Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama, Japan.
Department of Psychiatry and Behavioral Science, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Nat Commun. 2021 Jun 18;12(1):3750. doi: 10.1038/s41467-021-23453-w.
Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.
双相情感障碍是一种严重的精神疾病，其特征是反复发作的躁狂和抑郁发作。为了更好地理解其遗传结构，我们分析了 354 个双相情感障碍三联体的超罕见新生突变。对于种系新生突变，我们发现受约束基因中的功能丧失突变（校正后 P = 0.0410）和突触前活性区基因中的有害突变（FDR = 0.0415）显著富集。一项整合单细胞 RNA 测序数据的分析确定了一组兴奋性神经元优先表达受有害突变影响的基因，这些基因还表现出发育障碍基因的高表达。在后合子突变的分析中，我们观察到发育障碍基因中有害突变的显著富集（P = 0.00135），包括在两个无关先证者中突变的 SRCAP 基因。这些数据共同表明种系和后合子突变都对双相情感障碍的风险有贡献，支持后合子突变的发育障碍基因可能导致双相情感障碍的假说。
