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Letters to Nature
Nature 325, 805 - 806 (26 February 2002); doi:10.1038/325805a0

Molecular genetic evidence for heterogeneity in manic depression

Stephen  Hodgkinson*, Robin Sherrington*, Hugh Gurling*¶£, Roger Marchbanks, Stephen Reeders, Jacques Mallet§, Melvin Mclnnis, Hannes Petursson & Jon Brynjolfsson

*Genetics Section, Department of Psychiatry and Department of Biochemistry, Institute of Psychiatry (University of London), De Crespigny Park, London SE5 8AF, UK

Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK
§ Laboratoire de Neurobiologie Cellulaire et Moleculaire, Centre National de Recherche Scientifique, 91190 Gif sur Yvette, France
Department of Psychiatry, Borgaspitalinn, Reykjavik, Iceland
Present address: Molecular Psychiatry Laboratory, Department of Psychiatry, 321 Windeyer Building, Middlesex Hospital Medical School, Mortimer Street, London WIN 8AA, UK.
£ To whom correspondence should be addressed.

Manic depression is a severe cyclic mental illness1,2 that can be unipolar or bipolar and has a lifetime risk of approximately 7 per 1,000 in most populations3. Families with multiple cases of manic depression have been described that are compatible with both autosomal dominant and X-linked modes of genetic transmission2,4–6. Psychoactive antidepressant and stimulant drugs that help to ameliorate depression and mania are thought to act by affecting catecholamine neurotransmitter systems such as adrenaline, noradrenaline and dopamine, amongst others7. Mutations affecting the tyrosine hydroxylase (TH) gene8,9, which encodes the rate-limiting enzyme for the synthesis of these three neurotransmitters7, might therefore be responsible for causing the manic depressive phenotype. We have studied three Icelandic kindreds amongst whom it appears that a single autosomal dominant disease allele is segregating. In these families there were 44 cases amongst 73 individuals at risk. Genetic linkage studies were carried out using clones encoding tyrosine hydroxylase8,9 the variable portion of the Harvey-ras-1 (HRAS1)10 locus and the variable region of the insulin gene (INS)11. All three markers are closely linked on chromosome 11 (ref. 12) and were used to observe the segregation of restriction fragment length polymorphisms (RFLPs) in the three affected kindreds. We found no evidence for linkage to these markers in any of the three families. In contrast, Gerhard et al .13–15 found linkage between manic depression and HRAS1 in a single large Amish kindred. We conclude that there is genetic heterogeneity of linkage in manic depression. Therefore mutations at different loci are responsible for the manic depressive phentoype in the Amish and in Iceland.



1. Perris, C. in Genetic Aspects of Affective Illness (ed. Perris, C.) 9−19 (SP Medical and Scientific, New York, 1979).
2. Nurnberger, J. I. & Gershon, E. S. in Handbook of Affective Disorders (ed. Paykel, E. S.) 126−145 (Churchill Livingstone, London, 1982).
3. Boyd, J. H. & Weissman, M. W. Archs gen. Psychiat. 38, 1039−1046 (1981). | ChemPort |
4. Mendelwicz, J. IVth Wld Congr. Biol. Psychiat. Philadelphia 306 (1985).
5. Winokur, G. & Clayton, P. in Recent Adv. biol. Psychiat. 9, 35−50 (Plenum, New York, 1967).
6. Winokur, G., Clayton, P. & Reich, T. in Manic Depressive Illness (eds Winokur, G., Clayton, P. & Reich, T.) 1−150 (Mosley, St Louis, 1969).
7. Cooper, J. R., Bloom, F. E. & Roth, R. H. in The Biochemical Basis of Neuropharmacology (eds Cooper, J. Bloom, F. E. & Roth, R. H.) 1−367 (Oxford University Press, New York, 1982).
8. Lamouroux, A. et al. Proc. natn. Acad. Sci. U.S.A. 79, 3881−3885 (1982). | ChemPort |
9. Mallet, J. et al. in Role of RNA and DNA in Brain Function; a Molecular Biological Approach (ed. Guiditta, A. et al.) 57−70 (Nijhoff, Norwell, Massachusetts, 1987).
10. Krontiris, T. G., DiMartino, N. A., Colb, M. & Parkinson, D. R. Nature 313, 369−374 (1985). | Article | PubMed | ISI | ChemPort |
11. Bell, G. I., Selby, M. J. & Rutter, W. J. Nature 295, 31−35 (1982). | Article | PubMed | ISI | ChemPort |
12. Moss, P. A. H., Davies, K. E., Bon, I. C., Mallet, J. & Reeders, S. T. Nucleic Acids Res. 14, 9927−9932 (1986). | PubMed | ChemPort |
13. Gerhard, D. S. et al. Am. J. hum. Genet. 36, S35 (1984).
14. Gerhard, D. S. et al. Symp. Genet. Res. Psychiat. Berlin (1986).
15. Kidd, K. K., Gerhard, D. S., Kidd, J. R., Housman, D. & Egeland, J. Clin. Neuropharmac. 7, S1, 198−199 (1984).
16. Spitzer, J., Endicott, J. & Robins, E. Archs gen. Psychiat. 35, 773−782 (1978). | ChemPort |
17. Maniatis, T., Fritsch, E. F. & Sambrook, J. in Molecular Cloning, a Laboratory Manual (Cold Spring Harbor, New York, 1982).
18. Southern, E. M. J. molec. Biol. 98, 503−517 (1975). | PubMed | ISI | ChemPort |
19. Jeffreys, A. J., Wilson, V., Thein, S. L., Weatherall, D. J. & Ponder, B. A. J. Am. J. hum. Genet. 39, 11−24 (1986). | PubMed | ChemPort |
20. Hodgkinson, S., Gurling, H. M. D., Marchbanks, R. M., McInnis, M. & Petursson, H. J. psychiat. Res. (in the press).
21. Palmer, D. K. et al. Cytogenet. Cell Genet. 40, 370 (1985).
22. Rotwein, P., Yokoyama, S., Didier, D. K. & Chirgwin, J. M. Am. J. hum. Genet. 39, 291−299 (1986). | PubMed | ISI | ChemPort |
23. Lathrop, G. M., Lalouel, J. M., Julier, C. & Ott, J. Proc. natn. Acad. Sci. U.S.A. 81, 3443−3446 (1984). | ChemPort |
24. Piazza, A., Menozzi, P. & Cavalli-Sforza, L. L. Proc. natn. Acad. Sci. U.S.A. 78, 2638−2642 (1981). | ChemPort |
25. Gurling, H. M. D., Oppenheim, B. E. & Murray, R. M. Acta Genet. med. Gemell. 33, 333−339 (1984). | ChemPort |
26. Helgason, T. Acta psychiatr. scand. Suppl. 162, 81−90 (1961).

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