Departments of Biostatistics, Psychiatry, Neuroscience, Physiology, and Cellular Biophysics, Columbia University, New York, NY 10032.
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):343-8. doi: 10.1073/pnas.1309475110. Epub 2013 Dec 16.
We used a family-based cluster detection approach designed to localize significant rare disease-risk variants clusters within a region of interest to systematically search for schizophrenia (SCZ) susceptibility genes within 49 genomic loci previously implicated by de novo copy number variants. Using two independent whole-exome sequencing family datasets and a follow-up autism spectrum disorder (ASD) case/control whole-exome sequencing dataset, we identified variants in one gene, Fanconi-associated nuclease 1 (FAN1), as being associated with both SCZ and ASD. FAN1 is located in a region on chromosome 15q13.3 implicated by a recurrent copy number variant, which predisposes to an array of psychiatric and neurodevelopmental phenotypes. In both SCZ and ASD datasets, rare nonsynonymous risk variants cluster significantly in affected individuals within a 20-kb window that spans several key functional domains of the gene. Our finding suggests that FAN1 is a key driver in the 15q13.3 locus for the associated psychiatric and neurodevelopmental phenotypes. FAN1 encodes a DNA repair enzyme, thus implicating abnormalities in DNA repair in the susceptibility to SCZ or ASD.
我们使用了一种基于家系的聚类检测方法，旨在定位感兴趣区域内显著的罕见疾病风险变异簇，以系统地搜索先前由新生拷贝数变异提示的 49 个基因组位点内的精神分裂症（SCZ）易感基因。使用两个独立的全外显子组测序家系数据集和一个后续的自闭症谱系障碍（ASD）病例/对照全外显子组测序数据集，我们在一个基因中发现了变体，即范可尼相关核酸酶 1（FAN1），它与 SCZ 和 ASD 均有关联。FAN1 位于染色体 15q13.3 上的一个区域，该区域存在反复出现的拷贝数变异，易导致一系列精神和神经发育表型。在 SCZ 和 ASD 数据集，罕见的非同义风险变异在受影响个体的 20kb 窗口内显著聚类，该窗口跨越了该基因的几个关键功能域。我们的发现表明，FAN1 是与相关精神和神经发育表型相关的 15q13.3 基因座的关键驱动基因。FAN1 编码一种 DNA 修复酶，因此暗示 DNA 修复异常与 SCZ 或 ASD 的易感性有关。
