Chapter 4 (Schierding & Farrow et al 2020; Movement Disorders) Supplementary tables

This repository contains the supplementary tables for chapter 4: Common variants co-regulate expression of GBA and modifier genes to delay Parkinson’s disease onset. See below for supplementary table descriptions.

Supplementary Table 4.1. Hi-C datasets used in this study.

List of all Hi-C datasets used in this study and their reference to original article and GEO accession number.

Supplementary Table 4.2. Tissue-specific results from CoDeS3D significant (p<1x10-6) results from the GBA gene locus. Detailed data of eQTL-gene interactions when interrogating the 128 common SNPs at the GBA locus. Overall, 56 of the 128 (44%) common SNPs tested were identified as cis-acting spatial eQTLs that were associated with decreased GBA expression in 14 of 29 peripheral tissue types. Adj_p-value, FDR adjusted p-value. Cell_lines, Hi-C libraries in which connections were observed. Brain relevant cell lines, include: Brain astrocyte, Brain microvascular endothelial cell, Cortical plate neurons, Dorsolateral Prefrontal Cortex, Germinal zone neurons, Hippocampus, Neuronal progenitor, and Spinal cord astrocyte. cis_SNP-gene interaction, true = distance between SNP-gene is <1Mb, false = interaction involves loci separated by >1Mb or on different chromosomes. TPM, transcripts per million.

Supplementary Table 4.3. Haploreg v4.1 analysis of rsID, including proteins bound, motifs changed, promoter and enhancer histone marks. A large number of the SNPs associated with spatial eQTLs have been shown to alter transcription factor binding motifs. Overall, 38% (28 of 73) and 71% (52 of 73) of these SNPs display histone marks associated with promoter and enhancer activity, respectively. rsID, dbSNP identification number.

Supplementary Table 4.4. Literature review of the eGenes, expression in brain (GTEx V7, 03/03/2019), and their main features as related to PD. List of genes categorising their relevance to Parkinson’s disease and supporting references. aSyn, alpha synuclein.

Supplementary Table 4.5. Pathway analysis (KEGG), druggability analysis (DGIdb) and protein classification (Protein Atlas) of eGenes. List of genes categorising their functional and protein classification, and drug interactions.

Supplementary Table 4.6. The 55 Haplotype genotypes

Description of the 55 haplotype genotypes by allele identity for each informative variant. Haplotype analyses of the 229 PD patients using WhatsHap v0.1842 (default parameters) and haplotypes v1.1 R package to give 55 haplotype genotypes. Haplotypes were further organised into two major haplotype clusters (Euclidean distance, Ward clustering); haplotype cluster A = mutant/alternative/minor alleles, haplotype cluster B = majority reference alleles

* indicates presence of at least one known GBA coding mutations within the haplotype genotype. Variants are listed by dbSNP identification number (rsID), where available. ESE, exonic sequence enhancer

Supplementary Table 4.7. Haplotype group designations by patient ID. Designation of sample to haplotype group according to zygosity of haplotype presence. Patient ID, de-identified patient ID. * indicates presence of at least one known GBA coding mutations within the haplotype genotype.

Supplementary Table 4.8. Haplotype Groups and Phenotype data. Phenotypic data of individuals within each of the three haplotype groups. (PDD, Parkinson’s disease with dementia; yrs, years) ǂ 1, present; 0, absent. ¶ 0, low; 1, medium; 2, moderate.

Supplementary Table 4.9. Genome-wide significant (p<1x10-6) associations with GBA in substantia nigra and cortex, and associated histone marks and motifs. We undertook a genome-wide search (using 31,471,836 SNPs) to identify trans-acting eQTLs that regulate GBA expression in PD relevant brain tissues (substantia nigra and cortex), and the cerebellum, which is not strongly associated with PD. Four loci in the cortex, two in the substantia nigra, and zero loci in cerebellum were significant (p<1x10-6). These GBA interactions highlight a myriad of spatial regulators and their effect on DNA motifs altered, including associated histone marks. SNP ID, dbSNP identification number. ref, reference allele; alt, alternative allele from HaploReg v4.1.

Supplementary Table 4.10. Genome-wide significant loci which associate to GBA regulation in substantia nigra and cortex are themselves regulatory of many other genes in a tissue-specific manner. CoDeS3D analysis identified the regulatory effect associated with the variants on chromosome 22 on GBA expression to be specific to the substantia nigra. SNP ID, dbSNP identification number. Adj_p-value, FDR adjusted p-value. Cell_lines, Hi-C libraries in which connections were observed. TPM, transcripts per million.

Supplementary Table 4.11. Alpha-synuclein aggregates/pathology as observed in five tissues. Pubmed reference IDs for five non-neuronal tissues (Left Ventricle, Adrenal Gland, Pancreas, Salivary Glands, Stomach) identified from our spatial eQTL associations with GBA that have also been shown to have increased alpha-synuclein aggregates in PD. DLB, Dementia with Lewy Bodies.