Berrettini W H, Ferraro T N, Goldin L R, Detera-Wadleigh S D, Choi H, Muniec D, Guroff J J, Kazuba D M, Nurnberger J I, Hsieh W T, Hoehe M R, Gershon E S
Department of Psychiatry and Human Behavior, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa, USA.
Arch Gen Psychiatry. 1997 Jan;54(1):27-35. doi: 10.1001/archpsyc.1997.01830130031006.
Although genetic epidemiological studies of bipolar (BP) illness are consistent with a heritable component, inherited risk factors remain unknown. The goal of the present study is to describe the localization of BP susceptibility loci through linkage strategies, including a genome-wide search.
A linkage study of 22 BP families has been performed. These BP families include almost 400 persons, 173 of whom have been diagnosed as having BP I, schizoaffective, BP II with major depression, or recurrent unipolar illness. Using an autosomal dominant disease model with 85% or 50% age-dependent penetrance, and a recessive model with 85% penetrance, linkage analyses were performed assuming a narrow (BP and schizoaffective) or a broad (BP, schizoaffective, or unipolar) definition of the BP spectrum. Affected sibling pairs and affected pedigree member analyses were performed when positive lod scores were observed in multiple pedigrees. The present article describes linkage analysis of 310 DNA markers on chromosomes 1, 5p, 6, 8, 10q, 11q, and 12 to 18.
None of the loci examined disclosed compelling evidence for linkage using lod score analyses. Model-independent analysis by multilocus affected pedigree member method in the pericentromeric chromosome 18 region disclosed statistically significant evidence (P < .0001) for a BP susceptibility gene in this region. Multilocus analysis by affected sibling pair method also disclosed evidence for linkage (P < .00008).
Our results imply that a BP susceptibility gene exists near the centromere of chromosome 18. Confirmation of this finding (by independent investigators studying different pedigrees) has been published, suggesting that a valid BP disease linkage may have been discovered.
尽管双相情感障碍（BP）疾病的遗传流行病学研究表明其具有遗传成分，但遗传风险因素仍不明晰。本研究的目的是通过连锁策略，包括全基因组搜索，来描述BP易感基因座的定位。
对22个BP家系进行了连锁研究。这些BP家系包含近400人，其中173人被诊断患有I型双相情感障碍、精神分裂症伴情感障碍、伴有重度抑郁的II型双相情感障碍或复发性单相疾病。采用常染色体显性疾病模型，其年龄依赖性外显率分别为85%或50%，以及隐性模型，其外显率为85%，假定BP谱的定义较窄（BP和精神分裂症伴情感障碍）或较宽（BP、精神分裂症伴情感障碍或单相疾病），进行连锁分析。当在多个家系中观察到阳性对数优势比（lod）分数时，对受累同胞对和受累家系成员进行分析。本文描述了对染色体1、5p、6、8、10q、11q以及12至18上的310个DNA标记进行的连锁分析。
通过lod分数分析，所检测的基因座均未显示出令人信服的连锁证据。在18号染色体着丝粒周围区域，采用多位点受累家系成员法进行的与模型无关的分析，揭示了该区域存在BP易感基因的统计学显著证据（P <.0001）。采用受累同胞对法进行的多位点分析也揭示了连锁证据（P <.00008）。
我们的结果表明，18号染色体着丝粒附近存在一个BP易感基因。这一发现已得到独立研究不同家系的研究者的证实并发表，表明可能已发现了有效的BP疾病连锁关系。
