Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data.
OBJECTIVE
Genetic markers in the genes encoding ankyrin 3 (ANK3) and the α-calcium channel subunit (CACNA1C) are associated with bipolar disorder (BP). The associated variants in the CACNA1C gene are mainly within intron 3 of the gene. ANK3 BP-associated variants are in two distinct clusters at the ends of the gene, indicating disease allele heterogeneity.


METHODS
In order to screen both coding and non-coding regions to identify potential aetiological variants, we used whole-genome sequencing in 99 BP cases. Variants with markedly different allele frequencies in the BP samples and the 1,000 genomes project European data were genotyped in 1,510 BP cases and 1,095 controls.


RESULTS
We found that the CACNA1C intron 3 variant, rs79398153, potentially affecting an ENCyclopedia of DNA Elements (ENCODE)-defined region, showed an association with BP (p = 0.015). We also found the ANK3 BP-associated variant rs139972937, responsible for an asparagine to serine change (p = 0.042). However, a previous study had not found support for an association between rs139972937 and BP. The variants at ANK3 and CACNA1C previously known to be associated with BP were not in linkage disequilibrium with either of the two variants that we identified and these are therefore independent of the previous haplotypes implicated by genome-wide association.


CONCLUSIONS
Sequencing in additional BP samples is needed to find the molecular pathology that explains the previous association findings. If changes similar to those we have found can be shown to have an effect on the expression and function of ANK3 and CACNA1C, they might help to explain the so-called 'missing heritability' of BP.
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
Alessia
A
Fiorentino
Niamh Louise
NL
O'Brien
Devin Paul
DP
Locke
Andrew
A
McQuillin
Alexandra
A
Jarram
Adebayo
A
Anjorin
Radhika
R
Kandaswamy
David
D
Curtis
Robert Alan
RA
Blizard
Hugh Malcolm Douglas
HM
Gurling
D017487:Ankyrins / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People
C490613:ANK3 protein, human; D017487:Ankyrins; C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type
DNA sequencing; L-type calcium channel; allelic association study; ankyrin 3; bipolar disorder; genetic