A genome-wide linkage scan in a Dutch family identifies a premature ovarian failure susceptibility locus
A genome-wide linkage scan in a Dutch family identifies a premature ovarian failure susceptibility locus
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DOI：
10.1093/humrep/den278
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发表时间：
2008-12-01
影响因子：
6.1
通讯作者：
Bertoli-Avella, A. M.
中科院分区：
文献类型：
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作者：
Oldenburg, R. A.;van Dooren, M. F.;Bertoli-Avella, A. M.
卵巢早衰（POF）的特征是40岁以前促性腺激素水平升高和闭经，发生率约为1%。POF的病因是高度异质性的，具有广泛的病因学致病机制，包括遗传原因。这些主要涉及X染色体上的数量、结构或单基因缺陷。少数常染色体基因（如FOXL 2和NOBOX）的突变已被确定为POF的原因。然而，在大多数情况下，疾病的潜在机制在很大程度上是未知的。我们进行了全基因组连锁分析，在一个相对较大的荷兰家庭7例患者患有POF，显示了显性遗传模式。全基因组分析，使用50 K单核苷酸多态性阵列，与传统的参数连锁分析相结合，我们确定了三个基因组区域上的染色体5，14和18产生暗示性连锁（多点LOD得分为2.4为每个区域）。在纳入一位年长的未受影响的家庭成员后，只有5号染色体上的区域仍然是推定的POF位点。此外，我们调查了第二个家庭（三代以上的三个活着的患者）的染色体5，14和18上的区域。单倍型分析仅支持染色体5q14.1-q15上的位点。我们首次在家族性POF中进行了全基因组连锁搜索，并在染色体5q14.1-q15上发现了一个可能存在新的POF易感基因的区域。
Premature ovarian failure (POF) is characterized by elevated gonadotrophins and amenorrhea before the age of 40 years and occurs approximately in 1% of women. POF etiology is highly heterogeneous with a wide spectrum of etiological pathogenic mechanisms including genetic causes. These mostly involve numerical, structural or monogenic defects on the X-chromosome. Mutations in a small number of autosomal genes (such as FOXL2 and NOBOX) have been identified as a cause of POF. However, in most cases, the disease underlying mechanisms are largely unknown.We performed a genome-wide linkage analysis in a relatively large Dutch family with seven patients suffering from POF, showing a dominant pattern of inheritance. A genome-wide analysis, using 50K single nucleotide polymorphism arrays, was combined with conventional parametric linkage analysis.We identified three genomic regions on chromosomes 5, 14 and 18 yielding suggestive linkage (multipoint LOD score of 2.4 for each region). After inclusion of one elder unaffected family member, only the region on chromosome 5 remains as a putative POF locus. In addition, we investigated a second family (three living patients over three generations) for the regions on chromosome 5, 14 and 18. Haplotype analysis supported only the locus on chromosome 5q14.1-q15.We performed the first genome-wide linkage search in familial POF and identified a region on chromosome 5q14.1-q15, which may harbor a novel POF susceptibility gene.