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Channeling Mental Illness: GWAS Links Ion Channels, Bipolar Disorder

19 August 2008. A collaborative study of bipolar disorder that combines data from two previously published genomewide association studies (GWASs) with a new GWAS associates two genes that encode components of voltage-gated ion channels with the illness. These findings raise the possibility that bipolar disorder may partly result from channelopathies, disruptions in ion channel subunits or other channel-related proteins. Such molecular lesions underlie a diverse group of disorders, including central nervous system disorders such as epilepsy, migraine, and ataxia.

The results of the study will be viewed with interest by researchers in schizophrenia genetics, as the bright diagnostic line between schizophrenia and bipolar disorder, first drawn by Emil Kraepelin in the late nineteenth century, is increasingly called into question. As has been pointed out by Cardiff, Wales-based Nick Craddock and Michael Owen, both authors on the new study, the emergence of overlapping candidate genes (e.g., DISC1, DTNBP1, NRG1) and the similarity between the psychotic phenotype seen in the manic phase of bipolar disorder and in schizophrenia suggest that there will be a growing cross-fertilization in genetic research in these two arenas (see Craddock and Owen, 2005, and SRF live discussion).

In the new multicenter study, bipolar cases and controls from the Wellcome Trust Case Control Consortium (the WTCCC study; Wellcome Trust Case Control Consortium, 2007; see SRF related news story) were added to those from the recent GWAS by Pamela Sklar and colleagues (the STEP-UCL study; Sklar et al., 2008, first reported in an SRF meeting report from the 2007 WPCG meeting), as well as a new sample of 1,098 cases and 1,267 controls, including some from the University of Edinburgh and Trinity College Dublin (the new data set was hence dubbed ED-DUB-STEP2), for a combined sample of 4,387 cases and 6,209 controls. In the case sample, 81 percent had been diagnosed with bipolar 1, and 16 percent with bipolar 2.

This large sample was directly genotyped on more than 325,000 overlapping SNPs, a number that was greatly increased, to about 1.8 million SNPs, when imputed HapMap SNPs were added using PLINK, a GWAS tool developed by study author Shaun Purcell of the Broad Institute of MIT and Harvard and colleagues (Purcell et al., 2007). “Applying a leave-out-one procedure for every genotyped SNP,” the authors write, “we estimated concordance between imputed and true genotypes as 0.987.”

Although there had been no overlap in the “top hits” identified in the WTCCC and the STEP-UCL studies—the former identified a gene-rich locus on chromosome 16, while the latter’s strongest SNPs were in MYO5B, TSPAN8, and EGFR—a post hoc comparison of the two data sets by the Sklar group found concordant SNP signals in CACNA1C, a gene on chromosome 12 that encodes the alpha 1C subunit (Cav 1.2) of the L-type voltage-dependent calcium channel.

In an initial analysis of the ED-DUB-STEP2 dataset alone, none of 14 chromosomal regions showing associations exceeded the researchers’ genomewide significance threshold of 5 x 10-8. However, one of these regions spanned the CACNA1C association found in the Sklar team’s analysis of the WTCCC and STEP-UCL samples, providing further support for the hypothesis that mutations in CACNA1C may contribute to bipolar disorder.

In the combined WTCCC/STEP-UCL/ED-DUB-STEP2 sample, the strongest association (P = 9.1 x 10-9) was found in ANK3 (Ankyrin-G) on chromosome 10q21, a gene that is required for the clustering of voltage-gated sodium channels at axon initial segments (Zhou et al., 1998) and nodes of Ranvier (Poliak and Peles, 2003), a configuration that underlies the rapid and efficient propagation of action potentials along myelinated axons. The second-strongest association was at rs1006737, in the third intron of CACNA1C (P = 7.0 x 10-8). A third association was found near C15orf53, a gene on 15q14 of unknown significance. No differential associations for these three regions were found across bipolar disorder subtypes, presence of psychosis, age of onset, sex, or response to treatment.

The ANK3 and CACNA1C associations reported in the new study are particularly intriguing in light of other recent work by study coauthor Hugh Gurling and colleagues (McQuillin et al., 2007), in which lithium carbonate, the gold standard for treatment of bipolar disorder, was shown to downregulate both ANK3 and subunits of the calcium channel. In addition, many antiepileptic drugs also used to manage symptoms in bipolar disorder and schizophrenia are known to affect voltage-gated sodium or calcium channels (Johannessen Landmark, 2008).

Though channelopathies have long been known to contribute to cystic fibrosis as well as several heritable cardiac (e.g., Brugada syndrome, Long QT syndrome) and motor (e.g., myasthenia gravis, periodic paralysis) disorders, the exploration of ion channel mutations in psychiatric disorders is a fairly recent development. However, an association between a missense mutation in CACNA1C and Timothy syndrome, a complex disorder that includes cardiac abnormalities, webbing of the fingers and toes, and autism, was recently reported (Splawski et al., 2004). KCNQ5, which encodes a potassium channel crucial for the M-current, an important regulator of neuronal excitability, maps to risk loci for attention-deficit hyperactivity disorder, bipolar disorder, and schizophrenia. Another channel gene, SK3, which encodes a small-conductance calcium-activated potassium channel, has also been implicated in schizophrenia (see Gargus, 2006, for a review of ion channel candidate genes in psychiatric disease).—Peter Farley.

Reference:
Ferreira MAR and 62 others. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat. Genet., published online 17 August, 2008.

Q&A With Nick Craddock. Questions by Hakon Heimer.

Q: This a rather large sample compared to previous ones, yet only three regions were found to have genomewide significance. Is that a disappointing result, and does it argue against either the multigenic theory of mental illness causation, on the one hand, or the use of 10-8 as a cut-off for determining genomewide significance on the other?
A: The findings of our analysis are entirely consistent with the existence of many genes each having a small effect on susceptibility to bipolar disorder. It is important to think beyond the top few “hits.” The pattern that we see in bipolar disorder is very much the same sort of pattern that we see in studies of non-psychiatric disorders. When we have access to even larger samples, more loci will achieve genomewide significance.

Q: Do you think there is validity to the argument that large-scale studies such as this may “wash out” signals of genes that contribute to disease in certain populations but not others?
A: Large-scale studies like ours provide optimal power to detect genetic variants that influence susceptibility broadly across the bipolar phenotype and across populations. It is, however, true that they may not be the optimal approach for detecting susceptibility variants that are either specific to certain populations or confer risk specifically to certain aspects of the clinical phenotype. In such situations, specific signals could be washed out.

Q: Is there any evidence from other sources to suggest that channelopathies might play a role in schizophrenia as well (or any evidence that they probably do not)?
A: This is an issue that has not previously received much attention—but obviously now warrants specific investigation.

 
Comments on News and Primary Papers
Comment by:  Melvin G. McInnis
Submitted 19 August 2008 Posted 19 August 2008

The work by Ferreira et al. exemplifies the growing enthusiasm for collaborative work among investigators and marks the new era of collaborative genetic research in complex disorders. The LD data found in the extant HapMap SNPs allow investigators to use sophisticated computational approaches to impute genotypes based on these HapMap data sets and the data generated from the experimental sample, thereby maximizing the utility of the actual genotyping itself. Nothing short of brilliant. Correlates between imputed and true genotypes were estimated to be 0.987, which is quite good. The significance estimates of the combined data analyses of the three data sets identifies two genes (ANK3 and CACNA1C) in the genomewide significance range with a p value of 10-8, which is most reassuring and even more so considering that the CACNA1C gene was identified previously. The humbling fact in the mix is that the odds ratios are modest, ranging from 1.2 to 1.4, which is nonetheless in a similar arena as other complex genetic disorders such as diabetes. It is further humbling (and...  Read more


View all comments by Melvin G. McInnis

Comment by:  John I. Nurnberger, Jr.
Submitted 19 August 2008 Posted 19 August 2008

Ferreira et al. propose two specific genes to be related to bipolar disorder, ANK3, which is indirectly related to sodium channels, and CACNA1C, which is a calcium channel subunit. They hypothesize that bipolar disorder is, at least in part, a channelopathy. This hypothesis is consistent with a number of physiological observations made over the past several decades, as reviewed elsewhere.

The genetic data these authors present is certainly suggestive. They have analyzed three independent data sets, STEP-UCL (Sklar et al., 2008), Wellcome Trust (Wellcome Trust Case Control Consortium, 2007), and a third set called ED-DUB-STEP2 (not yet published). Their total sample exceeds 4,000 cases and 6,000 controls. They have direct genotype data on >300,000 SNPs and have imputed nearly 1.5 million additional. Their highest significance values (10-7 to 10-9) include a combination of genotyped and imputed SNPs. For each of these, the combined p value is a product of...  Read more


View all comments by John I. Nurnberger, Jr.

Comment by:  Peter P. Zandi
Submitted 21 August 2008 Posted 21 August 2008

Are we there yet? Have we in the field of bipolar genetics finally been delivered to the promised land by GWAS? For the past year or so since GWAS burst on the scene, we have had to watch with envy as an impressive list of genes were convincingly implicated in a range of other complex diseases like type 2 diabetes, the apparent poster child for GWAS. Now, is it our turn?

The first attempts at individual-level GWAS of bipolar disorder by WTCCC and STEP-UCL were exciting because of their novelty, but the results were not particularly overwhelming. None of the findings withstood correction for the massive multiple testing inherent in GWAS, and those at the top were of ambiguous relevance to bipolar disorder. Confronted with such uninspiring findings, one could not be faulted for experiencing pangs of doubt that maybe for psychiatric disorders, GWAS would prove no better than its dusty old predecessor, the genomewide linkage study, in illuminating the underlying genetic architecture.

Nevertheless, encouraged by the lessons learned from GWAS of type 2 diabetes that the...  Read more


View all comments by Peter P. Zandi
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