A gene hunt among more than 4,000 British, Irish and American patients suffering from bipolar disorder has turned up two genes that put new emphasis on a possible cause of the disease.
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Both genes are involved in ion channels, the minute pores in nerve cells which let charged atoms rush in and out. This is the heart of the process that sends an electrical signal from one end of the nerve to the other.
The idea, if confirmed, could offer insights into the biology of the disease
Earlier searches for genetic variants predisposing people to bipolar disorder have produced inconsistent results. A consortium of research teams led by Nick Craddock of Cardiff University in Wales and Pamela Sklar of the Massachusetts General Hospital have developed a clearer picture by amassing a larger number of patients than ever before.
The patientsí genomes were analyzed by a gene chip that spots changes at 500,000 sites along the genome where different DNA units occur quite commonly in the population. These sites of common variation, known as SNPs (snips), may hold the cause of common diseases.
The researchers then compared the SNPs of their bipolar patients with those of a large number of unaffected people, to see if any SNPs had a particularly strong association with the disease.
The results, reported on-line in Nature Genetics on August 17, are shown in the figure. The SNPs, shown as dots stretching across the human genome, are each ranked according to the statistical strength of their association with bipolar disorder (top line). Only two SNPs reach the required level of statistical significance (top dotted line) and a third comes close. (The genome is packaged into 23 separate chromosomes, shown in alternate red and blue for clarity).
The researchers then examined the genes in which the three SNPs occur (bottom line). The first SNP lies in a somewhat obscure gene called Ankyrin-G which helps to anchor proteins in the cell membrane, including those that serve as ion channels. The second SNP belongs to a gene that is part of the ion channel that lets calcium in and out of nerve cells. As before, the dots are the SNPs within each gene, the higher SNPs being the more significant statistically.)
These two genes probably have modest effects and each is involved in only a few cases of bipolar disorder, Dr. Craddock said. But they and other genes yet to be found may point to the underlying biology of the disease, which may affect a much larger number of patients.
This paper makes the point more clearly than ever before that there are no common genes that have a big effect, said Francis McMahon, a psychiatrist at the National Institute of Mental Health. Dr. McMahon said he was thrilled to see the ankyrin-G gene turn up because he had identified it earlier in a smaller survey.
David Goldstein, a geneticist at Duke University, expressed caution that after so much effort so few SNPs had come to light, none of them being of overwhelming statistical strength in terms of its link with the disease. A few SNPs are managing to just barely poke their heads above the parapet of genome-wide significance, after a good deal of encouragement, he said. So we may have a risk factor here left standing at the end of the day, or we may not, but they sure arenít very impressive.
The parapet he refers to is the top dotted line of the upper figure.
Dr. Craddock said he was recruiting yet more patients to the study. With great numbers, more SNPs may scale the parapet. It may be that much of the burden of the disease is caused by large numbers of rare SNPs, which are hard to detect with the gene chips used at present to scan the human genome. Dr. Craddock said he hopes to find enough common genes to identify the major biological pathways leading to bipolar disorder, and that these will provide a new basis for treatments.