Lin Ping-I, McInnis Melvin G, Potash James B, Willour Virginia, MacKinnon Dean F, DePaulo J Raymond, Zandi Peter P
Dept. of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, 624 N. Broadway, 8th Floor, Baltimore, MD 21205, USA.
Am J Psychiatry. 2006 Feb;163(2):240-6. doi: 10.1176/appi.ajp.163.2.240.
To assess whether age at onset variation reflects underlying genetic heterogeneity in bipolar disorder, the authors examined the clinical and familial characteristics of age at onset in bipolar disorder subjects from families with multiple affected members.
A total of 211 families with 1,856 subjects were ascertained through bipolar I disorder probands. All the subjects were assessed with the Diagnostic Interview for Genetic Studies and assigned diagnoses by trained clinicians using best estimate procedures. Admixture analysis with the 211 bipolar disorder probands was used to decompose the age-at-onset distribution into a mixture of theoretical normal distributions. Logistic regression with general estimating equations was then used to examine clinical correlates and familial aggregation of age at onset in all 717 bipolar disorder subjects.
The age-at-onset distribution consisted of a mixture of three normal distributions with means of 16.6 (SD=5.1), 26.0 (SD=1.4), and 34.7 (SD=6.6) years that comprised 79.7%, 7.2%, and 13.1% of the group, respectively. Cutoff points at ages 21 and 28 were derived from this analysis and used to define age-at-onset subgroups. Early-onset (age at onset </=21) subjects had higher risks of drug abuse, alcohol abuse, rapid cycling, and suicide attempts. Affected subjects from a family with an early-onset proband were more likely than others to have an early onset (odds ratio=4.53, 95% CI=3.09-6.64). Subjects from a family with a proband whose age at onset was <28 were also more likely to have higher risks of drug abuse (odds ratio=11.62, 95% CI=2.16-62.66).
Age at onset is associated with clinical heterogeneity in bipolar disorder and aggregates, possibly along with drug abuse, within families. These findings are consistent with the conclusion that age at onset reflects underlying genetic heterogeneity in bipolar disorder. Thus, age at onset may conceivably be used to identify more homogeneous groups of bipolar disorder families and thereby facilitate the mapping of bipolar disorder susceptibility genes.
为评估双相情感障碍起病年龄的差异是否反映其潜在的基因异质性，作者研究了来自多个患病成员家庭的双相情感障碍患者起病年龄的临床及家族特征。
通过双相I型障碍先证者确定了211个家庭的1856名受试者。所有受试者均接受了基因研究诊断访谈，并由训练有素的临床医生采用最佳估计程序进行诊断。对211名双相情感障碍先证者进行混合分析，将起病年龄分布分解为理论正态分布的混合。然后使用带有广义估计方程的逻辑回归分析，研究所有717名双相情感障碍受试者起病年龄的临床相关性和家族聚集性。
起病年龄分布由三个正态分布混合而成，均值分别为16.6岁（标准差=5.1）、26.0岁（标准差=1.4）和34.7岁（标准差=6.6），分别占该组的79.7%、7.2%和13.1%。根据该分析得出21岁和28岁的分界点，用于定义起病年龄亚组。早发型（起病年龄≤21岁）受试者药物滥用、酒精滥用、快速循环和自杀未遂的风险更高。来自有早发型先证者家庭的患病受试者比其他受试者更易早发（优势比=4.53，95%可信区间=3.09-6.64）。来自有起病年龄＜28岁先证者家庭的受试者药物滥用风险也更高（优势比=11.62，95%可信区间=2.16-62.66）。
双相情感障碍的起病年龄与临床异质性相关，且在家族中可能与药物滥用一起聚集。这些发现与起病年龄反映双相情感障碍潜在基因异质性的结论一致。因此，可以想象起病年龄可用于识别更同质的双相情感障碍家庭组，从而有助于双相情感障碍易感基因的定位。
