NEW YORK CITY— Of the approximately 30,000 genes in the human genome, about one third are expressed in the brain. That means there are about 10,000 candidate genes for bipolar disorder, pointed out Julien Mendlewicz, MD, at the 157th Annual Meeting of the American Psychiatric Association. Though difficult and expensive, international multicenter collaborative studies are the best way of finding the candidate genes that are actually involved in the development of bipolar disorder, said Dr. Mendlewicz, Chairman of the Department of Psychiatry at Erasme Hospital in Brussels. One such study—the European Collaborative Project on Affective Disorders—was initiated about six years ago.

GENETIC HOT SPOTS

The study has identified bipolar disorder–related hot spots on different chromosomal regions; the results were replicated at least twice in other populations. “On chromosome 11 is the gene for tyrosine hydroxylase, a rate-limiting enzyme in catecholamine synthesis that has been shown to be associated with certain forms of bipolarity,” said Dr. Mendlewicz. On chromosome 17, he added, is 5-HTT, the human serotonin transporter gene that has been implicated in bipolar and unipolar disorder. That gene and the tryptophan hydroxylase gene located on chromosome 11 are both associated with suicidal behavior in bipolar disorder, Dr. Mendlewicz stated.

A mutation on chromosomes 17 and 18 predicts clinical anticipation (decreasing age of onset and increasing severity with each successive generation) in bipolar disorder. Amino acid levels of more than 200 times normal characterize the mutation. “We have been able to document this type of mutation in several families,” he said.

LITTLE BUT USEFUL TOOLS

Investigators searching for genes for bipolar disorder are now focusing a great deal on single nucleotide polymorphisms—small variations in single base pairs on DNA that can predict an increased risk of bipolar disorder and other diseases. An enormous number of single nucleotide polymorphisms have been discovered and mapped —four million so far—making it easier to isolate chromosomal regions that contain candidate genes for bipolar disorder, explained Dr. Mendlewicz, who is also Professor of Psychiatry at the Free University of Brussels.

Single nucleotide polymorphisms of two overlapping genes (G30 and G72) on chromosome 13q33.2 were recently independently related to schizophrenia and bipolar disorder in a study of 98 probands. At the study’s inception, 71 of these probands were classified as schizophrenic while the remainder had a diagnosis of unspecified psychosis, although 13 of the latter group later developed bipolar disorder. Other studies have linked single nucleotide polymorphisms on a number of other chromosomes (3q29, 6q22, 17p13.1, and 18p11, for example) to bipolar disorder, Dr. Mendlewicz remarked.

PREDICTING TREATMENT RESPONSE

One of the ultimate goals of studies such as the European Collaborative Project on Affective Disorders, Dr. Mendlewicz said, is to make it possible to predict individual variation in the response to psychotropic medications. “If we are successful in identifying which polymorphisms put patients with bipolar disorder at better chance of responding to such-and-such drug, it would eventually lead to the individualization of pharmacotherapy,” he suggested.

The main data currently available to help predict the response of bipolar disorder to pharmacotherapy are from several older studies of lithium therapy. “These are classical studies basically showing that a good long-term response to lithium prophylaxis in bipolar patients is associated with the presence of a positive family history of mania or bipolarity,” Dr. Mendlewicz said. No similar studies have been done with antiepileptic drugs or mood stabilizers.

The relationship between polymorphisms and a sudden switch to the manic phase during antidepressant therapy has been investigated in patients with bipolar disorder, he noted. The investigation found no significant difference between patients who switched and those who did not in the distribution of polymorphisms. Thus, studies of other genetic variants that may influence the timing of the manic-depressive cycle are necessary, Dr. Mendlewicz said.

NOT JUST ONE DISEASE

In conclusion, Dr. Mendlewicz recommended that bipolar disorder be considered as a complex set of diseases, not just as one disease. “We have to deal with several forms,” he stressed. Furthermore, “the etiology is obviously multifactorial; there is no simple or single mode of inheritance and, surely, multiple genes must be involved.”

The contribution of each of these genes to bipolar disorder is likely to be moderate or minor, and they are difficult to identify through traditional association studies. Moreover, “gene identification may not necessarily lead to treatment,” Dr. Mendlewicz acknowledged.

—Timothy Begany

Suggested Reading
Mendlewicz J, Souery D, Del-Favero J, et al. Expanded RED products and loci containing CAG/CTG repeats on chromosome 17 (ERDA1) and chromosome 18 (CTG18.1) in trans-generational pairs with bipolar affective disorder. Am J Med Genet. 2004;128B:71-75.
Mendlewicz J, Massat I, Souery D, et al. Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study. Eur J Hum Genet. 2004;12:377-382.
Schulze TG, Buervenich S, Badner JA, et al. Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees. Biol Psychiatry. 2004;56:18-23.
Souery D, Lipp O, Serretti A, et al. European Collaborative Project on Affective Disorders: interactions between genetic and psychosocial vulnerability factors. Psychiatr Genet. 1998;8:197-205.

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