Baron M, Hamburger R, Sandkuyl L A, Risch N, Mandel B, Endicott J, Belmaker R H, Ott J
Columbia University College of Physicians and Surgeons, New York, New York.
Acta Psychiatr Scand. 1990 Sep;82(3):196-203. doi: 10.1111/j.1600-0447.1990.tb03052.x.
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.
基因连锁研究为行为遗传学和精神遗传学开辟了新的前景。然而，表型多样性和诊断的不确定性可能导致虚假的连锁发现。本文提出了一种将这些因素考虑在内的分析方法。当应用于躁郁症时，结果表明，先前关于位于X染色体长臂远端的一个主要基因的证据不能归因于表型的不确定性和错误分类，即I型错误。尽管随着对表型更严格的临床定义，支持连锁的优势对数计分（lod score）有所降低，但仍然显著。因此，在一系列表型模式和假定的拟表型频率范围内，连锁发现是可靠的。结果还表明，X连锁表型是躁郁症的一种特别严重的形式，其特征为发病早、双相型在家族中患病率高以及重度抑郁的复发率高。这些发现可能对基因连锁研究的设计和解释以及完善精神障碍的诊断技术具有重要意义。
