SNP frequency

Any SNP-based study needs to take these levels of attrition between SNP and working assay into account. There is only one solution to this problem to determine the frequency of the 10 million or so public SNPs in common ethnic groups. This is now widely recognized in the SNP research community, and there have been several large-scale SNP frequency determination projects that have provided frequencies for a little less than 10% of these SNPs. 

Lercher M., Smith N.G.C, Eyre-Walker A., Hurst L. (2002). The evolution of isochores evidence from SNP frequency distributions. Genetics 162 1805-1810. 

There are many common SNPs (frequency >1%) and many more rare SNPs (frequency <1%) and these vary by geography and ethnicity those common in one population may not be in another. Besides raising concerns about the wisdom of sending clinical trials overseas, this means that diagnostics might miss the less common ones. Also, medicines aren t likely to be personalized for those in the developing world. 

Variants compared with published SNP frequencies for controls... 

Recently, the presence of single nucleotide polymorphisms (SNPs) has been reported for several types of transporter. Extensive studies have been performed on the SNPs of OATP2 [100, 101], and the SNPs identified in African- and European-Americans are indicated in Fig. 12.3. Moreover, the frequency of SNPs differed among the African-American, European-Americans and Japanese, indicating the presence of an ethnic difference in the allelic mutation of this transporter [100, 101]. In addition, some of the mutations were associated with reduced transporter function and/or abnormalities in membrane targeting [100, 102] (Fig. 12.3). It is... 

To accommodate the possibility of both strong, uncommon and weak, common SNP models one may need to examine SNPs with a variety of frequencies. The successful evaluation of uncommon SNPs [1-10%) will depend in part on the ability to find these SNPs. Most publicly available SNPs have been discovered as a byproduct of large-scale sequencing efforts where the genomes of a small number of individuals are compared [40, 41]. Table 3.2 illustrates the likelihood of finding SNPs of various frequencies as a function of the number of individuals screened. Because of the small numbers of individuals screened, the methods employed to find publically-available SNPs are likely to miss SNPs of low frequency which may be most relevant. Therefore, the identification of uncommon SNPs will require directed efforts at screening larger numbers of individuals. 

Tab. 3.2 Likelihood of finding SNPs of various frequencies as a function of the number of individuals screened...

Sample sizes required for discovering SNPs associated with drug response depend on a number of factors, among which are the SNP allele frequencies, the number of SNPs being tested and, for LD mapping studies, the strength of LD. A marker... 

Fig. 3.2 G raph demonstrating the effect of varying linkage disequilibrium (D ) on relative risk. The underlying susceptibility SNP (D = 1.0) yields a relative risk of 2.5 and the marker and susceptibility SNPs have equal frequencies.

For example, if 400 patients were required to find an association by measuring the causative SNP directly, then 816 patients would be required to find the same association using random SNPs in LD with the causative SNP where D is 0.7, and 1,600 patients if D is 0.5. This situation becomes even more complex when large differences in allele frequencies exist between markers and susceptibility SNPs. If marker allele frequencies are substantially different from the susceptibility allele frequency, then the required sample size, the number of markers, or both will need to be dramatically increased [53]. 

A total of 13 polymorphisms in the gene and its transcriptional regulator beta-upstream peptide (BUP) have been identified [73]. Three closely linked polymorphisms, two coding block SNPs at amino acid positions 16 and 27, and a SNP in the BUP were found to be common (i.e., allele frequency >0.15) in the general Caucasian population [74, 75]. 

Power calculations assumed that there are two controls for each case and a SNP that operates as if it was a simple binary factor to which a proportion of the population are exposed in a manner directly related to the genotypic frequency (e.g., for 19% exposure, equivalent to a dominant allele at Hardy-Weinberg equilibrium with a prevalence of 10%). 

Both mode of inheritance (dominant, recessive) and allele frequency can have dramatic effects on required sample sizes (Table 10.2). Even for the best case scenario - a common SNP acting in a dominant fashion - a relatively large sample size of more than 300 cases (a total sample size of >900 subjects) is required at an a of 0.05 (Table 10.2). 

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