Computational protocol: Genetic Predisposition to Increased Blood Cholesterol and Triglyceride Lipid Levels and Risk of Alzheimer Disease: A Mendelian Randomization Analysis

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Protocol publication

[…] Individual QC filters in the MRC, WTCCC2 58C, WTCCC2 NBS, IOP+, and ADNI datasets were applied using tools implemented in PLINK . QC for the IOP+ group took place separately for the two different batches.Briefly, we excluded individuals with (a) gender mismatches (M>0.8, male; F<0.2, female rule in PLINK; (b) an individual call rate ≤98%; (c) individuals with autosomal heterozygosity outside ±4 standard deviation (SD) of the mean heterozygosity; and (d) duplicates and cryptically related by calculating identity by descent (IBD) estimates for all possible pairs of individuals in PLINK and removing one of each pair with an IBD estimate ≥0.1875 (the level expected for second cousins). Each of the five datasets were then merged with genotypes from 210 unrelated European (CEU), Asian (CHB and JPT), and Yoruban (YRI) samples from the HapMap project (www.hapmap.org). Following removal of SNPs in extensive regions of linkage disequilibrium and pruning of SNPs if any pair within a 50-SNP window had r2>0.2, principal components analysis (PCA) as implemented in SMARTPCA was used to infer continuous axes of genetic variation. Eigenvectors were calculated on the basis of the linkage disequilibrium (LD)-pruned subsets of each of the merged datasets to identify and then remove individuals of divergent ancestry displayed by plotting the first two principal components and using K-means clustering.EIGENSOFTplus was then applied to each of the datasets to additionally correct for population substructure, and genetic outliers defined as individuals whose ancestry is at least 6 SDs from the mean on one of the top ten axes of variation were removed. Four principal components explained most of the variation in the IOP+ and ADNI datasets and were extracted in order to be used as covariates in further analyses. Since the MRC and WTCCC2 datasets were merged at a later stage, extraction eigenvectors took place after sample merging. [...] Since some of the SNPs to be used in this study were not included on the Illumina platform or failed QC, imputation took place using IMPUTE_2.2.2 and the 1000G phase1 integrated reference panel (April 2012, National Center for Biotechnology Information [NCBI] build 37) (). […]

Pipeline specifications

Software tools PLINK, EIGENSOFT, IMPUTE
Databases ADNI
Applications Population genetic analysis, GWAS
Organisms Homo sapiens
Diseases Alzheimer Disease
Chemicals Cholesterol, Triglycerides