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

Research output: Contribution to journalArticlepeer-review

Abstract

Manic depression is a severe cyclic mental illness1,2that 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 neurotransmitters 7, 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 hydroxylase8,9the variable portion of the Harvey-ras-1 (HRAS1)10locus 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.13-15found 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.

Original languageEnglish (US)
Pages (from-to)805-806
Number of pages2
JournalNature
Volume325
Issue number6107
DOIs
StatePublished - 1987
Externally publishedYes

ASJC Scopus subject areas

  • General

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