Dai Wei, Zhang Heping
Department of Biostatistics, Yale University School of Public Health.
Ann Appl Stat. 2024 Sep;18(3):2277-2294. doi: 10.1214/24-aoas1880. Epub 2024 Aug 5.
Functional connectivity of the brain, characterized by interconnected neural circuits across functional networks, is a cutting-edge feature in neuroimaging. It has the potential to mediate the effect of genetic variants on behavioral outcomes or diseases. Existing mediation analysis methods can evaluate the impact of genetics and brain structurefunction on cognitive behavior or disorders, but they tend to be limited to single genetic variants or univariate mediators, without considering cumulative genetic effects and the complex matrix and group and network structures of functional connectivity. To address this gap, the paper presents an integrative network-based mediation model (NMM) that estimates the effect of multiple genetic variants on behavioral outcomes or diseases mediated by functional connectivity. The model incorporates group information of inter-regions at broad network level and imposes low-rank and sparse assumptions to reflect the complex structures of functional connectivity and selecting network mediators simultaneously. We adopt block coordinate descent algorithm to implement a fast and efficient solution to our model. Simulation results indicate the efficacy of the model in selecting active mediators and reducing bias in effect estimation. With application to the Human Connectome Project Youth Adult (HCP-YA) study of 493 young adults, two genetic variants (rs769448 and rs769449) on the gene are identified that lead to deficits in functional connectivity within visual networks and fluid intelligence.
大脑的功能连接以跨功能网络的相互连接的神经回路为特征，是神经影像学中的一个前沿特征。它有可能介导基因变异对行为结果或疾病的影响。现有的中介分析方法可以评估遗传学和脑结构功能对认知行为或障碍的影响，但它们往往局限于单一基因变异或单变量中介因素，而没有考虑累积遗传效应以及功能连接的复杂矩阵、群组和网络结构。为了弥补这一差距，本文提出了一种基于网络的综合中介模型（NMM），该模型估计多个基因变异对由功能连接介导的行为结果或疾病的影响。该模型在广泛的网络层面纳入了区域间的群组信息，并施加低秩和稀疏假设，以反映功能连接的复杂结构并同时选择网络中介因素。我们采用块坐标下降算法对模型实现快速有效的求解。模拟结果表明该模型在选择活跃中介因素和减少效应估计偏差方面的有效性。通过应用于对493名年轻人的人类连接组计划青年成人（HCP-YA）研究，确定了 基因上的两个基因变异（rs769448和rs769449），它们导致视觉网络内的功能连接和流体智力出现缺陷。
