| Cognition | GBA status was significantly associated with composite progression (β = 0.40, P = 0.001) and cognitive progression (β = -0.35, P = 0.0008), but not motor progression (β = 0.18, P = 0.10). | |
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| (Liu, 2021 #1487) GWAS for progression of PD to PDD, (not GBA specific) |
survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits-
PROgression locus:
| HR (progression to PDD in 10y since onset of PD) | Normal function | |
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RIMS
rs182987047 | 4.77 | the regulating synaptic membrane exocytosis 2 protein, a RIM family member, which is involved in docking and priming of presynaptic vesicles41,42 | Not susceptibility genes
not significantly linked to motor progression in PD as measured by transition to HY stage 3 | TMEM108
rs138073281 | 2.86 | synaptic spine formation48 | WWOX
rs8050111 | 2.12 | | | GBA | 1.93 | | | APOE | 1.48 | |
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| (Nalls, 2019 #1490) |
- 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.
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| (Nalls, 2019 #804) meta |
- Dataset: metaanalysis of 17 datasets, total n=37,688 PD cases,
Finding:
- Identified 90 risk signals (ie 90 variants) across 78 genoic regions, 90 variants explained 16-36% of heritable risk of PD. → via, nominating genes under GWAS peaks → 7 genes identified: LRRK2, GBA, CATSPER3 (rs11950533 and C5orf24 locus), LAMB2 (rs12497850 and IP6K2 locus), LOC442028 (rs2042477 and KCNIP3 locus), NFKB2 (rs10748818 and GBF1 locus), and SCARB2 (rs6825004 locus).
- significant genetic correlations with following four phenotypes: brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038)
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(Blauwendraat, 2019 #794)
AAO, GBA와 interaction이 초점 아님. |
Dataset: Discovery dataset (IPDGC n=17,415) → Replication dataset (23andMe, n=10,572)... 총 28,568 PD cases
- five genes → ↓ AAO of PD: SNCA, TMEM175, SCARB2, BAG3, and GBA, and BTS1,
- SNCA: three signals (variant 말하는 듯), 적어도 이들 중 둘이 ↓ AAO, 이중 3' end signal이 strongest and reduces AAO (~0.6Y)
- TMEM175 and GAK share a promoter,
- TMEM175 p.M393 T, exon 11, rs34311866) is among the highest associated variants (Fig.2A). This coding variant was also the most associated variant in this locus in our PD AAO analysis (P_meta =9.62E-9; β = −0.613; SE = 0.107), resulting in an average reduction of 0.6 years, TMEM175 has been shown to impair lysosomal and mitochondrial function and increases a–syn aggregation(36). TMEM175 is associated with PD, significantly decreases protein expression and enzyme activity of Cathepsin B in rat hippo-campal neurons (Sarah Jinn et al. 2017; S. Jinn et al. 2019).
- GBA: E326K, T369M, N370S, these three all → ↓ AAO (2.6-0.9 y)
- Note: 1-SD increase in GRS led to an earlier AAO by ~0.8 years
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(Blauwendraat et al. 2019, PMID),
목적: GBA와 interaction하는 gene을 찾는 목적임.
방법: PD patients with GBA variants와 controls with GBA variants.를 비교해서, CTSB & SNCA가 공존하면 GBA의 PD penetrance가 증가한다.는 의미임.
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Dataset: Discovery dataset... 총 22,757 PD cases, 13,431 PD proxy cases, 622 LBD cases and 180,355 controls)
Two independent replication dataset
GBA: overall PD 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 with similar degree of OR (Supplementary Figure 1, ranging ORs from 1.31 to 1.55).
아래 두 gene 말고는, 공존시 악화 안 시킨다는 의미? 는 살핀 것이 아님
| Coding | GWAS | Experiment | Mechanism |
|---|
| CTSB | Cathepsin B (=cysteine protease B) |
2nd) TMEM175: GBA와 무관히 독립적으로 낮출지도 모른다, associated with PD, significantly decreases protein expression and enzyme activity of Cathepsin B in rat hippocampal neurons (Sarah Jinn et al. 2017; S. Jinn et al. 2019).
(2nd) several genetic studies have nominated CTSB as causal gene for PD (Li et al. 2019; Nalls et al. 2018).
CTSB or SNCA가 GBA와 공존하면 GBA의 PD penetrance가 증가한다.
또한 Genetic Interaction between CTSB & GBA 존재함, ie CTSB 단독으로는 GBA와 공존시 PD risk가 높은데
However, with the exception of CTSB, none of the eQTLs were associated with PD (Supplementary Table 11). These results suggest that expression differences in other cathepsins, including CTSD and CTSL which were previously suggested to degrade alpha-syn (McGlinchey and Lee 2015), do not modulate risk for disease.: PD와 normal 간에 expression의 차이가 없다는 말임 (mutation 빈도수의 차이가 아니라)
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Fig5. IN iPSC-derived neurons derived from GBA+PD patients (N370S)(n=2 lines each group), lower level of processed (i.e. mature) Cathepsin B protein in GBA variant carriers compared to cells without GBA variants (CTSB는 안 흔하니 이건 consequence 임.) (aSyn wasn't observed like us),
Cf: Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. The protective allele (A) of the CTSB variant rs1293298 increases CTSB expression in the brain (risk와 protective variant가 다 존재하고, 서로 다른 의미로 용어씨이는 구나)
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GBA variant carriers have reduced levels of mature Cathepsin B which may result in even lower lysosomal protease activity decreased
CTSB mRNA and protein expression further impair lysosomal function,
Cathepsin B: involved in syn lysosomal (McGlinchey and Lee 2015)
| | SCARB1 | | SNCA가 공존하면 GBA의 PD ↑.
Genetic Interaction be-tween SNCA & GBA 는 | | variants in this locus increase SNCA expression of either total a-syn or specific a-syn isoforms, (Pihlstrom 2018; Soldner et al. | | SNCA | |
- CTSB & SNCA가 penetrance가 증가한다.
- Genetic Interaction be- 없음
| | |
to have at least one gene variant associated.
CTSB & SCARB1 는 lysosomal hydrolases 이기는 하지만 특정 lysosomal storage disorder가 없기 때문에 분석자 같은데?
- Q1. 이 네 gene variant이 GBA와 공존시 악화시키지 modification (interaction) 아니라, 공존해서 lysosomal responsive로 만들것 같다, 가 주안점임.
그런데 공존시 증가시킨다는 (ie interaction, synergy) 증거가 있어 말리는 거 아닌가? Blauwendraat 2019 에서는 modulation 안 한다고 발표했는데 변이1: 그런 evidence 이미 symptomatic PD pts에서는, 다른 원인으로 있고, 다만 이것 때문에 악화될 것이다 (aSyn 기전을 분리하는 전략),
- Q2. gBA Tx 줄 때 더 받을까? GBA 적어도 이 군에서는 mechanism 아니라 lysosomal dysfunction 에 의해서 (aSyn) 이 퍼지고 있다는 의미이니, 더 homogeneous 것이다. GBA Tx가 들을것이다.
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(Robak et al. 2017, PMID 29140481), GBA와 관계되는 gene을 찾는 목적이 아니라 gba와 독립적으로, PD를 일으키는 gene을 LSD gene 중에서 찾은 것임.
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- Method : 54개의 LSD gene을 뒤졌음, 세 independent cohorts (Parkinson's Disease Genomics Consortium (IPDGC, EOPD임)) WES discovery dataset, NeuroX replication cohort), ie whole-exome sequencing data from 1,156 patients with PD and 1,679 non-neurodegenerative controls
- More than half of the individuals with PD were found to have at least one gene variant associated with an LSD
- Results : 아래 다섯 gene 의 PD association을 발견함.
| Genes | | LSD |
|---|
| GBA | Expected | GD | | SMPD1 | Niemann-Pick disease type A/B | | CTSD | Novel discovery | Neuronal ceroid lipofuscinosis (CLN10) | | SLC17A5 | Salla disease | | ASAH1 | Farber Lipogranulomatosis |
- The average variant burden was 0.9 alleles per individual (0.8 alleles in controls)
- Any of 54 LSD (putative damaging) genes: 56% (fig 2)
- Any ≥2 of 54 (putative damaging)LSD genes: 21% (fig 2)
- Any of Five PD-associated (damaging) LSD genes (GBA, SMPD1, CTSD, SLC17A5 and ASAH2): 30% of PD pts (fig suppl 2)
- Any ≥2 of Five PD-associated (damaging) LSD genes: ~5% of PD pts (fig suppl 2)
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| (Chang, 2017 #1182) |
GWAS comparing 6,476 PD cases with 302,042 controls, → followed by a meta-analysis with a recent study of over 13,000 PD cases and 95,042 controls, at 9,830 overlapping variants. → We then tested 35 loci (P < 1 × 10-6) in a replication cohort of 5,851 cases and 5,866 controls.
[Results] We identified 17 novel risk loci (CTSB, GALC) + 27 previously reported PD risk genes (eg. GBA, TMEM175, SNCA, LRRK2)
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| (Iwaki, 2021 #2198) |
May have used the above Chang 2017 #1182 data + transcriptomics
Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both PPMI data + transcriptomics
and Brainase expression data sets. A fur-ther 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects.
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| SHL 2020: Abstract 199 (GBA와 무관) |
- 6.2 million variants, LDPred algorithm.
- AMP-PD (404 PD, 419 Control) & FinnGen Consortia genomic data (1250 PD, 78704 control) from 1,654 PD Cases & 79,123 Controls.
- PD odds for the top 8%, 2.5%, and 1% of PD-GPRS were three-, four-, and seven times greater compared with lower percentiles, respectively (p=10).
- PD age of onset and MDS-UPDRS motor scores also differed by PD-GPRS decile.
Enrichment for phagosome, immune response, dopamine signaling, and neuronal signaling pathways was found for genes nearest high PD-GPRS variants identified by MAF analysis.
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| gangliosides |
[2019 Huebecker]
- α-syn is a ganglioside-binding protein, which adopts a more stable, α-helical structure when bound to membranes, but starts to form absence of GM1 ganglioside [88, 89].
- Secondly, GM1a is crucial for efficient signalling of GDNF [42]. It has been proposed that even a modest decline in GM1a ganglioside levels might inhibit its trophic support in dopaminergic neurons [87].
- A significant decrease in gene expression of key biosynthetic enzymes involved in synthesis of GM1a/GD1b (B3GALT4) and GD1a/GT1b (ST3GAL2) was reported in residual neuromelanin-containing cells in the SN of PD patients compared to age-matched controls [90].
- Mice deficient in the ability to synthesise a-series gangliosides (genetic deletion of B4GALNT1, encoding GM2 synthase), specifically GM2 synthase deficiency, showed parkinsonism, including the loss of TH-positive cells, lower striatal dopamine levels, an accumulation of α-syn aggregates and impaired motor function [39].
- GM2 synthase deficiency in humans results in severe spastic paraplegia [91], which may reflect a more central role for gangliosides in myelinated neurons in humans compared to mice.
- Intriguingly, treatment with exogenous GM1a has been reported to be beneficial in several preclinical models of PD [92–96] and in PD patients [97–99].
Additionally, deletion of GD3 synthase, which leads to an increase in GM1a ganglioside, was neuroprotective in a preclinical PD model [100].
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