Genetics, GWAS, PRS, eQTL, and Pathway Analysis

This topic page reorganises the 9 source notes filed under genetics-pathway into reading-order axes. It does not replace the by-photo Markdown; every claim links back to a source note or the canonical transcription. Where a source carries Uncertain Spans, that uncertainty is preserved here rather than smoothed out.

Overview

The corpus treats genetics, association testing, PRS, eQTL, and pathway analysis as a single late-document methodological reference block — the chapters that the rest of the JS PD pipeline cites for variant-pathogenicity vocabulary, association-study scaffolding, and pathway-tool selection rather than for disease-mechanism claims. Seven overlapping axes organise the 9 sources. (1) Variant pathogenicity under the PADD > Pathogenicity of variant chapter, anchored on the ACMG-AMP-style Tables 3 / 4 / 5 classification grids (20240722_184314). (2) Pathway Analysis tool selection (VarElect / Reactome / KEGG / WikiPathways / GO / EnrichR / IPA / MetaCore / Cytoscape / R-Bioconductor / STRING) plus the Carling 2020 worked example (20240722_184317) and a prognosis-subtype / quartile-quintile stratification page (20240722_184509). The nav-trail tail of the Pathway-Analysis chapter drifts in body content into a PRC / PDE meeting-log page (20240722_184320). (3) The Genetic Association Study two-column comparison (Candidate-gene vs GWAS) and the SNP / GATK / VCF-gVCF / CNV / Genotype-Phenotype / Gene-network preliminaries (20240722_184633). (4) Polygenic Risk Score scaffolding — Statistical-analysis tail, Genetic Support Level / GWAS-criteria heatmaps, Genetic Prevalence workflow (GnomAD-based PRKN example), the PRS table, and the Steps-of-PRS-STUDY slide (20240722_184636). (5) eQTL methodology (cis / trans / distant), pLoF, and Genetic Engineering rows on the page that the Word navigation files under the 4 LPS root (20240722_184639). (6) Genetic Testing methods — direct-to-consumer panels, single-gene testing, Parkinson-disease multigene panels, Comprehensive Genomic Testing (WES / WGS), Chromosomal microarray, sequencing depth / coverage, and a vendor / laboratory list (20240722_184629). (7) The Mutation-rooted page whose visible body covers LRRK2 MOA / Inflammation / Mitophagy / Mutation bullets / a LRRK2 Pathogenic Variants reference table (20240722_183404).

This topic is methodology-side reference for downstream synthesis pages. PD-disease-context pathogenicity calls (PRKN variants, GBA mutations, LRRK2 MOA application), program-side genetic stratification, and disease- specific PRS / eQTL claims live on the relevant disease-side topic pages and are only linked here; this page does not re-narrate them.

Source Boundary / Delegation

This topic is bounded inside sections/genetics-pathway and does not include sources from sibling sections. Adjacent material that overlaps but is owned elsewhere:

boundary	adjacent material	owned by
HGVS sequence-variant nomenclature, Genotyping Methods table, Cre-LoxP / Tet system	upstream nomenclature / mutation chapters that the variant-pathogenicity tables here import	molecular-biology (20240722_184620, 20240722_184623, 20240722_184643, 20240722_184713)
Synaptic change in PD HGVS / FATHMM / Genotyping Methods page (20240722_184626) and the BMx Milestone Matrix / Analytical-validation framework that downstream PD-genetics calls cite	the disease-side application of HGVS / FATHMM-MKL prediction scoring and the biomarker-grade variant-call validation rubric	biomarkers-outcomes
PRKN variant catalog (HGVS / dbSNP / ClinVar / Schneider 2017 autopsy / heterozygous carrier-frequency penetrance / Korean YOPD / Portugal ARJP) and the Genetic-prevalence workflow’s PRKN GnomAD example as it applies to PARKN-PD prevalence	this topic narrates the methodology only; the PRKN-side disease application stays on parkin / parkn-gt	parkin
LRRK2 pathogenic-variant catalog, LRRK2 MOA / kinase / Rab / Mitophagy / Inflammation in microglia, G2019S / G2385R / R1628P risk profile	the body of _183404 is LRRK2-specific (Mutation-rooted) but the LRRK2 disease-side coverage proper is in lrrk2 (4 sources); inflammation / mitophagy biology in inflammation / mitochondria	lrrk2 · inflammation · mitochondria
Carling 2020 mitochondrial / lysosomal-dysfunctional DEG VarElect tables and KEGG enrichment table (SNCA, PLA2G6, RPS27A, GCH1, NDUFS1/2, NDUFAF5, CTSD, SMPD1, NPC1, …)	the disease-side biology of those gene calls (SNCA, GCH1, NDUFS, lysosomal enzymes)	alpha-synuclein, mitochondria, lysosome-autophagy
Power-analysis / sample-size primer applied here implicitly via PRS effect-size cells	the generic Statistics / Power-analysis primer is on _184417 (PD Proteomics)	molecular-biology
AAV / capsid / promoter / Route-of-Administration / FDA CTGT 2021 GT safety appendix that the Genetic Engineering table on _184639 extends into	the GT-safety appendix and program-side application	molecular-biology § GT Safety Appendix (_184756), pk-gt-pharmacology, parkn-gt, snca-aso-wave, snca-btv-hdo
Operations / PRC meeting governance / PDE template guidance	the PRC meeting-log body of _184320 is filed in sections/genetics-pathway because of its Pathway Analysis > Example of Pathway Analysis > PDE nav root, but the meeting-log content itself belongs to the Operations / PRC governance axis	operations
ACMG-AMP-style variant-pathogenicity application to PRKN, GBA1, LRRK2, SNCA in clinical-trial context	this topic narrates the criteria-table methodology only; disease-specific pathogenicity calls and entity-level program eligibility stay on the relevant program / biology topics	parkin, gba-pd-biology, alpha-synuclein

The topic also does not include the Synaptic change in PD HGVS / FATHMM / Genotyping Methods page (20240722_184626), the Reference range (normal range) UPS / TR-FRET page (20240722_184557), or any other source filed under biomarkers-outcomes / molecular-biology — even though they re-use the same variant-nomenclature / power-analysis vocabulary.

Source Coverage

9 source notes are assigned to the genetics-pathway section. They sit across 9 first-level nav_path clusters; the topic axes below collapse those clusters as follows:

nav root (first nav_path entry)	sources	covered axis
Mutation	1	LRRK2-side Mutation chapter (Inflammation / Mitophagy / pathogenic-variants table)
Pathogenicity of variant	1	ACMG-AMP-style variant pathogenicity criteria (Tables 3 / 4 / 5)
PADD	1	Pathway Analysis tool comparison + Carling 2020 worked example (PADD > Pathogenicity of variant > Pathway Analysis tail)
Pathway Analysis	1	Pathway Analysis > Example of Pathway Analysis > PDE — body drifts into a PRC meeting-log / PDE narrative-template page
Example of Pathway Analy...	1	VarElect / KEGG results, prognosis-subtype tables (Zhang 2019, Kaiser 2023), Grouping-subjects-into-equal-groups (tertile / quartile / quintile)
Genetic Association Study	1	SNP / GATK / VCF-gVCF / CNV / Genotype-Phenotype / Gene-network primer + Candidate-gene-vs-GWAS comparison
polygenic risk score	1	Statistical-analysis tail, Genetic Support Level + GWAS-criteria heatmaps, Genetic Prevalence workflow, PRS table, Steps-of-PRS-STUDY slide
4 LPS	1	eQTL methodology (cis / trans / distant), pLoF, Genetic engineering rows
(no nav path)	1	Genetic Testing methods chapter (multigene panels, WES / WGS, CMA, coverage, vendor list)

For exact nav_path strings and headings see genetics-pathway and the matching by-nav indexes listed in related_topics_by_nav. The Example of Pathway Analy... (with ellipsis) nav-root is preserved verbatim in nav-path-index as the Word navigation pane’s own truncation; the (no nav path) page on _184629 is indexed under unclassified.

Across the 9 sources, the source-note frontmatter records 37 uncertain_span_count entries and 0 body-embedded figure assets. The zero-figure-embed count reflects the 2026-04-29 body-purity decision (docs/decisions/2026-04-29-body-purity-and-figure-only-embeds.md): the genetics-pathway pages embed ACMG-AMP banded-criteria tables, LRRK2 protein-domain schematics, eQTL cis / trans / distant cartoons, the Spinal-Cord ASE / eQTL workflow slide, the Workflow-to-predict-genetic- prevalence slide (with PRKN GnomAD figures and a 4×4 compound-heterozygous matrix), the Genetic-Support-Level orange heatmap, the GWAS-criteria heatmap, the Steps-of-PRS-STUDY green workflow slide, the Carling 2020 DEG / KEGG-enrichment paper screenshots, the Grouping-subjects bell-curve diagrams, and the LRRK2 Armadillo-Ankyrin-LRR-Roc-COR-Kinase-WD40 domain diagrams as mixed text+figure crops on the source pages, so they are kept as evidence rather than embedded. The 37 uncertain spans are retained as review targets and not resolved here.

Variant Pathogenicity (PADD / Pathogenicity of variant)

20240722_184314 anchors the chapter with the ACMG-AMP-style Tables 3 / 4 / 5 (Pathogenic / Benign / Rules-for-Combining-Criteria), preceded by the tail of a multi-column evidence matrix carried over from a prior un-photographed page and followed by a Pathway Analysis > Goal heading whose Gene-disease-phenotype table is mostly cut off. The yellow <mark> highlights on the Pathogenic / Benign / Rules / Likely-Pathogenic / Likely-Benign cells and the Korean inline annotation 본문, mean >90% certainty… adjacent to the Likely Pathogenic heading are preserved verbatim; specific criterion cells are not paraphrased here. 4 Uncertain Spans. Disease-side application to PRKN / GBA1 / LRRK2 / SNCA pathogenicity calls is delegated per the boundary table.

Pathway Analysis — Tool Comparison and Worked Examples

20240722_184317 bridges the variant-pathogenicity chapter into pathway-analysis tooling: a wide tool-comparison table (VarElect / Reactome / KEGG / WikiPathways / GO / EnrichR / IPA / MetaCore / Cytoscape / R-Bioconductor / STRING) over row labels tool name / Web tool / Input / Output / Eg. / resource, plus a “Carling 2020” worked-example sub-section reproducing the paper’s mitochondrial-DEG, lysosomal-DEG, and KEGG-enrichment tables as HTML. The bottom-row Tx-response cell continues mid-sentence onto _184337 (filed under clinical-pd). 6 Uncertain Spans.

20240722_184509 is the Example of Pathway Analy... page (Word-navigation truncation preserved verbatim). The visible body strings together a VarElect / KEGG result pair, Comp Bio prognosis-comparison, Zhang 2019 PPMI subtype, Kaiser 2023 endotype, and a Grouping-subjects tertile / quartile / quintile stratification table with three bell-curve diagrams kept as evidence rather than embedded. <mark> highlights on prognosis-cell phrases and on the LPO token are preserved; the small-print VarElect / KEGG cells contain mojibake-style OCR fragments flagged at the bottom of the source page rather than guessed. 5 Uncertain Spans.

20240722_184320 is a nav-vs-body drift point: the Pathway Analysis > Example of Pathway Analysis > PDE nav-trail does not match the visible body, which is a 3-column PRC meeting-log + Meeting with PRC office PDE rough-notes block + a Narrative-template Word callout that spills onto the next photo. The drift is preserved as recorded, not reconciled; the page stays in sections/genetics-pathway by nav root while the operations / PRC governance content is delegated to operations in the boundary table. 3 Uncertain Spans.

Genetic Association Study — SNP / GATK / VCF / CNV / Gene Network

20240722_184633 carries the SNP / GATK / VCF-gVCF / CNV / Genotype-Phenotype / Gene-network preliminaries and a two-column (Candidate gene association study) vs GWAS: Genome-Wide Association Study comparison table (cuts mid-row inside the LD / Imputation paragraph and continues onto _184636). The Gene-network section reproduces an Ingenuity Pathway Analysis network diagram (Figure 2 from a WORLDSymposium 2021 GBA1-PD whole-exome study) with partially-OCR-readable node labels; the page also carries the bottom two body rows of a method-comparison table that begins on _184629. 3 Uncertain Spans. Disease-side application of the Candidate-gene-vs-GWAS framing to specific PD risk loci is delegated per the boundary table.

PRS, Genetic Support Level, Genetic Prevalence

20240722_184636 anchors the PRS scaffolding chapter. The body strings together (in source order) the tail of a Korean Statistical-analysis row (Rare variant / Burden test / SKAT / SKAT-O / Replication / Validation), a Genetic Support Level section with two heatmaps (Genetic-support-level rows × criteria 1–6; sibling GWAS-criteria rows 1–7) and a dropdown- selection list, a Genetic Prevalence section whose 3-step Workflow-to-predict-genetic-prevalence slide uses PRKN as a worked example (PRKN short variants from GnomAD v3.1; PRKN structural variants from GnomAD v2; a 4×4 compound-heterozygous matrix; a Mendelian-inheritance pedigree attributed to Emily Wong and Dorothée Diogo), a polygenic-risk-score table with Korean prose definitions, a Steps-of-PRS-STUDY workflow diagram, and the heading-only opening of a Results-of-PRS section that continues on _184700. Heatmap and slide cells stay as evidence rather than embedded. 4 Uncertain Spans. Notable preserved-verbatim items: the red callout No perfect scoring system - meant to be guidelines… on the Genetic-Support-Level section and the Add Separate column to indicate OMICs support? Discussions withCompBio annotation (the missing space in withCompBio is preserved as transcribed). The PRKN-side disease application of the Genetic-prevalence workflow is delegated to parkin / parkn-gt.

eQTL, pLoF, Genetic Engineering

20240722_184639 is the page whose Word navigation pane records the truncated 4 LPS root. The visible body strings together a Korean / English RegulomeDB-flavored bullet outline, a Mechanism that eQTL을 통한 유전자 발현 조절 Word table whose middle column hosts cis / trans / distant schematic cartoons, a Table 1 | Examples of disease risk loci correlated with eQTL genes table, three slide screenshots from an October 23, 2019 Takeda Confidential deck (Key-points / trans-eQTL Investigation / eQTL Investigation of Human Spinal Cord Tissue, the third paired with a Spinal Cord single cell transcriptome atlas for ALS snRNA-seq + Spatial-Transcriptomics block), a pLoF (predicted loss-of-function) outline, and a Genetic engineering table whose lower rows continue onto _184643 (filed under molecular-biology). Slide screenshots stay as evidence crops because each crop mixes slide diagrams with transcribable slide text; slide text is transcribed in the body but specific cell values are not re-quoted here. 4 Uncertain Spans.

Genetic Testing — Multigene Panels / WES / WGS / CMA / Coverage

20240722_184629 carries the Genetic Testing chapter under an empty nav_path (indexed under unclassified). The page is a wide multi-column table walking from direct-to-consumer genetic testing through Single-gene testing, Multigene Panels (Off-the-shelf, Parkinson-disease multigene panel including PRKN, Custom designed), Comprehensive Genomic Testing (WES / WGS), Chromosomal microarray (CMA) as a first-line test for developmental delay / intellectual disability / multiple congenital anomalies / autism spectrum disorder, gene set analysis (GSA) / Sequence analysis / deletion-duplication (=copy number) analysis (with SALSA P051 Parkinson MLPA kits / MRC Holland probes against SNCA / PARKIN / PINK1 / selected DJ-1 exons), the bioneer contact bullet, the coverage (=sequencing depth) definition, a germline-vs-somatic required-coverage distinction, and a recommended-coverage table for WGS / WES / RNA-seq / ChIP-Seq. The bottom genetic testing laboratory vendor table (Genewiz / Genome Insight / Scientst.com / RSA / Sanger sequencing / realtime PCR / TaqMan / MLPA parkin-gene-dosage rows) is clipped and should not be treated as fully transcribed; specific ratio thresholds and coverage examples are preserved on the source page rather than re-quoted here. 4 Uncertain Spans. Application of panel choice and coverage thresholds to specific disease-side workups is delegated to parkin / alpha-synuclein.

LRRK2-Side Mutation Chapter

20240722_183404 is the Mutation-rooted page whose visible body covers LRRK2 specifically: two trailing bullets from the prior Expression of LRRK2 section, an Inflammation and LRRK2 block (Kunisada hiPS-microglia note, Dong Hwan Ho 2018 TNFα reference), a wide MOA evidence table (Tag / Mutation / Phosphorylation / Kinase / Substrate / Rab10 / Localization / Trafficking / Autophagy / aSyn release / Spread), a small Mitophagy and LRRK2 two-row table citing (Singh, 2021 #1650), the Mutation section with bullet items h–o, a paired LRRK2 protein- domain + Armadillo-Ankyrin-LRR-Roc-COR-Kinase-WD40 schematic annotated with amino-acid variant labels, a LRRK2 Pathogenic Variants 4-column reference table, and a GeneReviews disclaimer footnote. The red / italic styling on the G2019S … G2385R and R1628P bullet and on several MOA cells is preserved verbatim; specific variant labels and MOA cell values are not re-quoted here. 4 Uncertain Spans. The page sits in sections/genetics-pathway by its Mutation nav root, not by its body content; LRRK2 disease-side coverage proper lives in lrrk2 (4 sources, incl. DNL151 / DNL201).

Source Table

All 9 sources, in capture-time order, with the per-page uncertain-span and embedded-image counts copied from front matter. nav path is the full nav_path recorded in the source note (joined by >).

stem	nav path / heading	source note	canonical	uncertain spans	embedded images
20240722_183404	Mutation	note	md	4	0
20240722_184314	Pathogenicity of variant	note	md	4	0
20240722_184317	PADD > Pathogenicity of variant > Pathway Analysis > Example of Pathway Analysis	note	md	6	0
20240722_184320	Pathway Analysis > Example of Pathway Analysis > PDE	note	md	3	0
20240722_184509	Example of Pathway Analy…	note	md	5	0
20240722_184629	(no nav path)	note	md	4	0
20240722_184633	Genetic Association Study	note	md	3	0
20240722_184636	polygenic risk score > Steps of PRS STUDY > Results of PRS > eQTL	note	md	4	0
20240722_184639	4 LPS	note	md	4	0

Totals across the 9 sources: uncertain_span_count = 37, embedded_image_count = 0. These are review surface area; the zero-figure-embed count reflects the 2026-04-29 body-purity decision (docs/decisions/2026-04-29-body-purity-and-figure-only-embeds.md) under which mixed text-and-figure crops on these pages are kept as evidence rather than embedded.

Uncertainties Carried Forward

This page does not paraphrase the ACMG-AMP-style Pathogenic / Benign / Rules cells, the Pathway-Analysis tool-comparison parameters, the Carling 2020 VarElect / KEGG / IPA worked-example rows, the prognosis-subtype / quartile-quintile stratification cells, the PRC meeting-log rows, the SNP / GATK / VCF / CNV definitions, the IPA gene-network node labels, the Genetic-Support-Level / GWAS-criteria heatmap cells, the Workflow-to-predict-genetic-prevalence PRKN GnomAD figures, the eQTL Mechanism schematic-diagram cells, the Spinal-Cord ASE-eQTL flowchart steps, the Genetic-Testing coverage / MLPA / vendor rows, or the LRRK2 MOA / Mitophagy / variant-label table rows. Specific uncertainty hot spots worth checking before any downstream extraction:

• Variant pathogenicity Tables 3 / 4 / 5 with <mark> highlights and the inline Korean annotation 본문, mean >90% certainty… preserved verbatim (20240722_184314, 4).
• Pathway-Analysis tool comparison + Carling 2020 worked example + Grouping-subjects stratification — small-print VarElect / KEGG cells with mojibake-style OCR fragments flagged at the bottom of the source pages, plus <mark> highlights on prognosis-cell phrases and on the LPO token (20240722_184317, 6; 20240722_184509, 5).
• Pathway-Analysis nav-vs-body drift on _184320: the Pathway Analysis > Example of Pathway Analysis > PDE nav-trail does not match the visible body (PRC meeting log + PDE narrative-template rough notes); preserved as recorded, not reconciled (20240722_184320, 3).
• Genetic Association Study primer — partially-OCR-readable IPA gene-network node labels and a Candidate-vs-GWAS comparison table that cuts mid-row inside the LD / Imputation paragraph (20240722_184633, 3).
• PRS scaffolding — small-print heatmap and slide cells; the Add Separate column to indicate OMICs support? Discussions withCompBio annotation preserves the missing space in withCompBio verbatim (20240722_184636, 4).
• eQTL methodology — Korean / English RegulomeDB bullet text, cis / trans / distant schematic-cell cartoons, Spinal-Cord ASE-eQTL flowchart steps, and Genetic engineering table rows continuing onto _184643 (20240722_184639, 4).
• Genetic Testing on _184629 carries an empty nav_path (indexed as by-nav/unclassified); the chapter mixes English and Korean prose with high-risk citation punctuation, MLPA ratio thresholds, and a clipped bottom vendor table that should not be treated as fully transcribed (20240722_184629, 4).
• LRRK2-side Mutation chapter — wide MOA evidence-table cells, the Armadillo-Ankyrin-LRR-Roc-COR-Kinase-WD40 domain schematic amino-acid variant labels, and the LRRK2 Pathogenic Variants reference table are partial-coverage; the G2019S … G2385R and R1628P red / italic styling is preserved rather than reconciled (20240722_183404, 4).

Related Pages

• genetics-pathway — section index for all 9 sources
• molecular-biology — sibling topic; HGVS sequence-variant nomenclature, Cre-LoxP / Tet-system, Genotyping Methods chain (_184643, _184713), GT Safety Appendix (_184756), Power-analysis primer (_184417)
• biomarkers-outcomes — sibling topic; Synaptic change in PD HGVS / FATHMM / Genotyping Methods page (_184626), BMx Milestone Matrix / Analytical-validation framework
• parkin — sibling topic; PRKN variant catalog, heterozygous-carrier penetrance, Korean YOPD / Portugal ARJP, that consume the Genetic-prevalence workflow’s PRKN GnomAD example
• alpha-synuclein — sibling topic; SNCA / aSyn / Lewy biology that consumes the Carling 2020 SNCA / GCH1 / NDUFS DEG calls, the SALSA P051 SNCA exon probes, and the Pathogenicity-of-variant criteria
• gba-pd-biology / gba-gcase-modalities — sibling topics on GBA-PD biology / therapeutic modalities that consume the Pathogenicity-of-variant criteria for GBA1 calls
• mitochondria — sibling topic; mitochondrial DEG / NDUFS / NDUFAF5 disease-side biology that consumes the Carling 2020 mitochondrial-dysfunctional VarElect rows
• inflammation — sibling topic; LRRK2 / TNFα / microglia inflammation biology that consumes the Inflammation and LRRK2 block
• lrrk2 — sibling section for LRRK2 pipeline (4 sources, including DNL151 / DNL201)
• lysosome-autophagy — sibling section for the lysosomal-dysfunctional DEG calls (CTSD, SMPD1, NPC1, …) that the Carling 2020 example surfaces
• operations — sibling section for PRC meeting governance / PDE narrative-template, where the body of _184320 properly belongs even though the page sits in sections/genetics-pathway by nav root
• pk-gt-pharmacology — sibling topic for the AAV / capsid / promoter / Route-of-Administration / FDA CTGT 2021 GT-safety material that the Genetic-engineering table on _184639 extends into
• therapeutic-programs — program-routing map (PARKN GT, NLRP3i, aSyn programs) that depends on the Genetic-prevalence workflow’s PRKN GnomAD example
• parkn-gt / snca-aso-wave / snca-btv-hdo — program entities that consume the variant-pathogenicity, Genetic-prevalence, and Genetic-Testing material
• mutation — Mutation first-nav_path index
• pathogenicity-of-variant — Pathogenicity of variant first-nav_path index
• padd — PADD first-nav_path index
• pathway-analysis — Pathway Analysis first-nav_path index
• example-of-pathway-analy — Example of Pathway Analy... first-nav_path index (Word-truncation preserved)
• genetic-association-study — Genetic Association Study first-nav_path index
• polygenic-risk-score — polygenic risk score first-nav_path index
• 4-lps — 4 LPS first-nav_path index
• unclassified — empty-nav_path index (covers _184629)
• source-catalog — all 447 sources in capture order
• nav-path-index — 376 distinct nav_paths