Analyses were carried out using the HYbrid Set-based Test (HYST) as implemented in the Knowledge-based mining system for Genome-wide Genetic studies software 14, 16. In the HYST approach, the SNPs within the tested set (i.e., where the set is a gene or a pathway, consisting of SNPs in linkage disequilibrium (LD)) are firstly partitioned into n weakly correlated blocks based on the LD information. Next, for each of these n LD blocks, a p-value (Pblock) is obtained with the Gene-based Association Test that uses the Extended Simes procedure (GATES)14; that is, for each ith LD-block (i=1..n), GATES (a) orders ascendingly the p-values (p(1)..p(m)) of the m SNPs assigned to that block, (b) estimates the effective number of independent SNPs me and me(j), among the m SNPs and among the top j SNPs (i.e., key SNPs), respectively, by taking account of the LD structure, and (c) computes the block-based p-value as Pblock=min(mep(j)me(j)). Lastly, HYST uses the scaled chi-square test to combine the n LD block-based p-values as to obtain the overall p-value for the gene/pathway 16. The LD blocks were inferred
