Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
J Child Psychol Psychiatry. 2013 Oct;54(10):1074-85. doi: 10.1111/jcpp.12109. Epub 2013 Jul 3.
The aim of this study was to determine if a latent variable approach might be useful in identifying shared variance across genetic risk alleles that is associated with antisocial behaviour at age 15 years.
Using a conventional latent variable approach, we derived an antisocial phenotype in 328 adolescents utilizing data from a 15-year follow-up of a randomized trial of a prenatal and infancy nurse-home visitation programme in Elmira, New York. We then investigated, via a novel latent variable approach, 450 informative genetic polymorphisms in 71 genes previously associated with antisocial behaviour, drug use, affiliative behaviours and stress response in 241 consenting individuals for whom DNA was available. Haplotype and Pathway analyses were also performed.
Eight single-nucleotide polymorphisms (SNPs) from eight genes contributed to the latent genetic variable that in turn accounted for 16.0% of the variance within the latent antisocial phenotype. The number of risk alleles was linearly related to the latent antisocial variable scores. Haplotypes that included the putative risk alleles for all eight genes were also associated with higher latent antisocial variable scores. In addition, 33 SNPs from 63 of the remaining genes were also significant when added to the final model. Many of these genes interact on a molecular level, forming molecular networks. The results support a role for genes related to dopamine, norepinephrine, serotonin, glutamate, opioid and cholinergic signalling as well as stress response pathways in mediating susceptibility to antisocial behaviour.
This preliminary study supports use of relevant behavioural indicators and latent variable approaches to study the potential 'co-action' of gene variants associated with antisocial behaviour. It also underscores the cumulative relevance of common genetic variants for understanding the aetiology of complex behaviour. If replicated in future studies, this approach may allow the identification of a 'shared' variance across genetic risk alleles associated with complex neuropsychiatric dimensional phenotypes using relatively small numbers of well-characterized research participants.
本研究旨在确定潜在变量方法是否可用于识别与 15 岁时反社会行为相关的遗传风险等位基因的共享方差。
我们使用传统的潜在变量方法，利用纽约埃尔迈拉一项产前和婴儿家访计划的随机试验 15 年随访中 328 名青少年的数据，得出反社会表型。然后，我们通过一种新颖的潜在变量方法，在 241 名同意提供 DNA 的个体中，研究了先前与反社会行为、药物使用、亲和行为和应激反应相关的 71 个基因中的 450 个信息性遗传多态性。还进行了单体型和途径分析。
来自 8 个基因的 8 个单核苷酸多态性（SNP）有助于潜在的遗传变量，该变量反过来又解释了潜在反社会表型内 16.0%的方差。风险等位基因的数量与潜在的反社会变量得分呈线性关系。包含所有 8 个基因的假定风险等位基因的单体型也与较高的潜在反社会变量得分相关。此外，当添加到最终模型中时，来自 63 个剩余基因的 33 个 SNP 也具有统计学意义。这些基因中的许多在分子水平上相互作用，形成分子网络。研究结果支持与多巴胺、去甲肾上腺素、血清素、谷氨酸、阿片和胆碱能信号以及应激反应途径相关的基因在介导反社会行为易感性方面的作用。
这项初步研究支持使用相关行为指标和潜在变量方法来研究与反社会行为相关的基因变异的潜在“共同作用”。它还强调了常见遗传变异对理解复杂行为病因学的累积相关性。如果在未来的研究中得到复制，这种方法可以使用相对较少的特征明确的研究参与者来识别与复杂神经精神维度表型相关的遗传风险等位基因的“共享”方差。
