在一项大型病例对照研究中，对乳腺癌 GWAS 基因座附近 38 个基因的编码序列进行靶向重测序。
Targeted Resequencing of the Coding Sequence of 38 Genes Near Breast Cancer GWAS Loci in a Large Case-Control Study.
机构信息
Department of Public and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
出版信息
Cancer Epidemiol Biomarkers Prev. 2019 Apr;28(4):822-825. doi: 10.1158/1055-9965.EPI-18-0298. Epub 2019 Jan 14.
BACKGROUND
Genes regulated by breast cancer risk alleles identified through genome-wide association studies (GWAS) may harbor rare coding risk alleles.
METHODS
We sequenced the coding regions for 38 genes within 500 kb of 38 lead GWAS SNPs in 13,538 breast cancer cases and 5,518 controls.
RESULTS
Truncating variants in these genes were rare, and were not associated with breast cancer risk. Burden testing of rare missense variants highlighted 5 genes with some suggestion of an association with breast cancer, although none met the multiple testing thresholds: , and . Six common alleles in (two), and (three) were associated at the < 0.0001 significance level, but these likely reflect linkage disequilibrium with causal regulatory variants.
CONCLUSIONS
There was no evidence that rare coding variants in these genes confer substantial breast cancer risks. However, more modest effect sizes could not be ruled out.
IMPACT
We tested the hypothesis that rare variants in 38 genes near breast cancer GWAS loci may mediate risk. These variants do not appear to play a major role in breast cancer heritability.
背景
通过全基因组关联研究（GWAS）鉴定的乳腺癌风险等位基因调控的基因可能含有罕见的编码风险等位基因。
方法
我们对 13538 例乳腺癌病例和 5518 例对照中 38 个 GWAS SNP 附近 500kb 范围内的 38 个基因的编码区域进行了测序。
结果
这些基因中的截断变异很少，与乳腺癌风险无关。对罕见错义变异的负担测试突出了 5 个与乳腺癌有一定关联的基因，尽管没有一个符合多重测试阈值： 、 、 。 （两个）和 （三个）中的 6 个常见等位基因在 水平上显著相关，但这些可能反映了与因果调节变异的连锁不平衡。
结论
没有证据表明这些基因中的罕见编码变异会导致乳腺癌的风险显著增加。然而，不能排除更小的效应大小。
影响
我们检验了这样一个假设，即乳腺癌 GWAS 位点附近的 38 个基因中的罕见变异可能介导风险。这些变异似乎在乳腺癌遗传率中不起主要作用。
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