Converging Evidence for an Association of ATP2B2 Allelic Variants with Autism in Male Subjects
Converging Evidence for an Association of ATP2B2 Allelic Variants with Autism in Male Subjects
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DOI：
10.1016/j.biopsych.2011.05.020
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发表时间：
2011-11-01
影响因子：
10.6
通讯作者：
Persico, Antonio M.
中科院分区：
文献类型：
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作者：
Carayol, Jerome;Sacco, Roberto;Persico, Antonio M.
背景：孤独症是一种严重的发育障碍，有很强的遗传基础。以前的全基因组扫描揭示了一个跨越3.5 Mb的连锁区域，位于人类染色体3p25上。该区域包含ATP 2B2基因，编码质膜钙转运ATP酶2（PMCA 2），其将钙（Ca 2+）从胞质溶胶挤出到细胞外空间中。多条证据支持自闭症谱系障碍（ASD）中细胞内钙离子信号过多，使ATP 2B2成为一个有吸引力的候选基因。方法：我们在277个自闭症遗传资源交换家庭的探索性样本和406个主要在意大利招募的家庭的复制样本中进行了基于家庭的关联研究。在探索性样本中，几个标记物与ASD显著相关，并且在单核苷酸多态性rs3774180，rs2278556，和rs241509与ASD相关。在这两个样本中，这种关联仅存在于男性受试者中。与自闭症相关的标志物都包括在一个单一的块跨越几个外显子的强连锁不平衡，和“风险”等位基因似乎遵循一个隐性模式transmission.Conclusions：这些结果提供了收敛的证据之间的关联ATP 2B2基因变异和自闭症的男性受试者，激发兴趣到识别的功能变异，最有可能参与的稳态Ca2+信号。自闭症基因组计划（Autism Genome Project）最近的一项全基因组关联研究提供了额外的支持，该研究强调了该基因的相同连锁不平衡区域。
Background: Autism is a severe developmental disorder, with strong genetic underpinnings. Previous genome-wide scans unveiled a linkage region spanning 3.5 Mb, located on human chromosome 3p25. This region encompasses the ATP2B2 gene, encoding the plasma membrane calcium-transporting ATPase 2 (PMCA2), which extrudes calcium (Ca2+) from the cytosol into the extracellular space. Multiple lines of evidence support excessive intracellular Ca2+ signaling in autism spectrum disorder (ASD), making ATP2B2 an attractive candidate gene.Methods: We performed a family-based association study in an exploratory sample of 277 autism genetic resource exchange families and in a replication sample including 406 families primarily recruited in Italy.Results: Several markers were significantly associated with ASD in the exploratory sample, and the same risk alleles at single nucleotide polymorphisms rs3774180, rs2278556, and rs241509 were found associated with ASD in the replication sample after correction for multiple testing. In both samples, the association was present in male subjects only. Markers associated with autism are all comprised within a single block of strong linkage disequilibrium spanning several exons, and the "risk" allele seems to follow a recessive mode of transmission.Conclusions: These results provide converging evidence for an association between ATP2B2 gene variants and autism in male subjects, spurring interest into the identification of functional variants, most likely involved in the homeostasis of Ca2+ signaling. Additional support comes from a recent genome-wide association study by the Autism Genome Project, which highlights the same linkage disequilibrium region of the gene.