Schizophrenia is thought to be a multifactorial disease with complex mode of inheritance. Using a two-stage strategy for another complex disorder, a number of putative IDDM-susceptibility genes have recently been mapped. We now report the results of a two-stage genome-wide search for genes conferring susceptibility to schizophrenia. In stage I, model-free linkage analyses of large pedigrees from Iceland, a geographical isolate, revealed 26 loci suggestive of linkage. In stage II, ten of these were followed-up in a second international collaborative study comprising families from Austria, Canada, Germany, Italy, Scotland, Sweden, Taiwan and the United States. Potential linkage findings of stage I on chromosomes 6p, 9 and 20 were observed again in the second sample. Furthermore, in a third sample from China, fine mapping of the 6p region by association studies also showed evidence for linkage or linkage disequilibrium. Combining our results with other recent findings revealed significant evidence for linkage to an area distal of the HLA region on chromosome 6p. However, in a fourth sample from Europe, the 6p fine mapping finding observed in the Chinese sample could not be replicated. Finally, evidence suggestive of locus heterogeneity and oligogenic transmission in schizophrenia was obtained.

SUMMARY The cyclic nature of cluster headache warranted a study of the 24-hour rhythms of serum cortisol and melatonin. They were both altered during cluster periods as compared with periods of remission and healthy controls. The 24-hour mean and maximal cortisol levels were higher and the timing of the cortisol minimum was delayed as compared to the same patients in remission. Although there was no relation between the cortisol and melatonin levels and headaches, the rise of cortisol following many attacks might in part represent an adaptive response to pain. The nocturnal melatonin maximum was lower during cluster periods than in remission. This finding, and the dysautonomic signs during attacks, may reflect a change of the vegetative tone in a hyposympathetic direction.The cyclic nature of cluster headache and dysautonomic signs during attacks may suggest a dysfunction in the central nervous system related to rhythm-regulating centres. Recently, increasing interest has been focused on changes in hormonal biological rhythms in cluster headache patients.'-9 The pineal hormone melatonin is influenced by bright light'0 and is believed to reflect the circadian organisation of biological rhythms in several species including man. " Serum cortisol also exhibits a circadian rhythm. A functional relation between the pineal gland and the hypothalamic-pituitary-adrenal axis has been suggested.'2 13 We recently reported that the nocturnal levels of serum melatonin were lower in cluster headache during the active headache period than during the remission state.7 Decreased nocturnal serum melatonin levels in patients in an active cluster period as compared to normal healthy controls have also been reported.8 In the present paper the 24-hour rhythms of serum cortisol and melatonin were studied in cluster headache patients during active cluster periods and remissions. Furthermore, the nocturnal urinary excretion of melatonin was examined in cluster headache and healthy control subjects. Patients and methodsStudy ofserum cortisol and melatonin Patients Thirty-one cluster headache patients were admitted to the hospital for the study during the years 1981 to 1984. They were diagnosed as suffering from episodic cluster headache (n = 27) according to Ekbom'4 or as chronic cluster headache (n = 4) according to Ekbom and Olivarius."The age distribution and some anamnestic data are summarised in table 1.Serum cortisol was examined in all 31 patients. Eleven males and five females of the episodic cases were examined both during and between periods ofcluster headache. Serum melatonin was studied in 20 episodic and four chronic cluster patients. From nine of the 20 patients with episodic cluster headache data were obtained both during a cluster period and during a remission. Some data from eight out of these nine patients have been reported previously.7When examined during the remission period all patients were free of medication. During the active cluster period prophylactic therapy (methysergide, pizotifen, ergotamine tartrate) was st...

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Schizophrenia is a severe mental illness with a typically chronic course affecting nearly 1% of the human population. It is generally accepted that genetic factors have an important pathogenic role in a substantial portion of schizophrenia cases; however, despite decades of family studies, there is no agreed-upon mode of inheritance. The discovery of genetic aetiologic factors and resolution of the inheritance pattern(s) will undoubtably emerge from genetic linkage studies. With these objectives in mind, we undertook a linkage project, starting in 1985, in a previously well-documented kindred from north Sweden. Multipoint linkage analyses were used to screen the proximal long arm of chromosome 5 using restriction fragment length polymorphism (RFLP) markers at five loci and the distal long arm using RFLPs at two loci, one of which was the locus for the glucocorticoid receptor. We found strong evidence against linkage between schizophrenia and the seven loci. These results, together with the positive evidence for linkage of schizophrenia with markers in the proximal long arm of chromosome 5 lead us to conclude that the genetic factors underlying schizophrenia are heterogeneous.