Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been... Show moreParkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocer-ebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23 and Me, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions. Show less
The evolution of lignified xylem allowed for the efficient transport of water under tension,but also exposed the vascular network to the risk of gas emboli and the spread of gas betweenxylem... Show moreThe evolution of lignified xylem allowed for the efficient transport of water under tension,but also exposed the vascular network to the risk of gas emboli and the spread of gas betweenxylem conduits, thus impeding sap transport to the leaves. A well-known hypothesis proposesthat the safety of xylem (its ability to resist embolism formation and spread) should trade offagainst xylem efficiency (its capacity to transport water). We tested this safety–efficiency hypothesis in branch xylem across 335 angiosperm and 89gymnosperm species. Safety was considered at three levels: the xylem water potentials where12%, 50% and 88% of maximal conductivity are lost. Although correlations between safety and efficiency were weak (r2 < 0.086), no species hadhigh efficiency and high safety, supporting the idea for a safety–efficiency tradeoff. However,many species had low efficiency and low safety. Species with low efficiency and low safetywere weakly associated (r2 < 0.02 in most cases) with higher wood density, lower leaf- to sap-wood-area and shorter stature. There appears to be no persuasive explanation for the considerable number of species withboth low efficiency and low safety. These species represent a real challenge for understandingthe evolution of xylem. Show less
