SORL1 Across Neurodegenerative Diseases: A Multi-Ancestry Biobank-Scale Assessment

GP2 ❤️ Open Science 😍

Last Updated: January 2026

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Summary

This repository contains the code, data workflows, and results associated with the manuscript titled:
“Is SORL1 a common genetic target across neurodegenerative diseases?: A multi-ancestry biobank-scale assessment.”

In this study, we performed the largest global genetic analysis of the SORL1 gene across Alzheimer’s disease (AD), related dementias (RD), and Parkinson’s disease (PD) using whole-genome sequencing (WGS) and imputed data from six large biobank-scale resources. We analyzed 67,749 cases and 111,969 controls from 11 genetically defined ancestries, evaluating rare protein-altering and splicing variants, performing burden and association tests, and expression impact across diseases and populations. In addition, we conducted a family-based analysis of 398 informative families with at least one PD case and at least two members.

Highlights of this work include:

• Identification of 53 potentially disease-causing SORL1 variants, including 41 novel variants
• Replication of SORL1 variants across AD, RD, and PD, highlighting pleiotropic effects
• Discovery of ancestry-specific and cross-ancestry associations
• A family-based analysis identified a rare predicted-damaging variant in East Asians and two in European ancestries that show evidence of segregation in PD families

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Data Statement

• Whole-genome sequencing (WGS) and imputed genotype data were obtained from the following cohorts:

  • All of Us (AoU) v7
  • Alzheimer’s Disease Sequencing Project (ADSP) v4
  • Accelerating Medicines Partnership – Parkinson’s Disease (AMP PD) v3
  • 100,000 Genomes Project (100KGP) v18
  • UK Biobank (UKB) v18.1
  • Global Parkinson’s Genetics Program (GP2) releases v9 and v10

• All cohorts underwent standardized quality control and ancestry inference using the GenoTools pipeline except for 100KGP.

• Access to each dataset must be requested from the respective data platforms.

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Citation

If you use this repository or find it helpful for your research, please cite the corresponding manuscript:

Is SORL1 a Common Genetic Target Across Neurodegenerative Diseases?: A Multi-Ancestry Biobank-Scale Assessment
Khani M, Yeboah SN, Cerquera-Cleves C, Kedmi A, Bustos BI, Grant SM, Akerman SC, Akçimen F, Lee PS, Reyes-Pérez P, Lange LM, Leonard H, Koretsky MJ, Makarious MB, Schneider Z, Jonson C, Chen PS, Tay YW, Rothstein JD, Lin CH, Lim SY, Klein C, Merchant K, Mencacci NE, Krainc D, Cookson MR, Singleton AB, Bandres-Ciga S; Global Parkinson's Genetics Program (GP2), 2026
(DOI: pending)

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Repository Orientation

.
├── ADSP/
│   └── 00_ADSP.ipynb
├── AllofUs/
│   └── 00_AllofUs.ipynb
├── AMP-PD/
│   ├── 00_AMP_Clinical data.ipynb
│   ├── 00_AMP_PD_DLB.ipynb
│   └── 00_AMP_PD.ipynb
├── GP2/
│   └── 00_GP2.ipynb
├── UKBiobank/
│   └── 00_UKB.ipynb
├── 06_Fine_mapping.R
├── Visualization_Protein_Structure/
│   └── q92673_model.cif
│   └── label_SORL1_PD.pml
│   └── label_SORL1_ADRD.pml
├── Family-based_Analysis/
│   └──r10_annotate_plink2_fams.sh
│   └──r10_extract_SORL1_rare_damaging_pfiles.sh
│   └──r10_extract_chr11_informative_pfiles.sh
│   └──r10_export_SORL1_rare_damaging_raw.sh
│   └──r10_extract_SORL1_strict3_variants_cc.sh
│   └──r10_make_informative_keep_files.R
│   └──r10_rank_SORL1_all_PD_carrier_variants.R
│   └──r10_SORL1_strict3_variants_fisher.R
│   └──r10_merge_core_fams_with_inferred_fams.R
│   └──r10_mark_informative_families.R
│   └──r10_annotate_core_ped_with_master.R
│   └──r10_kinship_clusters_to_ped.R
│   └──r10_summarize_SORL1_segregation_by_ancestry.R
│   └──r10_filter_SORL1_by_ancestry.R
│   └──r10_rebuild_unrelated_cc_mono_brainbank_IIDpsam.R
│   └──r10_breakdown_top3_SORL1_variants.R
└── LICENSE

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Key Analyses

1. Variant Filtering
   • Filtering based on CADD > 20, MAC ≥ 2, protein-altering or splicing impact, and case-only presence
2. Association and Burden Analysis
   • Case-control comparisons using logistic regression and burden tests (SKAT-O) via RVTESTS
3. Fine Mapping
   • Bayesian colocalization using coloc with diverse AD/PD GWAS datasets to nominate causal variants
4. eQTL Annotation
   • Multivariate brain eQTLs using the mmQTL resource from PsychENCODE, GTEx, and ROSMAP
5. Family-based analysis
   • Family-based analysis of 398 informative families with at least one PD case and at least two members

Analysis Notebooks / Scripts

Scripts	Description
06_Fine_mapping.R	Colocalization fine-mapping using multiple AD/PD GWAS datasets across ancestries
ADSP/00_ADSP.ipynb	Variant filtering, association, and burden testing in the ADSP cohort
AllofUs/00_AllofUs.ipynb	SORL1 variant exploration in AD, RD, and PD within the AoU dataset
AMP-PD/00_AMP_PD.ipynb	PD-focused analysis of SORL1 variants from AMP PD WGS data
AMP-PD/00_AMP_PD_DLB.ipynb	Variant analysis in Dementia with Lewy Bodies (DLB) cases from AMP PD
AMP-PD/00_AMP_Clinical data.ipynb	Clinical characterization and cognitive profiling of variant carriers in AMP PD
GP2/00_GP2.ipynb	Variant filtering, Case-control association and burden analysis across ancestries using GP2 imputed data
UKBiobank/00_UKB.ipynb	Variant filtering, Gene-based and single-variant association analysis in UKB AD/RD/PD populations
q92673_model.cif,label_SORL1_PD.pml,label_SORL1_ADRD.pml	Visualization of Protein Structure
r10_annotate_plink2_fams.sh	Annotate SORL1 Region Variants
r10_extract_SORL1_rare_damaging_pfiles.sh	Extract SORL1 Rare Damaging files
r10_extract_chr11_informative_pfiles.sh	Extract chr11 SORL1 region
r10_export_SORL1_rare_damaging_raw.sh	Export SORL1 Rare Damaging Raw Genotypes
r10_extract_SORL1_strict3_variants_cc.sh	SORL1 Variant Carrier Analysis
r10_make_informative_keep_files.R	Build Informative WGS PLINK Keep Files by Ancestry
r10_rank_SORL1_all_PD_carrier_variants.R	Rank SORL1 Variants by All-PD-Carrier Families with Strict Segregation Filter
r10_SORL1_strict3_variants_fisher.R	Compute Carrier Counts and Fisher Tests for SORL1 Variants
r10_merge_core_fams_with_inferred_fams.R	Merge Core and Kinship-Inferred Pedigrees into Master PED Table
r10_mark_informative_families.R	Mark Informative Families and Individuals in Master Pedigree
r10_annotate_core_ped_with_master.R	Annotate Core Pedigree with Master Key and Extended Clinical Fields
r10_kinship_clusters_to_ped.R	Build Kinship-Inferred Families for Non-Core WGS Samples
r10_summarize_SORL1_segregation_by_ancestry.R	Summarize SORL1 Rare Variant Segregation by Ancestry
r10_filter_SORL1_by_ancestry.R	Filter Rare Damaging SORL1 Variants by Ancestry
r10_rebuild_unrelated_cc_mono_brainbank_IIDpsam.R	Build Unrelated WGS Cohort by Ancestry and Study Type
r10_breakdown_top3_SORL1_variants.R	Top SORL1 Variants Family Segregation

Software

Software	Version	Resource URL	RRID	Notes
R	4.3.1	r-project.org	RRID:SCR_001905	Core data analysis and plotting
PLINK	1.9 / 2.0	cog-genomics.org/plink/	RRID:SCR_001757	Genotype extraction and frequency calc
RVTESTS	2.1.0	github.com/zhanxw/rvtests	RRID:SCR_019033	SKAT-O burden testing
ANNOVAR	2019Oct24	wannovar.wglab.org	RRID:SCR_012821	Variant annotation
GenoTools	-	github.com/dvitale199/GenoTools	-	Ancestry prediction and QC
coloc	6.0.0	CRAN - coloc	-	Fine-mapping & colocalization

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For questions, please open an issue or contact the corresponding author.