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Bipolar Disorder - ANK3 and CACNA1C genes
Journal Articles
Source: http://www.topnews.in/brain-speaks-paralysis-2273164 (Permission pending)
“Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder” (Ferreira et al.)
Purpose
To identify susceptibility loci for bipolar disorder
Methodology
In a genome-wide association study (GWAS), researchers tested a total of 1.8 million variants in 4,387 cases and 6,209 controls (1). The article first presents data from three independent GWAS that were utilized and analyzed: two previously published and one new (1). Baum et al. used DNA pooling to identify a single nucleotide polymorphism (SNP) in the DGKH gene that was linked to bipolar disorder in 1,233 cases and 1,439 controls with 1.5 x 10^-8 as the P value (1). With 1,868 cases and 2,938 controls, the Wellcome Trust Case Control Consortium (WTCCC) found a locus in a gene-rich region of high linkage disequilibrium on chromosome 16p12 with 6.3 x 10^-8 as the P value (1). The more recent GWAS, known as the STEP-UCL study, was done by Sklar et al., analyzing 1,461 cases and 2,008 controls with the strongest single SNP result in MYO5B, with 1.7 x 10^-7 as the P value (1). The article goes on to explain how the researchers completed their own study, ED-DUB-STEP2, and compared it with the WTCCC and STEP-UCL studies in order to come to a more reliable conclusion using more genomic coverage (1).
The ED-DUB-STEP2 study tested 1,098 bipolar disorder cases and 1,267 controls on a similar platform used by the WTCCC and STEP-UCL GWAS (1). Researchers then combined the results from all three studies (325,690 overlapping SNPs), with the samples displaying the following phenotypes: 81% bipolar 1, 16% bipolar 2, 2% schizoaffective manic, and 1% bipolar NOS (1). The number of SNPs was increased to 1,769,948 by using PLINK, a tool set for whole-genome association and population-based linkage analyses, to impute genotypes for HapMap (The International HapMap Consortium) SNPs (1).
Researchers performed a logistic regression of disease state on single SNP allelic dosage (1). The ANK3 gene showed the strongest association for the imputed SNP rs10994336, with 0.1 x 10^-9 as the P value (1). The third intron of the CACNA1C gene on chromosome 12p13 (rs1006737, P = 7.0 x 10^-8) showed the second strongest association (1). The third strongest association was located 3.3 kb away from the uncharacterized gene C15orf53 on chromosome 15q14 (rs12899449, P = 3.5 x 10^-7) (1).
Chromosomal regions with at least one SNP associated with bipolar disorder at P < 10-6 in the combined analysis of WTCCC, STEP-UCL and ED-DUB-STEP2 datasets (1)
|
|
Combined analysis |
WTCCC |
STEP-UCL |
ED-DUB-STEP2 |
|||||||||
|
|
|
|
MA frequency |
|
MA frequency |
|
MA frequency |
|
MA frequency |
||||
Type |
SNP, minor allele |
P |
OR |
Cases |
Controls |
P |
Cases |
Controls |
P |
Cases |
Controls |
P |
Cases |
Controls |
Chromosome 10q21 (ANK3) |
||||||||||||||
Imputed |
rs10994336,T |
9.1 × 10-9 |
1.450 |
0.070 |
0.053 |
0.0006 |
0.070 |
0.054 |
0.0004 |
0.073 |
0.056 |
0.0002 |
0.070 |
0.049 |
Genotyped |
rs1938526,G |
1.3 × 10-8 |
1.395 |
0.075 |
0.056 |
0.0014 |
0.074 |
0.058 |
0.0008 |
0.076 |
0.059 |
0.0002 |
0.073 |
0.047 |
Chromosome 12p14 (CACNA1C) |
||||||||||||||
Genotyped |
rs1006737,A |
7.0 × 10-8 |
1.181 |
0.356 |
0.0324 |
0.0015 |
0.357 |
0.324 |
0.0003 |
0.357 |
0.315 |
0.0108 |
0.353 |
0.337 |
Imputed |
rs1024582,A |
1.7 × 10-7 |
1.180 |
0.382 |
0.351 |
0.0019 |
0.381 |
0.349 |
0.0012 |
0.384 |
0.348 |
0.0056 |
0.379 |
0.359 |
Chromosome 15q14 |
||||||||||||||
Imputed |
rs12899449,G |
3.5 × 10-7 |
0.836 |
0.246 |
0.276 |
0.0140 |
0.253 |
0.277 |
0.0005 |
0.237 |
0.276 |
0.0013 |
0.247 |
0.273 |
Genotyped |
rs2172835,T |
7.5 × 10-7 |
0.853 |
0.281 |
0.312 |
0.0314 |
0.292 |
0.315 |
0.0004 |
0.267 |
0.309 |
0.0011 |
0.281 |
0.312 |
The most associated directly genotyped and imputed SNPs are shown for each region. MA, minor allele.
Table 1:This table displays the results of the combined analysis of the WTCCC, STEP-UCL, and ED-DUB-STEP2 studies in terms of SNP and bipolar disorder association. ANK3 shows the lowest P values and the strongest association, CACNA1C shows the second strongest association, and the uncharacterized gene on chromosome 15q14 shows the third strongest association.
Source: (Ferreira et al.)
Results
Researchers identified a region of strong association (rs10994336, P = 0.1 x 10^-9) in the gene ANK3 (1). The lower the P value, the stronger the association. They also found further support for the previously reported CACNA1C (rs1006737, P = 7.0 x 10^-8) (1). Results suggest that ion channelopathies (sodium and calcium) may be involved in the pathogenesis of bipolar disorder (1). The article also mentions a study that showed downregulated ANK3 and calcium channel subunits in mouse brain in response to lithium, commonly used to treat bipolar disorder (1). This reinforces their conclusions.
Overview
The article consolidates a large amount of fairly complicated data in a way that makes it simple to understand the final results and implications. Researchers identified the two most statistically reliable genes associated with bipolar disorder. They also point out the similar functions of the genes, as both encode proteins that play key roles with ion channels (ANK3 with voltage-gated sodium channels; CACNA1C with voltage-dependent calcium channels). This implies the possibility of bipolar disorder being in part an ion channelopathy. The article does not go into detail about how changes in these ion channels could affect neurological development and symptoms.
References
1. Ferreira MAR, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. PubMed [Internet]. 2009 Jun 30 [cited 2011 Jan 23]; [1056-1058]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703780/.
2. Kua E, Reder M, Grossel MJ. 2004. "Science in the News: A Study of Reporting Genomics." Public Understanding of Science. 13: 309–322.
3. National Center for Biotechnology Information. ANK3 ankyrin 3, node of Ranvier (ankyrin G) [Homo sapiens]. Genes and mapped phenotypes [Internet]. 2011 Jan 11 [cited 2011 Jan 30]. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=288#
4. National Center for Biotechnology Information. CACNA1C calcium channel, voltage-dependent, L type, alpha 1C subunit [Homo sapiens]. Genes and mapped phenotypes [Internet]. 2011 Jan 11 [cited 2011 Jan 30]. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=775
5. National Institute of Mental Health. [Internet]. Bethesda (MD): Bipolar Disorder; [modified 2010 Aug 31; cited 2011 Jan 23]. Available from: http://www.nimh.nih.gov/health/publications/bipolar-disorder/complete-index.shtml.
6. UniProtKB. Ankyrin-3-Homo sapiens (Human) [Internet]. [modified 2011 Jan 11; cited 2011 Jan 23]. Available from: http://www.uniprot.org/uniprot/Q12955.
7. Wade N. Gene hunt hints at cause of Bipolar Disorder. The New York Times [Internet]. 2008 Aug 18 [cited 2011 Jan 23]; [1]. Available from: http://www.nytimes.com/2008/08/15/science/15visual.html.
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