Supplementary Material for: A Candidate Gene Association Study Further Corroborates Involvement of Contactin Genes in Autism

Although autism spectrum disorder (ASD) shows a high degree of heritability, only a few mutated genes and mostly de novo copy number variations (CNVs) with a high phenotypic impact have as yet been identified. In families with multiple ASD patients, transmitted CNVs often do not appear to cosegregate with disease. Therefore, also transmitted single nucleotide variants which escape detection if genetic analyses were limited to CNVs may contribute to disease risk. In several studies of ASD patients, CNVs covering at least one gene of the contactin gene family were found. To determine whether there is evidence for a contribution of transmitted variants in contactin genes, a cohort of 67 ASD patients and a population-based reference of 117 healthy individuals, who were not related to the ASD families, were compared. In total, 1,648 SNPs, spanning 12.1 Mb of genomic DNA, were examined. After Bonferroni correction for multiple testing, the strongest signal was found for a SNP located within the <i>CNTN5</i> gene (rs6590473 [G], p = 4.09 × 10^-7; OR = 3.117; 95% CI = 1.603-6.151). In the ASD cohort, a combination of risk alleles of SNPs in <i>CNTN6 </i>(rs9878022 [A]; OR = 3.749) and in <i>CNTNAP2 </i>(rs7804520 [G]; OR = 2.437) was found more frequently than would be expected under random segregation, albeit this association was not statistically significant. The latter finding is consistent with a polygenic disease model in which multiple mutagenic mechanisms, operating<b> </b>concomitantly, elicit the ASD phenotype. Altogether, this study corroborates the possible involvement of contactins in ASD, which has been indicated by earlier studies of CNVs.

尽管自闭症谱系障碍（autism spectrum disorder, ASD）具有较高的遗传力，但目前仅鉴定出少数致病基因突变，以及绝大多数具有显著表型影响的新发拷贝数变异（copy number variations, CNVs）。在存在多名ASD患者的家庭中，传递而来的CNVs通常并不与疾病共分离。因此，若遗传分析仅局限于CNVs，则会被漏检的传递型单核苷酸变异（single nucleotide variants, SNVs）也可能参与疾病风险的构成。
在多项针对ASD患者的研究中，均发现了覆盖接触蛋白基因家族（contactin gene family）中至少一个基因的CNVs。为明确接触蛋白基因的传递型变异是否与ASD发病相关，本研究对67名ASD患者队列，以及117名与ASD家系无亲缘关系的人群对照健康个体进行了比较分析。本研究共检测了覆盖12.1 Mb基因组DNA的1648个单核苷酸多态性（single nucleotide polymorphism, SNPs）。经多重检验的邦弗朗尼校正（Bonferroni correction）后，位于<i>CNTN5</i>基因内的SNP rs6590473（G等位基因）呈现出最强的关联信号（p = 4.09 × 10⁻⁷；比值比（odds ratio, OR）= 3.117；95%置信区间（confidence interval, CI）= 1.603~6.151）。
在ASD患者队列中，<i>CNTN6</i>基因rs9878022（A等位基因，OR=3.749）与<i>CNTNAP2</i>基因rs7804520（G等位基因，OR=2.437）的风险等位基因组合出现频率，高于随机分离（random segregation）预期的概率，尽管该关联未达到统计学显著性。上述结果符合多基因疾病模型（polygenic disease model）：即多种诱变机制协同作用，共同诱发ASD表型。
综上，本研究证实了接触蛋白可能参与ASD发病的假说，这一假说也得到了此前CNVs相关研究的支持。