Research Article: Variants in calcium voltage-gated channel subunit Alpha1 C-gene (CACNA1C) are associated with sleep latency in infants

Date Published: August 9, 2017

Publisher: Public Library of Science

Author(s): Katri Kantojärvi, Johanna Liuhanen, Outi Saarenpää-Heikkilä, Anna-Liisa Satomaa, Anneli Kylliäinen, Pirjo Pölkki, Julia Jaatela, Auli Toivola, Lili Milani, Sari-Leena Himanen, Tarja Porkka-Heiskanen, Juulia Paavonen, Tiina Paunio, Thomas H. J. Burne.


Genetic variants in CACNA1C (calcium voltage-gated channel subunit alpha1 C) are associated with bipolar disorder and schizophrenia where sleep disturbances are common. In an experimental model, Cacna1c has been found to modulate the electrophysiological architecture of sleep. There are strong genetic influences for consolidation of sleep in infancy, but only a few studies have thus far researched the genetic factors underlying the process. We hypothesized that genetic variants in CACNA1C affect the regulation of sleep in early development. Seven variants that were earlier associated (genome-wide significantly) with psychiatric disorders at CACNA1C were selected for analyses. The study sample consists of 1086 infants (520 girls and 566 boys) from the Finnish CHILD-SLEEP birth cohort (genotyped by Illumina Infinium PsychArray BeadChip). Sleep length, latency, and nightly awakenings were reported by the parents of the infants with a home-delivered questionnaire at 8 months of age. The genetic influence of CACNA1C variants on sleep in infants was examined by using PLINK software. Three of the examined CACNA1C variants, rs4765913, rs4765914, and rs2239063, were associated with sleep latency (permuted P<0.05). There was no significant association between studied variants and night awakenings or sleep duration. CACNA1C variants for psychiatric disorders were found to be associated with long sleep latency among 8-month-old infants. It remains to be clarified whether the findings refer to defective regulation of sleep, or to distractibility of sleep under external influences.

Partial Text

CACNA1C encodes the alpha subunit of the L-type voltage-dependent calcium channel Cav1.2, which is highly expressed in hippocampus, cerebral cortex, and cerebellum [1]. Until now, genome-wide association studies have detected seven variants at CACNA1C which are associated with psychiatric disorders. The Psychiatric GWAS Consortium Bipolar Disorder Working Group [2] reported genome-wide, significant association between CACNA1C variant rs4765913 and bipolar disorder. They also showed, together with the Psychiatric Genomic Consortium (PGC), that association was stronger between rs4765913 and a combined sample of schizophrenia and bipolar disorder than with schizophrenia alone [2]. The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium [3] conducted a mega-analysis of samples consisting of schizophrenia and bipolar disorder which reached a genome-wide significant association with variant rs4765905. This association was replicated in two studies [4,5].

The study sample, CHILD-SLEEP [27], is a Finnish birth cohort collected from Pirkanmaa Hospital District, comprising 1643 infants born April 2011−February 2013, and their parents. The focus of CHILD-SLEEP is on the role of early sleep and circadian rhythm in general population. In this study, the parental questionnaire data related to the sleep of children and successfully genotyped DNA samples were available from 1086 babies (520 girls and 566 boys) who were 8 months old. The ethical approval for CHILD-SLEEP was obtained from the Ethical Committee of Pirkanmaa Hospital District (R11032/9.3.2011). The written informed consents were obtained from the parents. Families were informed of their rights to terminate their participation in the study at any time during data collection.

All seven variants included in the analyses of this study lie within 167 kb region of the CACNA1C intron three (Fig 1). LD-structure of the studied variants is presented in Fig 2. There are two LD-blocks in the region. The first region comprises the variants rs2007044, rs1006737, rs4765905, and rs1024582 (D`≥ 0.95). Another LD-block consists of SNPs rs4765913, rs4765914, and rs2239063 (D`≥ 0.81).

In this study, some of the variants related to psychiatric traits showed nominally significant association with sleep. In the analyses of the whole sample variants rs4765913, rs4765914, and rs2239063 were associated with sleep latency. The minor allele A of rs4765913 was associated with longer sleep latency. Psychiatric GWAS Consortium Bipolar Disorder Working Group [2] reported that allele A is associated with bipolar disorder (P = 1.52×10-8) and with combined samples of bipolar disorder and schizophrenia (P = 7.7×10-8). In our study, the minor allele T of rs4765914 was associated with longer time of sleep latency in infants. Cross-Disorder of the Psychiatric Genomics Consortium [6] reported that this same allele is associated with bipolar disorder, major depressive disorder, and schizophrenia. T allele is also associated with amygdala structure and function in adolescents; in the study of Sumner and colleagues [38] homozygous carriers of T allele exhibited smaller amygdala volume compared to individuals with homozygous major C allele [38]. Reduced amygdala volume has been observed in bipolar disorder in adults and youth in earlier studies [39,40]. There is a complex interplay between sleep and emotions; sleep deprivation impairs the connectivity between amygdala and prefrontal cortex, which have a direct impact on individual´s ability to regulate emotions [41].