Investigation of autism and GABA receptor subunit genes in multiple ethnic groups.
Investigation of autism and GABA receptor subunit genes in multiple ethnic groups.
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DOI：
10.1007/s10048-006-0045-1
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发表时间：
2006-07
期刊：
影响因子：
2.2
通讯作者：
Pericak-Vance, Margaret A.
中科院分区：
文献类型：
--
作者：
Collins, Ann L.;Ma, Deqiong;Whitehead, Patrice L.;Martin, Eden R.;Wright, Harry H.;Abramson, Ruth K.;Hussman, John P.;Haines, Jonathan L.;Cuccaro, Michael L.;Gilbert, John R.;Pericak-Vance, Margaret A.
自闭症是一种复杂遗传的神经发育障碍，其特征是社会互动和沟通障碍以及重复行为。多种证据，包括自闭症患者GABA和GABA受体水平的改变，表明负责成人大脑突触抑制的GABA能系统可能与自闭症有关。我们实验室以前的研究表明，在高加索自闭症患者中，4号染色体GABRA 4上的GABA受体亚基基因内的非编码单核苷酸多态性（SNP）与GABRA 4和GABRB 1（也在4号染色体上）中的SNP之间的相互作用有关。关于非裔美国人自闭症家庭遗传变异的研究很少。对557名高加索人和54个非洲裔美国家庭的独立人群进行了分析，这些家庭在GABRB 1和GABRA 4中有35个SNP，加强了GABRA 4参与高加索人自闭症风险的证据（rs17599165，p=0.0015; rs1912960，p=0.0073;和rs 17599416，p=0.0040），并提供了在非洲裔美国人中显著相关的证据（rs 2280073，p=0.0287和rs 16859788，p=0.0253）。在高加索人数据集中也证实了GABRA 4和GABRB 1的相互作用（最显著对，rs 1912960和rs 2351299; p=0.004）。对至少一名自闭症患者中具有癫痫发作活动阳性史的家族亚组的分析显示与GABRA 4没有关联;然而，GABRB 1中的三个SNP显示出显著的等位基因关联; rs 2351299（p=0.0163），rs 4482737（p=0.0339）和rs3832300（p=0.0253）。这些结果证实了我们早期的发现，表明GABRA 4和GABRB 1是导致自闭症易感性的基因，将影响扩展到多个种族群体，并表明癫痫发作是一种分层表型。
Autism is a neurodevelopmental disorder of complex genetics, characterized by impairment in social interaction and communication, as well as repetitive behavior. Multiple lines of evidence, including alterations in levels of GABA and GABA receptors in autistic patients, indicate that the GABAergic system, which is responsible for synaptic inhibition in the adult brain, may be involved in autism. Previous studies in our lab indicated association of noncoding single nucleotide polymorphisms (SNPs) within a GABA receptor subunit gene on chromosome 4, GABRA4, and interaction between SNPs in GABRA4 and GABRB1 (also on chromosome 4), within Caucasian autism patients. Studies of genetic variation in African-American autism families are rare. Analysis of 557 Caucasian and an independent population of 54 African-American families with 35 SNPs within GABRB1 and GABRA4 strengthened the evidence for involvement of GABRA4 in autism risk in Caucasians (rs17599165, p=0.0015; rs1912960, p=0.0073; and rs17599416, p=0.0040) and gave evidence of significant association in African-Americans (rs2280073, p=0.0287 and rs16859788, p=0.0253). The GABRA4 and GABRB1 interaction was also confirmed in the Caucasian dataset (most significant pair, rs1912960 and rs2351299; p=0.004). Analysis of the subset of families with a positive history of seizure activity in at least one autism patient revealed no association to GABRA4; however, three SNPs within GABRB1 showed significant allelic association; rs2351299 (p=0.0163), rs4482737 (p=0.0339), and rs3832300 (p=0.0253). These results confirmed our earlier findings, indicating GABRA4 and GABRB1 as genes contributing to autism susceptibility, extending the effect to multiple ethnic groups and suggesting seizures as a stratifying phenotype.
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