Department of Cell Biology, the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Center for Applied Genomics, the Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Transl Psychiatry. 2021 Jan 21;11(1):69. doi: 10.1038/s41398-020-01195-5.
Neuropsychiatric disorders, such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), bipolar disorder (BIP), and major depressive disorder (MDD) share common clinical presentations, suggesting etiologic overlap. A substantial proportion of SNP-based heritability for neuropsychiatric disorders is attributable to genetic components, and genome-wide association studies (GWASs) focusing on individual diseases have identified multiple genetic loci shared between these diseases. Here, we aimed at identifying novel genetic loci associated with individual neuropsychiatric diseases and genetic loci shared by neuropsychiatric diseases. We performed multi-trait joint analyses and meta-analysis across five neuropsychiatric disorders based on their summary statistics from the Psychiatric Genomics Consortium (PGC), and further carried out a replication study of ADHD among 2726 cases and 16299 controls in an independent pediatric cohort. In the multi-trait joint analyses, we found five novel genome-wide significant loci for ADHD, one novel locus for BIP, and ten novel loci for MDD. We further achieved modest replication in our independent pediatric dataset. We conducted fine-mapping and functional annotation through an integrative multi-omics approach and identified causal variants and potential target genes at each novel locus. Gene expression profile and gene-set enrichment analysis further suggested early developmental stage expression pattern and postsynaptic membrane compartment enrichment of candidate genes at the genome-wide significant loci of these neuropsychiatric disorders. Therefore, through a multi-omics approach, we identified novel genetic loci associated with the five neuropsychiatric disorders which may help to better understand the underlying molecular mechanism of neuropsychiatric diseases.
神经精神疾病，如自闭症谱系障碍 (ASD)、注意缺陷多动障碍 (ADHD)、精神分裂症 (SCZ)、双相情感障碍 (BIP) 和重度抑郁症 (MDD) 具有共同的临床特征，表明其病因存在重叠。神经精神疾病基于 SNP 的遗传度很大程度上归因于遗传成分，并且针对个别疾病的全基因组关联研究 (GWAS) 已经确定了这些疾病之间存在多个遗传位点。在这里，我们旨在确定与个体神经精神疾病相关的新的遗传位点以及神经精神疾病共有的遗传位点。我们根据精神疾病基因组学联盟 (PGC) 的汇总统计数据，对五个神经精神疾病进行了多性状联合分析和荟萃分析，并在一个独立的儿科队列中对 ADHD 进行了 2726 例病例和 16299 例对照的复制研究。在多性状联合分析中，我们发现了五个 ADHD 的新全基因组显著位点，一个 BIP 的新位点和十个 MDD 的新位点。我们在独立的儿科数据集上进一步实现了适度的复制。我们通过综合多组学方法进行了精细映射和功能注释，并在每个新位点确定了因果变异和潜在的靶基因。基因表达谱和基因集富集分析进一步表明，候选基因在这些神经精神疾病的全基因组显著位点上具有早期发育阶段的表达模式和突触后膜区室的富集。因此，通过多组学方法，我们确定了与五种神经精神疾病相关的新遗传位点，这可能有助于更好地理解神经精神疾病的潜在分子机制。
