King's College London, Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, De Crespigny Park, London, United Kingdom.
PLoS One. 2013 Jul 9;8(7):e65789. doi: 10.1371/journal.pone.0065789. Print 2013.
Callous-unemotional behavior (CU) is currently under consideration as a subtyping index for conduct disorder diagnosis. Twin studies routinely estimate the heritability of CU as greater than 50%. It is now possible to estimate genetic influence using DNA alone from samples of unrelated individuals, not relying on the assumptions of the twin method. Here we use this new DNA method (implemented in a software package called Genome-wide Complex Trait Analysis, GCTA) for the first time to estimate genetic influence on CU. We also report the first genome-wide association (GWA) study of CU as a quantitative trait. We compare these DNA results to those from twin analyses using the same measure and the same community sample of 2,930 children rated by their teachers at ages 7, 9 and 12. GCTA estimates of heritability were near zero, even though twin analysis of CU in this sample confirmed the high heritability of CU reported in the literature, and even though GCTA estimates of heritability were substantial for cognitive and anthropological traits in this sample. No significant associations were found in GWA analysis, which, like GCTA, only detects additive effects of common DNA variants. The phrase 'missing heritability' was coined to refer to the gap between variance associated with DNA variants identified in GWA studies versus twin study heritability. However, GCTA heritability, not twin study heritability, is the ceiling for GWA studies because both GCTA and GWA are limited to the overall additive effects of common DNA variants, whereas twin studies are not. This GCTA ceiling is very low for CU in our study, despite its high twin study heritability estimate. The gap between GCTA and twin study heritabilities will make it challenging to identify genes responsible for the heritability of CU.
冷酷无情行为（CU）目前被认为是行为障碍诊断的一种亚型指标。双胞胎研究通常估计 CU 的遗传率大于 50%。现在，可以使用来自非相关个体的 DNA 样本单独估计遗传影响，而无需依赖双胞胎方法的假设。在这里，我们首次使用这种新的 DNA 方法（称为全基因组复杂性状分析，GCTA）来估计 CU 的遗传影响。我们还报告了 CU 作为定量性状的首次全基因组关联（GWA）研究。我们将这些 DNA 结果与使用相同测量方法和相同社区样本的双胞胎分析结果进行比较，该样本由 2930 名儿童的老师在 7、9 和 12 岁时进行评分。GCTA 对遗传率的估计接近零，尽管该样本中的 CU 双胞胎分析证实了文献中报道的 CU 遗传率很高，尽管 GCTA 对该样本中认知和人类学特征的遗传率估计很高。在 GWA 分析中没有发现显著关联，GWA 与 GCTA 一样，只能检测常见 DNA 变体的加性效应。“遗传缺失”一词是指在 GWA 研究中与 DNA 变体相关的方差与双胞胎研究遗传率之间的差距。然而，GCTA 遗传率而不是双胞胎研究遗传率是 GWA 研究的上限，因为 GCTA 和 GWA 都仅限于常见 DNA 变体的总体加性效应，而双胞胎研究则不是。尽管 CU 的双胞胎研究遗传率很高，但在我们的研究中，GCTA 的上限非常低。GCTA 和双胞胎研究遗传率之间的差距将使确定 CU 遗传率的基因变得具有挑战性。
