A pedigree study shows close linkage of bipolar affective illness (manic depression) to the X-chromosome markers colour blindness and glucose-6-phosphate dehydrogenase deficiency. The maximum lod score ranges from 7.52 (assuming homogeneity) to 9.17 (assuming heterogeneity); that is, the odds in favour of linkage range between 3 X 10(7) to 1 and 10(9) to 1. These results provide confirmation that a major psychiatric disorder can be caused by a single genetic defect. As a possible first step in characterizing the primary genetic abnormality, this finding may have important implications for the aetiology, nosology, pathophysiology and, possibly, prevention and treatment of bipolar affective disorder. It also provides a means for identifying and characterizing homogeneous populations of patients and may help in clarifying aetiological heterogeneity.

Genetic linkage studies have opened new vistas for behavioral and psychiatric genetics. However, phenotypic diversity and diagnostic uncertainties can lead to spurious linkage findings. A method of analysis is proposed that takes these factors into account. When applied to manic-depressive disease, the results indicate that previous evidence for a major gene localized on the distal long arm of the X-chromosome cannot be ascribed to phenotypic uncertainties and misclassifications, i.e., a type I error. Although the lod score (the logarithm of odds) favoring linkage is reduced with the more restrictive clinical definitions of the phenotype, it remains significant nonetheless. Thus, the linkage finding is robust over a range of phenotypic patterns and presumed phenocopy frequencies. The results also suggest that the X-linked phenotype is a particularly severe form of manic depression characterized by early onset, high familial prevalence of the bipolar form, and high recurrence rate of major depression. These findings may have important implications for the design and interpretation of genetic linkage studies and for refining diagnostic techniques in mental disorders.

Bipolar manic-depressive patients in remission are considered normal by phenomenological criteria but many psychotherapists have noted specific personality markers. The Rorschach test was chosen to study such personality markers since it may provide rich information at a psychological level distant from overt behavior and symptoms. 35 bipolar manic-depressives in a euthymic state were tested with the Rorschach Projective Technique. The scores were analyzed using Exner’s Comprehensive System methods and compared with his stratified normal control sample. Nine variables differentiated the patients from controls so that at least 50% of the patients were beyond one standard deviation from the controls’ mean. These variables might be personality expressions of the genetic predisposition to bipolar illness and might thus be measurable even when the patients are clinically free of affective illness.

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