Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
Bipolar Disord. 2019 Feb;21(1):68-75. doi: 10.1111/bdi.12659. Epub 2018 Jun 28.
Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.
A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.
BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.
The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
发病年龄较早的双相情感障碍（BD）与不良临床结局相关，且构成了异质性 BD 谱内具有临床和生物学同质性的亚组。先前的研究发现 BD 家族中存在发病年龄较早（AAO）的累积现象，因此假设早期发病病例的遗传贡献大于迟发性 BD。为了探究该亚表型的遗传背景，我们评估了 BD 和精神分裂症（SCZ）相关风险变异的多基因负担增加是否与 BD 患者 AAO 较早有关。
共纳入来自 Consortium of Lithium Genetics（ConLiGen）、 PsyCourse 和 Bonn-Mannheim 样本的 1995 例 BD 1 型患者，使用 Psychiatric Genomics Consortium 的汇总统计数据作为训练数据集，对患者进行基因分型并计算其 BD 和 SCZ 多基因风险评分（PRS）。AAO 被分为具有临床意义的发病年龄组（儿童和青少年[≤18 岁]与成年[>18 岁]），或被视为连续变量。使用回归模型评估 BD 和 SCZ-PRS 与 AAO 之间的关联。
BD 和 SCZ-PRS 与发病年龄均无显著相关性。按招募地点分层进行分析时，结果仍然不变。
本研究是迄今为止最大规模的探究 BD 患者累积 BD 和 SCZ 多基因风险与 AAO 之间关联的研究。阴性结果提示，如果存在这种多基因影响，其程度也不大，突显了进一步开展更大规模研究以获取更多有关该具有临床意义表型遗传结构信息的重要性。
