A Rare Variant in <b><i>CACNA1D</i></b> Segregates with 7 Bipolar I Disorder Cases in a Large Pedigree

Abstract

Whole-genome sequencing was performed on 3 bipolar I disorder (BPI) cases from a multiplex pedigree of European ancestry with 7 BPI cases. Within CACNA1D, a gene implicated by genome-wide association studies, a G to C nucleotide transversion at 53,835,340 base pairs (bps) was found predicting the substitution of proline for alanine at amino acid position 1751 (A1751P). Using Sanger sequencing, the DNA variant was shown to co-segregate with the remaining 4 BPI cases within the pedigree. A high-resolution DNA denaturing curve method was then used to screen for the presence of the A1751P change in 4,150 BPI cases from the NIMH Genetics Initiative. The A1751P variant was found in 4 BPI cases. A second variant within exon 43, a C to T nucleotide transition, was found in 1 case at 53,835,355 bps, predicting the substitution of tryptophan for arginine at amino acid position 1771 (R1771W). In the NHLBI Exome Sequencing Project database, the heterozygous A1751P variant was present in 3 of 4,300 subjects of European ancestry, and the R1771W change was not present in any subject. Given the rarity of these variants, large-scale case/control rare variant sequencing studies will be required for definitive conclusions.

Genome-wide analysis of insomnia disorder

“…Of potential interest, a similar gene on Chr 19, ANO8 was identified in the gene-based analysis ( Table S1 ), and elsewhere on Chr 12, ANO2 is immediately adjacent to NTF3 that harbors an insomnia associated SNP among AFR subjects. CACNA1D is an L-type calcium channel gene, previously associated with a variety of other conditions including bipolar disorder 58 , 59 (itself almost invariably associated with sleep disturbance) and cardiometabolic disease. 60 A functionally similar L-type calcium channel gene, CACNA1C was previously linked with sleep latency, 18 and both CACNA1C and CACNA1D were reported in a genomic pathway analyses to contribute to sleep duration.…”

Combined cellomics and proteomics analysis reveals shared neuronal morphology and molecular pathway phenotypes for multiple schizophrenia risk genes

“…Within each set, most parameters show a relatively strong positive correlation. Interestingly, preand postsynaptic intensities are negatively correlated with the other synaptic parameters (i.e., the intensities of Table 1 List of selected genes and evidence for their association with SCZ, ASD of BPD Gene SCZ evidence ASD evidence BPD evidence Adnp Exome sequencing [44], FMRP target [45,46] De novo mutation [39] Ank2 FMRP target [45,46] De novo mutation [39] Arid1b FMRP target [45,46] SNP [47], de novo mutation [39] SNP [48] Atp2a2 GWAS [12], FMRP target [45,46] Bcl11a miR137 target [14] C4a GWAS [12] Cacna1c GWAS [12] SNP [49] SNP [50] Cacna1d miR137 target [14] SNP [51] Cacna1i GWAS [12], miR137 target [14], FMRP target [45,46] SNP [49] Cacna2d3…”

Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders

“…[193]. Furthermore, two coding variations in CACNA1D (A1751P and R1771W) segregate with BD type I cases in a large pedigree [194]. Although a study in a Han Chinese population found no association between CACNA1D SNPs and SCZ [195], more recent studies that include larger populations of East Asian, Chinese, European and Ashkenazi Jewish individuals identified the SNP rs2358740 located in a putative promoter region for CACNA1D and the mRNA decapping enzyme 1A gene (DCP1A) as a risk variant for SCZ [173,196,197].…”

“…Purcell et al, found three de novo variations in CACNA2D2 in patients with SCZ. Two of these three variations introduced premature stop codons, and a the third one is predicted to disrupt a splice donor site [194]. A CACNA2D2 variation (A900T) scored as a putative second hit in a study of 558 patients with SCZ in a Spanish population [246].…”