GWAS have been one of the most widely used methods for identifying risk loci in the past decade.37-40 In a typical GWAS, one million or more common variants known as single nucleotide polymorphisms (SNPs) are examined for their association to disease. “Common variants” are generally defined as those alleles that are carried by at least 5% of the population. GWAS are typically conducted using a case-control design in which allele frequencies are compared between cases with a disease to controls without the disease. Compared to candidate gene studies, GWAS provide a hypothesis free or “unbiased” approach to detecting susceptibility loci. However, to account for the large number of tests conducted, the threshold for declaring genome-wide significance in a GWAS is a p-value of less than 5×10-8, equivalent to a p-value of 0.05 corrected for a million independent tests (p<0.00000005).41 Because common variant effects are typically modest, large samples (on the order of 10,000 or more cases and controls) are usually needed to have sufficient power to detect such effects at this statistical threshold.
