Ramoz Nicolas, Reichert Jennifer G, Smith Christopher J, Silverman Jeremy M, Bespalova Irina N, Davis Kenneth L, Buxbaum Joseph D
Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Am J Psychiatry. 2004 Apr;161(4):662-9. doi: 10.1176/appi.ajp.161.4.662.
Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region.
Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families.
Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci.
A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism.
自闭症/孤独症谱系障碍（MIM编号209850）是一种复杂的、主要由基因决定的精神疾病。作者最近将一个自闭症易感基因座定位到2号染色体区域2q24 - q33（MIM编号606053）。在本研究中，对2q24 - q33区间内的基因进行分析，以确定该区域的一个自闭症易感基因。
对定位候选基因的突变筛查分两个阶段进行。第一阶段是在与2q24 - q33连锁的无关受试者中，鉴定候选基因外显子和侧翼序列中的基因变异，并比较自闭症受试者与无关非自闭症受试者之间变异的频率。在编码线粒体天冬氨酸/谷氨酸载体（AGC1）的基因SLC25A12内，鉴定出两个在自闭症和非自闭症受试者之间显示出分布差异证据的单核苷酸多态性（SNP）。第二阶段，在411个自闭症家庭中对SLC25A12中的两个SNP进行进一步基因分型，并在197个信息丰富的家庭中进行连锁和关联测试。
在自闭症谱系障碍与SLC25A12中发现的两个SNP（rs2056202和rs2292813）之间观察到连锁和关联。使用每个家庭一个受影响个体或所有受影响个体，通过对rs2056202、rs2292813和一个双位点G*G单倍型进行传递不平衡检验，发现了过度传递的证据。使用TRANSMIT进行分析也观察到了类似结果。通过对这两个SNP进行连锁分析支持了连锁证据，最大多点非参数连锁评分是1.57，最大多点异质性对数评分是2.11。对于在这些位点纯合的个体，基因型相对风险估计在2.4至4.8之间。
证明了自闭症与SLC25A12基因内的SNP有很强的关联。需要进一步研究来证实这种关联，并解读AGC1在自闭症中的任何潜在病因学作用。
