Estimating single nucleotide polymorphism associations using pedigree data: applications to breast cancer

Abstract

Background:Pedigrees with multiple genotyped family members have been underutilised in breast cancer (BC) genetic-association studies. We developed a pedigree-based analytical framework to characterise single-nucleotide polymorphism (SNP) associations with BC risk using data from 736 BC families ascertained through multiple affected individuals. On average, eight family members had been genotyped for 24 SNPs previously associated with BC.Methods:Breast cancer incidence was modelled on the basis of SNP effects and residual polygenic effects. Relative risk (RR) estimates were obtained by maximising the retrospective likelihood (RL) of observing the family genotypes conditional on all disease phenotypes. Models were extended to assess parent-of-origin effects (POEs).Results:Thirteen SNPs were significantly associated with BC under the pedigree RL approach. This approach yielded estimates consistent with those from large population-based studies. Logistic regression models ignoring pedigree structure generally gave larger RRs and association P-values. SNP rs3817198 in LSP1, previously shown to exhibit POE, yielded maternal and paternal RR estimates that were similar to those previously reported (paternal RR=1.12 (95% confidence interval (CI): 0.99–1.27), P=0.081, one-sided P=0.04; maternal RR=0.94 (95% CI: 0.84–1.06), P=0.33). No other SNP exhibited POE.Conclusion:Our pedigree-based methods provide a valuable and efficient tool for characterising genetic associations with BC risk or other diseases and can complement population-based studies.

Breast-Cancer Risk in Families with Mutations in PALB2

“…10,11 Pedigree likelihoods were constructed with the use of the pedigree-analysis software Mendel, version 3.3, 12 and a maximum-likelihood approach was used to obtain parameter estimates.…”

“…For all models allowing for a residual familial component, we constrained the sum of the variance in breast-cancer risk due to PALB2 mutations and the residual variance, σ R 2 , to agree with external estimates of the total familial breast-cancer variance, σ P 2 , following the procedure described in detail elsewhere. 11 The total familial variance, σ P 2 , was assumed to be equal to 1.66, a value estimated in previous breast-cancer segregation analyses. 13,14 …”

Analysis of Multivariate Failure Times in the Presence of Selection Bias with Application to Breast Cancer

“…Various versions of conditional likelihood functions have been considered in the literature to correct for the bias due to the ascertainment with familial data (Chatterjee et al ., ; Zhang et al ., ; Schaid et al ., ; Barnes et al ., ). Typically, this strategy requires knowledge of the relationships between family members.…”

Breast-Cancer Risk in Families With Mutations in PALB2

“…10,11 Pedigree likelihoods were constructed with the use of the pedigree-analysis software Mendel, version 3.3, 12 and a maximumlikelihood approach was used to obtain parameter estimates.…”

“…For all models allowing for a residual familial component, we constrained the sum of the variance in breast-cancer risk due to PALB2 mutations and the residual variance, σ R 2 , to agree with external estimates of the total familial breast-cancer variance, σ P 2 , following the procedure described in detail elsewhere. 11 The total familial variance, σ P 2 , was assumed to be equal to 1.66, a value estimated in previous breast-cancer segregation analyses. 13,14 Because families were ascertained in multiple ways, failure to adjust for the methods of ascertainment could have led to a biased estimation of cancer risk.…”