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Evaluation of significant genome-wide association studies risk - SNPs in young breast cancer patients.

ABSTRACT: PURPOSE:Genome-wide-association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) that are associated with an increased risk of breast cancer. Most of these studies were conducted primarily in postmenopausal breast cancer patients. Therefore, we set out to assess whether or not these breast cancer variants are also associated with an elevated risk of breast cancer in young premenopausal patients. METHODS:In 451 women of European ancestry who had prospectively enrolled in a longitudinal cohort study for women diagnosed with breast cancer at or under age 40, we genotyped 44 SNPs that were previously associated with breast cancer risk. A control group was comprised of 1142 postmenopausal healthy women from the Nurses' Health Study (NHS). We assessed if the frequencies of the adequately genotyped SNPs differed significantly (p?0.05) between the cohort of young breast cancer patients and postmenopausal controls, and then we corrected for multiple testing. RESULTS:Genotyping of the controls or cases was inadequate for comparisons between the groups for seven of the 44 SNPs. 9 of the remaining 37 were associated with breast cancer risk in young women with a p-value <0.05: rs10510102, rs1219648, rs13387042, rs1876206, rs2936870, rs2981579, rs3734805, rs3803662 and rs4973768. The directions of these associations were consistent with those in postmenopausal women. However, after correction for multiple testing (Benjamini Hochberg) none of the results remained statistically significant. CONCLUSION:After correction for multiple testing, none of the alleles for postmenopausal breast cancer were clearly associated with risk of premenopausal breast cancer in this relatively small study.

SUBMITTER: Rath M

PROVIDER: S-EPMC6534300 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Evaluation of significant genome-wide association studies risk - SNPs in young breast cancer patients.

Rath Michelle M Li Qiyuan Q Li Huili H Lindström Sara S Miron Alexander A Miron Penelope P Dowton Anne E AE Meyer Meghan E ME Larson Bryce G BG Pomerantz Mark M Seo Ji-Heui JH Collins Laura C LC Vardeh Hilde H Brachtel Elena E Come Steven E SE Borges Virginia V Schapira Lidia L Tamimi Rulla M RM Partridge Ann H AH Freedman Matthew M Ruddy Kathryn J KJ

PloS one 20190524 5

<h4>Purpose</h4>Genome-wide-association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) that are associated with an increased risk of breast cancer. Most of these studies were conducted primarily in postmenopausal breast cancer patients. Therefore, we set out to assess whether or not these breast cancer variants are also associated with an elevated risk of breast cancer in young premenopausal patients.<h4>Methods</h4>In 451 women of European ancestry who had prospe ...[more]

PMID: 31125336

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Project description:BackgroundRecently mixed linear models are used to address the issue of "missing" heritability in traditional Genome-wide association studies (GWAS). The models assume that all single-nucleotide polymorphisms (SNPs) are associated with the phenotypes of interest. However, it is more common that only a small proportion of SNPs have significant effects on the phenotypes, while most SNPs have no or very small effects. To incorporate this feature, we propose an efficient Hierarchical Bayesian Model (HBM) that extends the existing mixed models to enforce automatic selection of significant SNPs. The HBM models the SNP effects using a mixture distribution of a point mass at zero and a normal distribution, where the point mass corresponds to those non-associative SNPs.ResultsWe estimate the HBM using Gibbs sampling. The estimation performance of our method is first demonstrated through two simulation studies. We make the simulation setups realistic by using parameters fitted on the Framingham Heart Study (FHS) data. The simulation studies show that our method can accurately estimate the proportion of SNPs associated with the simulated phenotype and identify these SNPs, as well as adapt to certain model mis-specification than the standard mixed models. In addition, we analyze data from the FHS and the Health and Retirement Study (HRS) to study the association between Body Mass Index (BMI) and SNPs on Chromosome 16, and replicate the identified genetic associations. The analysis of the FHS data identifies 0.3% SNPs on Chromosome 16 that affect BMI, including rs9939609 and rs9939973 on the FTO gene. These two SNPs are in strong linkage disequilibrium with rs1558902 (Rsq =0.901 for rs9939609 and Rsq =0.905 for rs9939973), which has been reported to be linked with obesity in previous GWAS. We then replicate the findings using the HRS data: the analysis finds 0.4% of SNPs associated with BMI on Chromosome 16. Furthermore, around 25% of the genes that are identified to be associated with BMI are common between the two studies.ConclusionsThe results demonstrate that the HBM and the associated estimation algorithm offer a powerful tool for identifying significant genetic associations with phenotypes of interest, among a large number of SNPs that are common in modern genetics studies.

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Evaluation of significant genome-wide association studies risk - SNPs in young breast cancer patients.

Publications

Evaluation of significant genome-wide association studies risk - SNPs in young breast cancer patients.

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