IntegraGen SA, Evry, France.
Mol Autism. 2011 Oct 21;2(1):17. doi: 10.1186/2040-2392-2-17.
The inheritance pattern in most cases of autism is complex. The risk of autism is increased in siblings of children with autism and previous studies have indicated that the level of risk can be further identified by the accumulation of multiple susceptibility single nucleotide polymorphisms (SNPs) allowing for the identification of a higher-risk subgroup among siblings. As a result of the sex difference in the prevalence of autism, we explored the potential for identifying sex-specific autism susceptibility SNPs in siblings of children with autism and the ability to develop a sex-specific risk assessment genetic scoring system.
SNPs were chosen from genes known to be associated with autism. These markers were evaluated using an exploratory sample of 480 families from the Autism Genetic Resource Exchange (AGRE) repository. A reproducibility index (RI) was proposed and calculated in all children with autism and in males and females separately. Differing genetic scoring models were then constructed to develop a sex-specific genetic score model designed to identify individuals with a higher risk of autism. The ability of the genetic scores to identify high-risk children was then evaluated and replicated in an independent sample of 351 affected and 90 unaffected siblings from families with at least 1 child with autism.
We identified three risk SNPs that had a high RI in males, two SNPs with a high RI in females, and three SNPs with a high RI in both sexes. Using these results, genetic scoring models for males and females were developed which demonstrated a significant association with autism (P = 2.2 × 10-6 and 1.9 × 10-5, respectively).
Our results demonstrate that individual susceptibility associated SNPs for autism may have important differential sex effects. We also show that a sex-specific risk score based on the presence of multiple susceptibility associated SNPs allow for the identification of subgroups of siblings of children with autism who have a significantly higher risk of autism.
大多数自闭症病例的遗传模式较为复杂。自闭症患儿的兄弟姐妹患自闭症的风险增加，先前的研究表明，通过积累多个易感单核苷酸多态性（SNP），可以进一步确定风险水平，从而在自闭症患儿的兄弟姐妹中确定一个高风险亚组。由于自闭症的患病率存在性别差异，我们探讨了在自闭症患儿的兄弟姐妹中确定性别特异性自闭症易感 SNP 的可能性，以及开发性别特异性风险评估遗传评分系统的能力。
从已知与自闭症相关的基因中选择 SNP。这些标记物在自闭症基因资源交换（AGRE）存储库的 480 个家庭的探索性样本中进行了评估。在所有自闭症患儿以及男性和女性中分别提出并计算了重现指数（RI）。然后构建了不同的遗传评分模型，以开发一种旨在识别自闭症高风险个体的性别特异性遗传评分模型。随后，在一个独立的样本中，对该遗传评分识别高风险儿童的能力进行了评估和复制，该样本包含了 351 名受影响的和 90 名未受影响的来自至少有 1 名自闭症患儿的家庭的兄弟姐妹。
我们鉴定出了 3 个在男性中 RI 较高的风险 SNP，2 个在女性中 RI 较高的 SNP，以及 3 个在两性中 RI 均较高的 SNP。使用这些结果，我们为男性和女性开发了遗传评分模型，结果显示与自闭症显著相关（分别为 P = 2.2 × 10-6 和 1.9 × 10-5）。
我们的研究结果表明，自闭症的个体易感相关 SNP 可能具有重要的性别差异效应。我们还表明，基于多个易感相关 SNP 存在的性别特异性风险评分可以识别自闭症患儿的兄弟姐妹亚组，他们患有自闭症的风险显著增加。
