Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder

Masaki Nishioka, An-a Kazuno, Takumi Nakamura, Naomi Sakai, Takashi Hayama, Kumiko Fujii, Koji Matsuo, Atsuko Komori, Mizuho Ishiwata, Yoshinori Watanabe, Takashi Oka, Nana Matoba, Muneko Kataoka, Ahmed N. Alkanaq, Kohei Hamanaka, Takashi Tsuboi, Toru Sengoku, Kazuhiro Ogata, Nakao Iwata, Masashi Ikeda, Naomichi Matsumoto, Tadafumi Kato () and Atsushi Takata ()
Additional contact information
Masaki Nishioka: RIKEN Center for Brain Science
An-a Kazuno: RIKEN Center for Brain Science
Takumi Nakamura: RIKEN Center for Brain Science
Naomi Sakai: RIKEN Center for Brain Science
Takashi Hayama: Yokohama Mental Clinic Totsuka
Kumiko Fujii: Shiga University of Medical Science
Koji Matsuo: Saitama Medical University
Atsuko Komori: RIKEN Center for Brain Science
Mizuho Ishiwata: RIKEN Center for Brain Science
Yoshinori Watanabe: Ichigaya Himorogi Clinic
Takashi Oka: Juzen Hospital
Nana Matoba: RIKEN Center for Brain Science
Muneko Kataoka: RIKEN Center for Brain Science
Ahmed N. Alkanaq: Yokohama City University Graduate School of Medicine
Kohei Hamanaka: Yokohama City University Graduate School of Medicine
Takashi Tsuboi: The University of Tokyo
Toru Sengoku: Yokohama City University Graduate School of Medicine
Kazuhiro Ogata: Yokohama City University Graduate School of Medicine
Nakao Iwata: Fujita Health University
Masashi Ikeda: Fujita Health University
Naomichi Matsumoto: Yokohama City University Graduate School of Medicine
Tadafumi Kato: RIKEN Center for Brain Science
Atsushi Takata: RIKEN Center for Brain Science

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23453-w

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DOI: 10.1038/s41467-021-23453-w

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