The Impact of Phenotypic Variation on Genetic Analysis: Application
to X-Linkage in Manic-Depressive Illness
M. Baron, R. Hamburger, L.A. Sandkuyl, N. Risch,
B. Mandel, J. Endicott, R.H. Belmaker, J. Ott
Acta Psychiatrica Scandinavica , 82(3),196--203 (1990 Sep)
Abstract
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.
