MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.
Am J Med Genet B Neuropsychiatr Genet. 2012 Oct;159B(7):859-68. doi: 10.1002/ajmg.b.32093. Epub 2012 Aug 22.
Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder.
全基因组研究在重度抑郁症中仅识别出少数可重复的关联，这可能是由于该疾病存在异质性。一些研究表明，发病年龄（AAO）可以区分具有特定遗传成分的抑郁症亚型。本文使用来自 RADIANT 研究的 2746 例病例和 1594 例筛查对照的全基因组关联数据，以及来自两个慕尼黑研究的 1471 例病例和 1403 例对照的复制数据，研究了 AAO 在抑郁遗传易感性中的作用。使用三种方法分析 AAO：首先是对对照进行时间事件分析并进行截断，其次是将对照与使用 AAO 截止值定义的病例子集进行比较，最后是将 AAO 分析为定量性状。在时间事件分析中，三个 SNP 达到了提示性显著水平（P < 5E-06），与该研究的原始病例对照分析重叠。在使用 AAO 截止值的病例对照分析中，10 个基因组区域的 SNP 显示出提示性关联，但没有一个达到全基因组显著水平。最后，仅对 AAO 作为定量性状进行病例分析导致 5 个 SNP 达到提示性显著水平。作为次要分析进行了性别特异性分析，在早发性男性中发现一个 SNP 达到全基因组显著水平。在经过多次测试校正后，复制研究中没有 SNP 达到显著水平。对 AAO 作为定量性状的分析表明，在所有 SNP 中，常见遗传变异解释了大部分方差（51%，P = 0.04）。本研究首次对抑郁症中 AAO 的遗传贡献进行了专门分析，并建立了一个统计框架，可应用于任何疾病的潜在定量性状。
