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PLoS Genet. 2014 Mar 20;10(3):e1004174. doi: 10.1371/journal.pgen.1004174. eCollection 2014 Mar.

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

Author information

1
Biostatistics Branch, NIEHS, NIH, DHHS, Research Triangle Park, North Carolina, United States of America.
2
Epidemiology Branch, NIEHS, NIH, DHHS, Research Triangle Park, North Carolina, United States of America.

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.

PMID:
24651610
PMCID:
PMC3961172
DOI:
10.1371/journal.pgen.1004174
[Indexed for MEDLINE]
Free PMC Article

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