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Chapter 5: Single Nucleotide Polymorphis... > Structural Variants And Common Disea... - Pg. 119

Single Nucleotide Polymorphism and its Application in Mapping Loci Involved in Developing for detecting sequence variants increases linearly with 1/MAF. For association studies, sample size also scales approximately quadratically with 1/|(OR-1)| (Manolio et al., 2009). As the odds ratio (OR) decreases, sample size needed to detect an association increases sharply, presenting a burden in both cost and capacity to the traditional capil- lary sequencing technology. The development of "next generation" sequencing technologies, which can generate millions of sequence reads in parallel, make it possible to quickly survey genetic variations in hundreds of samples (Mardis, 2008). Presently two deep sequencing strategies are employed to identify rare alleles associated with common diseases: targeted sequencing of genomic regions that have strong and replicated associations with common traits; whole genome sequencing of individuals with extreme phenotypes. There is no guarantee that associations with rare alleles will provide immediate biological be widespread in the human genome, and may contribute more to phenotypic variations than SNPs (Redon et al., 2006; Stranger et al., 2007). To this date structural variations have also been implicated in gene expression variations, female fertility, systematic autoimmunity, and other clini- cal conditions (Stefansson et al., 2005; Fanciulli et al., 2007; Stranger et al., 2007). It is likely that structural variations may account for some of the unexplained heritability of common human diseases. Innovation in the genotyping array design makes it possible to integrate analysis of copy number variations (CNVs) into GWAS. Using the hybrid genotyping array (Affymetrix SNP 6.0), McCarroll et al (2008) have shown that approximately 80% of observed copy number difference between any two individuals arise from common copy number polymorphisms (CNPs) with an allele frequency > 5%, and more than