- Natural history study in PRKN-PD to facilitate clinical trial development
People	People – at least personal professional objectives everyone to be the best they can become Regular meetings with all TMLs across PD projects Develop and execute Individual development plan
Places	Places (which I also view as Processes; Establish and maintain PD translational subteam to address and priotize key gaps and opportunities and develop strategies in person and strengthen inter-and intra-site team performance Focus on the patient
Partnerships	Help guide NDU strategy as pipeline development level (BD deals)
수정방법	My workday → 내 사진을 click → 왼쪽에서 more 누르면 → performance → (노린) Edit
NSTM	here: 2022-07-11 - NSTM FY22 Obj Setting_v2.pptx

GWAS

Modifiers

• Objective: homogeneity vs acceleration?
• Flow of analysis using AMP-PD database
  • Correlation between GBA and PD progression (by Aug7 2020), if positive →
  • Correlation between Lysosomal genes and PD progression
  • Interaction between GBA and Lysosomal genes (in one month)
  • Cf) can we quantify the contribution of genes to PD progression?
    • AUC, PGS, PREDICTIVE Model?
• Preclinical studies
  • Validation
    • ↑ PD risk,
      • Do we need this?
    • 공존시 ↑ PD phenotype
      • Do we need this? Already clinically proven?
    • GBA Tx → ↓ lysosomal alteration → ↓ aSyn
      • Do we need this?
• genes of interest include
  • Lysosomal genes of interest include
    • All LSD genes (54 genes)
      • 5 LSD genes that is known increase PD risk (Robak et al., 2017, doi: 10.1093/brain/awx285): SMPD1, CTSD, SLC17A5, ASAH1, GBA
    • non-LSD genes
      • TMEM175
        • This gene is not an LSD gene but is known to increase PD risk and reduces PD age of onset (by ~0.6 year), {Blauwendraat, 2019 #794}, reduces cathepsin B expression
      • CTSB
        • CTSB is not a LSD gene but is known to increase PD risk and interacts with GBA to further increase PD risk (Blauwendraat et al., 2019, doi: 10.1101/738351)
  • Non-Lysosomal genes of interest include
    • SNCA
      • increase PD risk and interacts with GBA to further increase PD risk (Blauwendraat et al., 2019, doi: 10.1101/738351)

Summary

	↑ PD by GBA와 독립적으로?		↑ PD via interaction with GBA?
AD/PD 2023	Page 72. 23 and me, and meta-analysis, PD 27,590, control: 3,106,080 (?)
(Robak, 2017 #240)	GBA, SMPD1 CTSD SLC17A5 ASAH1		NA
(Blauwendraat, 2019 #157)	NA		(Penetrance) CTSB, SNCA (↑ aSyn) CTSB
(Blauwendraat, 2019 #794)	five genes → ↓ AAO of PD: SNCA, TMEM175, SCARB2, BAG3, and GBA, and BTS1, note: SCARB2 is a LSD gene. 적어도 이들 중 둘이 ↓ AAO, 이중 3' end signal이 strongest and reduces AAO (~0.6Y)
Nalls, 2019 #804) meta AAO	7 genes → ↑ PD Risk: LRRK2, GBA, CATSPER3, LAMB2, LOC442028, NFKB2, SCARB2
Individual GWAS studies
(Ngo, 2024 #2792) pesticides	[genes for disease progression in pesticides-related patients] FBXP7, EP300, HDAC6, HIP1R, MAPT, TSC1, BAG6, BLOC1S1, GAK, GALC, HTT, LAMP1 variants in genes associated with lysosomal function, notably autophagy, were enriched in PD patients exposed to agricultural pesticides 26 genes that linked pesticide exposure to PD (Progression 지칭 아닐 것) EP300, HDAC6, HTT, CTSD, ACP2, PRKN, FBX07, APP, MAPT, ATG4C, HIP1R, GNPTAB, GBA1, LAMP1, SMPD1, PINK1, BLOC1S1, MCCC1, BAG6, GAK, GALC, NPC1, ACMSD, MCOLN1, TSC1, LAMP3
(Tan, 2022 #2084) GWAS for progression of motor and cognition, and mortality	We studied 11 cohorts, 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to motor progression, defined by , cognitive impairment as defined by , and death (mortality). Mortality (death) One locus within the TBXAS1 gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10-10). Another locus near the SYT10 gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], pvalue=5.31x10-8). -There was a robust effect of the APOE e4 allele on mortality and cognitive impairment -Of the known PD risk variants, p.E326K (=p.E365K) was associated with mortality and cognitive impairment Cognition Motor progression (= reaching H&Y 3 or greater) A genomic variant associated with the expression of ADORA2A, encoding the A2A adenosine receptor (intracellular cAMP levels), was associated with motor progression (HR=4.83 [95% CI 2.89 to 8.08], p-value=1.94x10-9).
(Iwaki, 2021 #1521) GWAS for progression of motor and cognition	We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and PPMI. We included clinical data for 3364 patients with 12,144 observations (mean follow-up 4.2 years). → we did not find any overlap between the variants associated with i) PD risk, ii) AAO, & iii) progression. (ie There is minimal overlap in the genetic architecture of PD risk and PD progression.) Similarly, the AAO GWAS showed only a partial overlap with the genetics of PD risk.21 총평 TOP 5 genes Composite (motor+cognition) The APOE e4 tagging variant, rs429358, was significantly associated with composite and cognitive progression in PD TOMM40, APOE, APOC1, NALCN, WDR46 Motor No single variants were associated with motor progression, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression ATP8B2 ATP8B2 (phospholipid, plasma memb), ATP6V0A4 (acidification of intracellular compartments), AQP10 (Aquaporins, water transport), DES (desmin, cytoskeleton), OCA2 (melanin) 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). APOE, APOC1, TOMM40, PFDN6, WDR46
(Iwaki, 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 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
{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.
{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)
{Blauwendraat, 2019 #794} GBA와 interaction이 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
{Blauwendraat et al. 2019, #1490}	Dataset: Discovery dataset... 총 22,757 PD cases, 13,431 PD proxy cases, 622 LBD cases and 180,355 controls) Two independent replication dataset GBA와 interaction하는 gene을 찾는 목적임. 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 PD patients with GBA across all tested GBA risk variants with similar degree of OR (Supplementary Figure 1, ranging ORs from 1.31 to 1.55). ts와 controls with GBA ts.를 비교해서, CTSB & 가 공존하면 GBA의 PD penetrance가 증가한다.는 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: GBAS onset age 낮출지도 모른다, associated with PD, significantly decreases protein expression 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 in even GBA variant carriers have reduced levels of mature Cathepsin B which may result in even lower lysosomal

Uncertain Spans

location	transcription	uncertainty
Tan 2022 #2084 / TBXAS1 mortality locus	reads TBXAS1; preserved verbatim.	low confidence on capitalization.
Nalls 2019 #1490 reference number	the row labelled {Nalls, 2019 #1490} here appears to share the #1490 tag with the Blauwendraat 2019 #1490 reference cited later; both preserved verbatim.	low confidence on intended citation key.
Blauwendraat 2019 #794 / Sarah Jinn	the in-text citation reads (Sarah Jinn et al. 2017; S. Jinn et al. 2019); preserved verbatim.	low confidence on author capitalization.
Blauwendraat 2019 #1490 / CTSB row / GWAS column	the cell mixes a 2nd) TMEM175 cross-reference into the CTSB row’s GWAS column and reads as written.	source layout preserved verbatim; cell may be misaligned in the original.
Robak 2017 #240 row / 5 LSD genes	reads SMPD1, CTSD, SLC17A5, ASAH1, GBA; the count 5 matches the listed genes.	low confidence on SMPD1 vs SMPD-1.