Genetic architecture of cancer and other complex diseases: lessons learned and future directions

Abstract

Genome-wide association studies have broadened our understanding of the genetic architecture of cancer to include common variants, in addition to the rare variants previously identified by linkage analysis. We review current knowledge on the genetic architecture of four cancers--breast, lung, prostate and colorectal--for which the balance of common and rare alleles identified ranges from fewer common alleles (lung cancer) to more common alleles (prostate cancer). Although most variants are cancer specific, pleiotropy has been observed for several variants, for example, variants at the 8q24 locus and breast, ovarian and prostate cancers or variants in KITLG in relation to hair color and testicular cancer. Although few studies have been adequately powered to investigate heterogeneity among ancestry groups, effect sizes associated with common variants have been reported to be fairly homogenous among ethnic groups. Some associations appear to be ancestry specific, such as HNF1B, which is associated with prostate cancer in European Americans and Latinos but not in African-Americans. Studies of cancer and other complex diseases suggest that a simple dichotomy between rare and common allelic architectures may be too simplistic and that future research is needed to characterize a fuller spectrum of allele frequency (common (>5%), uncommon (1-5%) and rare (<<1%) alleles) and effect size. In addition, a broadening of the concept of genetic architecture to encompass both population architecture, which reflects differences in exposures, genetic factors and population level risk among diverse groups of people, and genomic architecture, which includes structural, epigenomic and somatic variation, is envisioned.

Fig. 1.

Cancer-associated genetic variants identified through GWA studies. Genetic variants were identified from the NHGRI Genome-wide Association Study catalog (www.genome.gov/gwastudies) and include all cancer associations at P < 5 × 10⁻⁸ through 2010.

Fig. 2.

Allele frequency and effect sizes for genetic variants associated with breast cancer. Allele frequencies and ORs are taken from published literature where available and are not depicted to scale. Associations identified through GWA or GWA follow-up studies are shown with solid colored bars; all others are shaded from dark (top) to light (bottom).

Fig. 3.

Allele frequency and effect sizes for genetic variants associated with colorectal cancer. Allele frequencies and ORs are taken from published literature where available and are not depicted to scale. Associations identified through GWA or GWA follow-up studies are shown with solid colored bars; all others are shaded from dark (top) to light (bottom).

Fig. 4.

Allele frequency and effect sizes for genetic variants associated with prostate cancer. Allele frequencies and ORs are taken from published literature where available and are not depicted to scale. Associations identified through GWA or GWA follow-up studies are shown with solid colored bars; all others are shaded from dark (top) to light (bottom).

Fig. 5.

Allele frequency and effect sizes for genetic variants associated with lung cancer. Allele frequencies and ORs are taken from published literature where available and are not depicted to scale. Associations identified through GWA or GWA follow-up studies are shown with solid colored bars; all others are shaded from dark (top) to light (bottom).

Fig. 6.

Transethnic linkage disequilibrium plots for 8q24 locus and prostate cancer. Results for scanning across the admixture peak for each population separately. Data for the entire admixture peak (125.6–129.4 Mb) is on the left, with a blow up of the region of highest interest on the right (128.1–128.7 Mb). Results for African-Americans are restricted to cases age <72 (the group that initially gave the admixture signal in Freedman et al. 2006). The number of variants tested is: 2111 for African-Americans, 1565 for Japanese Americans, 1565 for Native Hawaiians, 275 for Latinos and 2056 for European Americans. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (39), (2007).