Pre-eclampsia is a common pregnancy disorder that is a major cause for maternal and perinatal mortality and morbidity. Variants predisposing to pre-eclampsia might be under negative evolutionary selection that is likely to keep their population frequencies low. We exome sequenced samples from a hundred Finnish pre-eclamptic women in pools of ten to screen for low-frequency, large-effect risk variants for pre-eclampsia. After filtering and additional genotyping steps, we selected 28 low-frequency missense, nonsense and splice site variants that were enriched in the pre-eclampsia pools compared to reference data, and genotyped the variants in 1353 pre-eclamptic and 699 non-pre-eclamptic women to test the association of them with pre-eclampsia and quantitative traits relevant for the disease. Genotypes from the SISu project (n = 6118 exome sequenced Finnish samples) were included in the binary trait association analysis as a population reference to increase statistical power. In these analyses, none of the variants tested reached genome-wide significance. In conclusion, the genetic risk for pre-eclampsia is likely complex even in a population isolate like Finland, and larger sample sizes will be necessary to detect risk variants.

中文翻译：

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在合并的DNA样本中进行外显子组测序，以鉴定孕妇先兆子痫的风险变异体。

子痫前期是一种常见的妊娠疾病，是孕产妇和围产期死亡率和发病率的主要原因。易患先兆子痫的变体可能处于负进化选择之下，这很可能使它们的种群频率保持较低。我们外显子组测序了来自一百名芬兰先兆子痫妇女的样本，并在十人的池中进行了筛查，以筛查先兆子痫的低频，大影响风险变异体。经过过滤和其他基因分型步骤后，我们选择了28种低频错义，无义和剪接位点变异体，与参考数据相比，它们在子痫前期库中富集，并在1353个子痫前期和699个非子痫前期对变异体进行了基因分型。妇女要测试他们与先兆子痫和与该疾病相关的定量性状的关联。来自SISu项目的基因型（n = 6118个外显子组测序的芬兰样品）被包括在二元性状关联分析中，作为增加统计学效力的种群参考。在这些分析中，测试的所有变体均未达到全基因组意义。总之，即使在像芬兰这样的人群中，先兆子痫的遗传风险也可能很复杂，并且需要更大的样本量来检测风险变异。