Research Article: Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism

Date Published: July 23, 2015

Publisher: Public Library of Science

Author(s): Jun Li, Linnan Zhao, Yang You, Tianlan Lu, Meixiang Jia, Hao Yu, Yanyan Ruan, Weihua Yue, Jing Liu, Lin Lu, Dai Zhang, Lifang Wang, Deyou Zheng.


Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with a strong genetic component. Many lines of evidence indicated that ASD shares common genetic variants with other psychiatric disorders (for example, schizophrenia). Previous studies detected that calcium channels are involved in the etiology of many psychiatric disorders including schizophrenia and autism. Significant association between CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit) and schizophrenia was detected. Furthermore, rare mutation in CACNA1C is suggested to cause Timothy syndrome, a multisystem disorder including autism-associated phenotype. However, there is no evidence for association between CACNA1C and autism in Chinese Han population. To investigate the association between single nucleotide polymorphisms (SNP) in CACNA1C and autism, we first performed a family-based association study between eighteen SNPs in CACNA1C and autism in 239 trios. All SNPs were genotyped by using Sequenom genotyping platform. Two SNPs (rs1006737 and rs4765905) have a trend of association with autism. To further confirm the association between these two SNPs with autism, we expanded the sample size to 553 trios by adding 314 trios. Association analyses for SNPs and haplotype were performed by using family-based association test (FBAT) and Haploview software. Permutation tests were used for multiple testing corrections of the haplotype analyses (n=10,000). The significance level for all statistical tests was two-tailed (p<0.05). The results demonstrated that G allele of rs1006737 and G allele of rs4765905 showed a preferential transmission to affected offspring in 553 trios (p=0.035). Haplotype analyses showed that two haplotypes constructed from rs1006737 and rs4765905 were significantly associated with autism (p=0.030, 0.023, respectively; Global p=0.046). These results were still significant after permutation correction (n=10,000, p=0.027). Our research suggests that CACNA1C might play a role in the genetic etiology of autism in Chinese Han population.

Partial Text

Autism is a neurodevelopmental disorder characterized by deficits in social interaction and communication, and the presence of repetitive or stereotypic behaviors [1]. These symptoms become apparent in the first three years of life. Twin studies have provided evidence for a strong genetic component for autism. The concordance rate for monozygotic twins is much higher than that for dizygotic twins (70%-82% vs. 0%-10%). The estimated heritability of autism is more than 90% [2]. The contribution of common variants is not only substantial but also highly polygenic. By analyzing common variations throughout the genome, a recent study showed that common variations, individually of small effect, exert substantial additive genetic effects on autism spectrum disorder (ASD) liability [3]. It provides evidence for the common disease-common variant hypothesis.

The concordance rate of genotype in the re-genotyped samples by Sequenom was more than 99%. All of these eighteen SNPs in CACNA1C were successfully genotyped in 239 nuclear families and polymorphic with minor allele frequency (MAF) more than 5%. None of the genotype distributions of these SNPs in parents and affected children deviated from Hardy-Weinberg equilibrium (S1 Table). The power to detect these risk alleles was ranged from 69% to 86.6% except for rs1006737 and rs4765905 in 239 trios.

Previous studies demonstrated that CACNA1C was associated with schizophrenia. To test whether CACNA1C is involved in the etiology of autism, we performed a family based association study. Our results identified a nominal significant association between two SNPs (rs1006737 and rs4765905) in CACNA1C and autism in 553 nuclear families of Chinese Han ancestry. Moreover, haplotype analyses indicated statistically significant association between CACNA1C and autism.

Our study indicates that CACNA1C is associated with autism in Han Chinese population. CACNA1C might play a role in the pathogenesis of autism.