over 90% of disease cases.”
Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease (2016, positive): “These include effects by the microbiota on autophagy (Lin et al., 2014), a cellular recycling process that is genetically linked to PD risk and when impaired may lead to reduced clearance of aSyn aggregates (Beilina andCookson, 2015; Nalls et al., 2014).”
Integrative functional genomic analysis of human brain development and neuropsychiatric risks (2018, methodology): “Toward this end, we collected GWAS data concerning neuropsychiatric disorders or personality traits including schizophrenia (SCZ) from CLOZUK (37), Alzheimer’s disease (AD) from IGAP (38), Parkinson’s disease (PD) (39), autism spectrum disorder (ASD) (40), attention deficit hyperactivity disorder (A”