Computational protocol: Genome-Wide Meta-Analysis Identifies Regions on 7p21 (AHR) and 15q24 (CYP1A2) As Determinants of Habitual Caffeine Consumption

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Protocol publication

[…] Each study used either MACH (ARIC, NHS, HPFS, WGHS) or IMPUTE (PLCO) to impute up to ∼2.5 million autosomal SNPs with NCBI build 36 of Phase II HapMap CEU data (release 22) as the reference panel. Genotypes were imputed for SNPs not present in the genome-wide arrays or for those where genotyping had failed to meet the quality control criteria. Imputation results are summarized as an “allele dosage” (a fractional value between 0 and 2), defined as the expected number of copies of the minor allele at that SNP. [...] We examined 515 SNPs in 23 genes (±50 kb) either previously studied or members of the key biological pathway: ‘Caffeine metabolism’ (KEGG , supplemented with candidates from, ) for association with caffeine consumption in our GWA meta-analysis sample. SNPs mapping to TAS2R10, 43 and 46, implicated in the oral detection of caffeine, did not pass our stringent QC criteria and thus were not included. Gene-based analyses were performed using VEGAS . The software applies a test that incorporates information from a set of markers within a gene (or region) and accounts for LD between markers by using simulations from the multivariate normal distribution. The number of simulations per gene is determined adaptively. In the first stage, 1000 simulations are performed. If the resulting empirical P value is less than 0.1, 10000 simulations are performed. If the empirical P value from 10000 simulations is less than 0.0001, the program will perform 1000000 simulations. At each stage, the simulations are mutually exclusive. For computational reasons, if the empirical P value is 0, then no more simulations will be performed. An empirical P value of 0 from 1000000 simulations can be interpreted as P<10 E-6, which exceeds a Bonferroni-corrected threshold of P<2.8E-6 [∼0.05/17,787 (number of autosomal genes)]. […]

Pipeline specifications

Software tools IMPUTE, VEGAS
Databases KEGG
Application GWAS
Chemicals Caffeine