Biology subjects

von Coelln, R.

Publications and source records attributed to von Coelln, R..

3 recordsLinked to original sources

bioRxiv2020

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

OBJECTIVETo 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 Parkinsons 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, {beta} = -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 = 6.6x10-7), 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.

genomics↗

bioRxiv2018

Parkinson disease age of onset GWAS: defining heritability, genetic loci and a-synuclein mechanisms

Increasing evidence supports an extensive and complex genetic contribution to Parkinsons disease (PD). Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age of onset are largely unknown. Here we performed an age of onset GWAS based on 28,568 PD cases. We estimated that the heritability of PD age of onset due to common genetic variation was ~0.11, lower than the overall heritability of risk for PD (~0.27) likely in part because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni corrected significant effect at other known PD risk loci, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. In addition, we identified that GBA coding variant carriers had an earlier age of onset compared to non-carriers. Notably, SNCA, TMEM175, SCARB2, BAG3 and GBA have all been shown to either directly influence alpha-synuclein aggregation or are implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci such as GCH1, MAPT and RAB7L1/NUCKS1 (PARK16) did not show a significant effect on age of onset of PD. While for some loci, this may be a measure of power, this is clearly not the case for the MAPT locus; thus genetic variability at this locus influences whether but not when an individual develops disease. We believe this is an important mechanistic and therapeutic distinction. Furthermore, these data support a model in which alpha-synuclein and lysosomal mechanisms impact not only PD risk but also age of disease onset and highlights that therapies that target alpha-synuclein aggregation are more likely to be disease-modifying than therapies targeting other pathways.

genetics↗

bioRxiv2018

Parkinson’s disease genetics: identifying novel risk loci, providing causal insights and improving estimates of heritable risk

We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.

genetics↗