Association between the LRP1B and APOE loci and the development of Parkinson’s disease dementia

The Morris Lab is based at the Department of Clinical and Movement Neurosciences, University College London. Its focus is on the translational, genetic and pathological aspects of Parkinson’s disease and atypical parkinsonisms. The team collaborates actively with the Global Parkinson’s Genetics Program (GP2).

The following brief summaries are taken from the Materials and methods section of the original publication.

Data quality control Whole-genome sequence data were available from participants in AMP-PD cohorts. The remainder of samples were genotyped with the Illumina HumanCoreExome array (TPD), Illumina HumanCoreExome-12 v.1.1 or Illumina Infinium HumanCoreExome-24 v.1.1 arrays (OPDC) and the Illumina Infinium Multi-Ethnic Global (MEGA) array (DIGPD). Time-to-event genome-wide survival study and meta-analysis A time-to-event genome-wide survival study (GWSS) was performed in R in each cohort, using the Cox proportional hazards (CPH) function in the survival package, in which time to PDD was regressed against each single nucleotide polymorphism (SNP), with age at diagnosis, sex and first five principal components as covariates. Conditional analysis To understand whether one or more genome-wide significant variants at the same locus were contributing to the signal, we performed conditional analysis on single SNPs using a conditional and joint association analysis approach. We used the GWSS meta-analysis summary statistics and the entire AMP-PD cohort (n = 10 418) as the reference sample for linkage disequilibrium estimation. The reference sample was subjected to the same QC steps as described before. We then used CGTA-COJO software to perform association analysis conditional on SNPs of interest. Colocalization analysis To investigate whether there is an overlap between PDD loci and expression quantitative trait loci (eQTLs), we used the coloc R package. We took a Bayesian inference approach to test the H4 null hypothesis that there is a shared causal variant associated with both progression to PDD and gene expression regulation. Signal interaction between APOE and LRP1B Given the affinity of LRP1B for ApoE-carrying lipoproteins, we conducted a survival analysis based on APOE ε4 allele and LRP1B rs80306347 carrier status to understand whether the effect of LRP1B rs80306347 signal was dependent on APOE. Candidate loci analysis We additionally performed a candidate loci analysis of specific loci or variants of interest in the combined cohorts to increase power (n = 3923), using CPH models adjusted for age at diagnosis, sex, the first five principal components and a cohort term. The regions of interest consisted of genetic variants or loci previously identified in association with cognitive impairment in PD and/or dementia with Lewy bodies: APOE ε4 allele (rs429358), GBA variants E365K (or E326K, rs2230288), T408M (or T369M, rs75548401) and N409S (or N370S, rs76763715), SNCA (rs356219, rs7680557, rs7681440, rs11931074, rs7684318), MAPT H1 haplotype (rs1800547), RIMS2 (rs182987047), TMEM108 (rs138073281) and WWOX (rs8050111). In addition, participants from DIGPD and a subset of individuals from the TPD study were Sanger sequenced for GBA (n = 1793). Genetic risk scores To understand whether there is overlap in the risk of development of PDD and the risk of PD or Alzheimer’s disease, we performed a genetic risk score (GRS) analysis using PLINK v.1.9 software. Association of clinical phenotype and APOE genotype with CSF biomarkers A subset of AMP-PD participants [from the Investigation for New Discovery of Biomarkers (BioFIND) and Parkinson’s Progression Markers Initiative (PPMI) studies] included in the analysis have longitudinal CSF Alzheimer's disease biomarker data available (n = 434). We investigated the association of phenotype (PDD versus PD) and APOE ε4 carrier status with average levels of amyloid beta (Aβ) 42, total tau and tau phosphorylated at threonine 181 (p-Tau181) using unpaired two-sample Wilcoxon rank-sum tests (R stats package, v.4.1.2) at baseline, 12, 24 and 36 months of follow-up. Significance was set at α = 0.05.