Asymmetry in family history implicates nonstandard genetic mechanisms: application to the genetics of breast cancer - PubMed (original) (raw)

Asymmetry in family history implicates nonstandard genetic mechanisms: application to the genetics of breast cancer

Clarice R Weinberg et al. PLoS Genet. 2014.

Abstract

Genome-wide association studies typically target inherited autosomal variants, but less studied genetic mechanisms can play a role in complex disease. Sex-linked variants aside, three genetic phenomena can induce differential risk in maternal versus paternal lineages of affected individuals: 1. maternal effects, reflecting the maternal genome's influence on prenatal development; 2. mitochondrial variants, which are inherited maternally; 3. autosomal genes, whose effects depend on parent of origin. We algebraically show that small asymmetries in family histories of affected individuals may reflect much larger genetic risks acting via those mechanisms. We apply these ideas to a study of sisters of women with breast cancer. Among 5,091 distinct families of women reporting that exactly one grandmother had breast cancer, risk was skewed toward maternal grandmothers (p<0.0001), especially if the granddaughter was diagnosed between age 45 and 54. Maternal genetic effects, mitochondrial variants, or variant genes with parent-of-origin effects may influence risk of perimenopausal breast cancer.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Risk of breast cancer in either grandmother as related to the youngest age at diagnosis of a granddaughter in the family studied (data taken from Table 1).

Figure 2

Figure 2. Grandmothers' odds ratio (maternal versus paternal) in the Sister Study as a function of youngest age at diagnosis of a granddaughter in the family studied.

Dots connected by solid line segments are estimated odds ratios (approximately the relative risks); dashed lines connect 95% point-wise confidence limits.

Figure 3

Figure 3. Progenitors relative risk (mothers versus fathers or maternal grandmothers versus paternal grandmothers) as a function of maternally mediated relative risk () under a log-additive risk model (), or the imprinting relative risk, I, for allele frequency 0.2 for a locus for which only a specific parental copy is expressed.

The curve for parents for imprinting would overlay the curve for grandparents for a maternal effect.

References

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