What can genome-wide association studies tell us about the genetics of common disease?

Abstract

The success of genome-wide association studies relies on much of the risk of common diseases being due to common genetic variants; but evidence for this is inconclusive. The results of published genome-wide association studies are examined to see what can be learnt about the distribution of disease-associated variants and how this might influence future study design. Although replicated disease-associated variants tend to be very common and frequency is inversely correlated with estimated effect size, our simulations suggest that such observations are the result of power. We find that for studies conducted to date, the frequency and effect size of significantly associated alleles are likely to be similar to those of the underlying disease alleles that they represent. Little of the genetic variation of disease has been explained so far, but current studies are only adequately powered to detect very common alleles unless they greatly increase disease risk. Thus, although the truth of the common disease / common variant hypothesis remains undecided, recent successes suggest that there are many more common genetic disease-associated variants, requiring larger studies to be identified.

Figure 1. Allele Frequencies and ORs Observed in GWA Studies

(A and B) Histograms of susceptibility allele frequency and MAF, respectively, at confirmed susceptibility loci. (C) Histogram of estimated ORs at confirmed susceptibility loci. (D) Plot of estimated OR against susceptibility allele frequency at confirmed susceptibility loci. “I”s represent SNPs associated with autoimmune disease, “C”s represent SNPs associated with cancer, and small circles represent SNPs associated with other diseases.

Figure 2. Simulations Showing Frequencies of Disease-Susceptibility–Related Loci Found with p < 5 × 10⁻⁷ and a Sample Size of 1,000

Rows are (from top to bottom) GRR = 1.2, 1.5, 2; columns are (from left to right) β_S = 0.1, 1, 3.

Figure 3. Simulations Showing Frequencies of Disease-Susceptibility–Related Loci Found with p < 5 × 10⁻⁷ and a Sample Size of 3,000

Rows are (from top to bottom) GRR = 1.2, 1.5, 2; columns are (from left to right) β_S = 0.1, 1, 3.

Figure 4. Power Calculated Using Quanto for 1,000 Cases and Controls (A) and 3,000 Cases and Controls (B)

Lines are for GRR = 2 (solid), 1.5 (dashed), 1.3 (dotted), 1.2 (dashed and dotted). A multiplicative mode of inheritance is assumed.