Adult-onset neuropsychiatric diseases are one of the most challenging areas of medicine. While symptomatic treatments are available, for most of these diseases the exact pathomechanism is not known, thus, disease-modifying therapies are difficult to conceptualize and find. The two most common and best studied neuropsychiatric diseases affecting higher cortical functions in humans are schizophrenia and Alzheimer’s disease; both diseases have high heritability, however, the genetic architecture is not fully elucidated. Robust Single Nucleotide Variant (SNV) studies have identified several loci with modest effect sizes. While Copy Number Variants (CNV) make an important contribution to genetic variation, CNV GWAS suffer from dependence on mainly SNP arrays with underperforming genotyping accuracy. We evaluated dynamic range of the assays for three types of CNV loci, including biallelic deletion, high copy gain, and fusion gene, to assess the depth of exploration of the contribution of CNVs to disease susceptibility. Despite the suboptimal genotyping, novel mechanisms are emerging and further large-scale studies with genotyping assays optimized for CNV detection are needed. Furthermore, the CHRFAM7A human-specific fusion gene association warrants large scale locus specific association studies in AD, schizophrenia, bipolar disorder and ADHD.

中文翻译：

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成人发病神经精神疾病的拷贝数变异

成人发病的神经精神疾病是最具挑战性的医学领域之一。虽然可以进行对症治疗，但对于大多数这些疾病，确切的发病机制尚不清楚，因此，难以概念化和找到改善疾病的疗法。影响人类高级皮层功能的两种最常见和研究最深入的神经精神疾病是精神分裂症和阿尔茨海默病。这两种疾病都具有很高的遗传性，但是，遗传结构尚未完全阐明。稳健的单核苷酸变体 (SNV) 研究已经确定了几个具有中等影响大小的基因座。虽然拷贝数变异 (CNV) 对遗传变异做出了重要贡献，但 CNV GWAS 主要依赖于基因分型准确性不佳的 SNP 阵列。我们评估了三种类型的 CNV 基因座的检测动态范围，包括双等位基因缺失、高拷贝增益和融合基因，以评估对 CNV 对疾病易感性的贡献的探索深度。尽管基因分型不理想，但新的机制正在出现，需要使用针对 CNV 检测优化的基因分型分析进行进一步的大规模研究。此外，CHRFAM7A 人类特异性融合基因关联保证了在 AD、精神分裂症、双相情感障碍和 ADHD 中进行大规模基因座特异性关联研究。新的机制正在出现，需要对 CNV 检测进行优化的基因分型分析进行进一步的大规模研究。此外，CHRFAM7A 人类特异性融合基因关联保证了在 AD、精神分裂症、双相情感障碍和 ADHD 中进行大规模基因座特异性关联研究。新的机制正在出现，需要对 CNV 检测进行优化的基因分型分析进行进一步的大规模研究。此外，CHRFAM7A 人类特异性融合基因关联保证了在 AD、精神分裂症、双相情感障碍和 ADHD 中进行大规模基因座特异性关联研究。