論文 - 石塚 佳奈子
-
Possible involvement of a cell adhesion molecule, Migfilin, in brain development and pathogenesis of autism spectrum disorders. 査読あり 国際誌
Kanako Ishizuka, Hidenori Tabata, Hidenori Ito, Itaru Kushima, Mariko Noda, Akira Yoshimi, Masahide Usami, Kyota Watanabe, Mako Morikawa, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki, Koh-Ichi Nagata
Journal of neuroscience research 96 ( 5 ) 789 - 802 2018年05月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Migfilin, encoded by FBLIM1 at the 1p36 locus, is a multi-domain adaptor protein essential for various cellular processes such as cell morphology and migration. Small deletions and duplications at the 1p36 locus, monosomy of which results in neurodevelopmental disorders and multiple congenital anomalies, have also been identified in patients with autism spectrum disorder (ASD). However, the impact of FBLIM1, the gene within 1p36, on the pathogenesis of ASD is unknown. In this study, we performed morphological analyses of migfilin to elucidate its role in brain development. Migfilin was detected specifically in the embryonic and perinatal stages of the mouse brain. Either silencing or overexpression of migfilin in embryos following in utero electroporation disrupted Neocortical neuronal migration. Additionally, neurite elongation was impaired when migfilin was silenced in cultured mouse hippocampal neurons. We then screened FBLIM1 for rare exonic deletions/duplications in 549 Japanese ASD patients and 824 controls, detecting one case of ASD and intellectual delay that harbored a 26-kb deletion at 1p36.21 that solely included the C-terminal exon of FBLIM1. The FBLIM1 mRNA expression level in this case was reduced compared to levels in individuals without FBLIM1 deletion. Our findings indicate that tightly regulated expression of migfilin is essential for neuronal development and that FBLIM1 disruption may be related to the phenotypes associated with ASD and related neurodevelopmental disorders.
DOI： 10.1002/jnr.24194
-
精神疾患のジェネティクス・自閉スペクトラム症 招待あり
石塚佳奈子, 尾崎紀夫
Clinical Neuroscience 36 ( 2 ) 238-241 2018年02月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
-
Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. 国際誌
Atsushi Takata, Noriko Miyake, Yoshinori Tsurusaki, Ryoko Fukai, Satoko Miyatake, Eriko Koshimizu, Itaru Kushima, Takashi Okada, Mako Morikawa, Yota Uno, Kanako Ishizuka, Kazuhiko Nakamura, Masatsugu Tsujii, Takeo Yoshikawa, Tomoko Toyota, Nobuhiko Okamoto, Yoko Hiraki, Ryota Hashimoto, Yuka Yasuda, Shinji Saitoh, Kei Ohashi, Yasunari Sakai, Shouichi Ohga, Toshiro Hara, Mitsuhiro Kato, Kazuyuki Nakamura, Aiko Ito, Chizuru Seiwa, Emi Shirahata, Hitoshi Osaka, Ayumi Matsumoto, Saoko Takeshita, Jun Tohyama, Tomoko Saikusa, Toyojiro Matsuishi, Takumi Nakamura, Takashi Tsuboi, Tadafumi Kato, Toshifumi Suzuki, Hirotomo Saitsu, Mitsuko Nakashima, Takeshi Mizuguchi, Fumiaki Tanaka, Norio Mori, Norio Ozaki, Naomichi Matsumoto
Cell reports 22 ( 3 ) 734 - 747 2018年01月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.
-
Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility. 国際誌
Yanjie Yu, Yingni Lin, Yuto Takasaki, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Kanako Ishizuka, Miho Toyama, Itaru Kushima, Daisuke Mori, Yuko Arioka, Yota Uno, Tomoko Shiino, Yukako Nakamura, Takashi Okada, Mako Morikawa, Masashi Ikeda, Nakao Iwata, Yuko Okahisa, Manabu Takaki, Shinji Sakamoto, Toshiyuki Someya, Jun Egawa, Masahide Usami, Masaki Kodaira, Akira Yoshimi, Tomoko Oya-Ito, Branko Aleksic, Kinji Ohno, Norio Ozaki
Translational psychiatry 8 ( 1 ) 12 - 12 2018年01月
記述言語：英語 掲載種別：研究論文（学術雑誌）
In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-D-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.
-
乳幼児期の環境と発育発達〜精神医学の観点から〜 招待あり
石塚佳奈子
子どもと発育発達 15 ( 4 ) 271-277 2018年01月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
-
Successful post-transplant psychiatric interventions during long-term follow-up of patients receiving liver transplants for alcoholic liver disease 国際誌
Hiroyuki Kimura, Yasuharu Onishi, Shinichi Kishi, Nobuhiko Kurata, Satoshi Ogiso, Hideya Kamei, Chisato Tsuboi, Naoko Yamaguchi, Azusa Shiga, Mai Kondo, Yushun Yokoyama, Fumika Takasato, Hiroshige Fujishiro, Kanako Ishizuka, Takashi Okada, Yasuhiro Ogura, Norio Ozaki
American Journal of Case Reports 18 1215 - 1219 2017年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Scientific Information, Inc.
Objective: Unusual setting of medical care Background: Around 20-30% of patients who undergo liver transplantation (LT) for alcoholic liver disease (ALD) will resume heavy drinking after LT. It is crucial to control post-transplant relapse of alcohol use, because alcoholic recidivism has been shown to have a negative impact on post-transplant compliance and long-term outcomes of LT recipients. However, there is currently no specific, effective psychiatric intervention for preventing additional alcohol consumption in clinical practice. Case Report: We present 3 patients who underwent LT for ALD at Nagoya University Hospital who were followed up for prolonged periods (7.2, 8.8, and 11.3 years, respectively), and review the psychiatric interventions employed to address critical situations. Additional alcohol consumption was noted in Case 1, but prompt collaborative care led to stable abstinence. In Case 2, marked anger and irritation were exacerbated as a result of work, but the anger was controlled by anger management. Case 3 abused a minor tranquilizer, but limit-setting resulted in adequate medical adherence. Conclusions: Transplant teams need to provide comprehensive treatment for alcoholic recidivism to improve long-term health after LT for ALD.
DOI： 10.12659/AJCR.906446
-
MUTATION SCREENING OF THE PCDH15 GENE IN PATIENTS SUFFERING FROM AUTISM SPECTRUM DISORDERS AND SCHIZOPHRENIA 査読あり
Kanako Ishizuka, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Itaru Kushima, Yuko Arioka, Akira Yoshimi, Yukako Nakamura, Tomoko Oya-Ito, Yuto Takasaki, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki
EUROPEAN NEUROPSYCHOPHARMACOLOGY 27 S162 - S163 2017年10月
記述言語：英語 掲載種別：研究論文（国際会議プロシーディングス）
-
統合失調症発症に強い影響を及ぼす、頻度の低い稀な遺伝子変異を22q11.2欠失領域に存在するミエリン関連遺伝子のRTN4Rに同定した
木村 大樹, 藤田 幸, 川端 猛, 石塚 佳奈子, Wang Chenyao, 岩山 佳美, 岡久 祐子, 久島 周, 宇野 洋太, 岡田 俊, 森川 真子, 森 大輔, 池田 匡志, 稲田 俊也, Aleksic Branko, 吉川 武男, 岩田 仲生, 中村 春木, 山下 俊英, 尾崎 紀夫
日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集 39回・47回 190 - 190 2017年09月
記述言語：日本語 出版者・発行元：日本生物学的精神医学会・日本神経精神薬理学会
-
Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders 査読あり
K. Ishizuka, Y. Fujita, T. Kawabata, H. Kimura, Y. Iwayama, T. Inada, Y. Okahisa, J. Egawa, M. Usami, I. Kushima, Y. Uno, T. Okada, M. Ikeda, B. Aleksic, D. Mori, To Someya, T. Yoshikawa, N. Iwata, H. Nakamura, T. Yamashita, N. Ozaki
TRANSLATIONAL PSYCHIATRY 7 ( 8 ) e1184 2017年08月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：NATURE PUBLISHING GROUP
CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio = 8.3, P = 0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.
DOI： 10.1038/tp.2017.173
-
A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility
H. Kimura, Y. Fujita, T. Kawabata, K. Ishizuka, C. Wang, Y. Iwayama, Y. Okahisa, I. Kushima, M. Morikawa, Y. Uno, T. Okada, M. Ikeda, T. Inada, A. Branko, D. Mori, T. Yoshikawa, N. Iwata, H. Nakamura, T. Yamashita, N. Ozaki
TRANSLATIONAL PSYCHIATRY 7 2017年08月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：NATURE PUBLISHING GROUP
Reticulon 4 receptor (RTN4R) plays an essential role in regulating axonal regeneration and plasticity in the central nervous system through the activation of rho kinase, and is located within chromosome 22q11.2, a region that is known to be a hotspot for schizophrenia (SCZ) and autism spectrum disorder (ASD). Recently, rare variants such as copy-number variants and single-nucleotide variants have been a focus of research because of their large effect size associated with increased susceptibility to SCZ and ASD and the possibility of elucidating the pathophysiology of mental disorder through functional analysis of the discovered rare variants. To discover rare variants with large effect size and to evaluate their role in the etiopathophysiology of SCZ and ASD, we sequenced the RTN4R coding exons with a sample comprising 370 SCZ and 192 ASD patients, and association analysis using a large number of unrelated individuals (1716 SCZ, 382 ASD and 4009 controls). Through this mutation screening, we discovered four rare (minor allele frequency <1%) missense mutations (R68H, D259N, R292H and V363M) of RTN4R. Among these discovered rare mutations, R292H was found to be significantly associated with SCZ (P = 0.048). Furthermore, in vitro functional assays showed that the R292H mutation affected the formation of growth cones. This study strengthens the evidence for association between rare variants within RTN4R and SCZ, and may shed light on the molecular mechanisms underlying the neurodevelopmental disorder.
DOI： 10.1038/tp.2017.170
-
自閉スペクトラム症の診断と病態 招待あり
石塚佳奈子, 尾崎紀夫
日本生物学的精神医学会誌 28 ( 1 ) 11-17 2017年04月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
-
High-resolution copy number variation analysis of schizophrenia in Japan
I. Kushima, B. Aleksic, M. Nakatochi, T. Shimamura, T. Shiino, A. Yoshimi, H. Kimura, Y. Takasaki, C. Wang, J. Xing, K. Ishizuka, T. Oya-Ito, Y. Nakamura, Y. Arioka, T. Maeda, M. Yamamoto, M. Yoshida, H. Noma, S. Hamada, M. Morikawa, Y. Uno, T. Okada, T. Iidaka, S. Iritani, T. Yamamoto, M. Miyashita, A. Kobori, M. Arai, M. Itokawa, M-C Cheng, Y-A Chuang, C-H Chen, M. Suzuki, T. Takahashi, R. Hashimoto, H. Yamamori, Y. Yasuda, Y. Watanabe, A. Nunokawa, T. Someya, M. Ikeda, T. Toyota, T. Yoshikawa, S. Numata, T. Ohmori, S. Kunimoto, D. Mori, N. Iwata, N. Ozaki
MOLECULAR PSYCHIATRY 22 ( 3 ) 430 - 440 2017年03月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：NATURE PUBLISHING GROUP
Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (< 100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio = 3.04, P = 9.3 x 10 (-9), 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e. g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio = 2.79, P = 0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e. g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.
DOI： 10.1038/mp.2016.88
-
選択性緘黙 招待あり
石塚佳奈子, 本城秀次
臨床精神医学 45 216-219 2016年12月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
-
Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes. 査読あり
Kanako Ishizuka, Hiroki Kimura, Akira Yoshimi, Masahiro Banno, Itaru Kushima, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki
Nagoya journal of medical science 78 ( 4 ) 465 - 474 2016年12月
記述言語：英語 掲載種別：研究論文（学術雑誌）
MBD5 (Methyl-CpG-binding domain 5) is a critical gene for normal development. While deletion or duplication of MBD5 may contribute to a genetic predisposition to autism spectrum disorders (ASD), intellectual disability, or epilepsy, the impact of rare MBD5 single nucleotide variants (SNVs) on neurodevelopmental features, particularly features with late onset, has not been fully explored. In this study, we conducted exon-targeted resequencing of MBD5 with next-generation sequencing technology in 562 Japanese patients (192 with idiopathic ASD and 370 with schizophrenia (SCZ)) and detected 16 MBD5 SNVs with allele frequencies of ≤1%. We then performed phenotype analyses with 12 novel variants of these 16 SNVs. SCZ patients with these variants exhibited mainly within normal development ranges until the first psychosis and ASD patients with SNVs did not precisely overlap with the core characteristics described in previous literature as being associated with MBD5 SNVs. Our results suggested that MBD5 variants might contribute to a broad spectrum of neurodevelopmental pathophysiology. Further research and assessment of clinical diagnostic screening are necessary for understanding the burden of rare MBD5 SNVs for these neurodevelopmental disorders.
-
Identification of a rare variant in CHD8 that contributes to schizophrenia and autism spectrum disorder susceptibility 査読あり
Hiroki Kimura, Chenyao Wang, Kanako Ishizuka, Jingrui Xing, Yuto Takasaki, Itaru Kushima, Branko Aleksic, Yota Uno, Takashi Okada, Masashi Ikeda, Daisuke Mori, Toshiya Inada, Nakao Iwata, Norio Ozaki
SCHIZOPHRENIA RESEARCH 178 ( 1-3 ) 104 - 106 2016年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：ELSEVIER SCIENCE BV
-
Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population. 査読あり 国際誌
Yuto Takasaki, Takayoshi Koide, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Itaru Kushima, Kanako Ishizuka, Daisuke Mori, Mariko Sekiguchi, Masashi Ikeda, Miki Aizawa, Naoko Tsurumaru, Yoshimi Iwayama, Akira Yoshimi, Yuko Arioka, Mami Yoshida, Hiromi Noma, Tomoko Oya-Ito, Yukako Nakamura, Shohko Kunimoto, Branko Aleksic, Yota Uno, Takashi Okada, Hiroshi Ujike, Jun Egawa, Hitoshi Kuwabara, Toshiyuki Someya, Takeo Yoshikawa, Nakao Iwata, Norio Ozaki
Scientific reports 6 33311 - 33311 2016年09月
記述言語：英語 掲載種別：研究論文（学術雑誌）
N-methyl-d-aspartate receptors (NMDARs) play a critical role in excitatory synaptic transmission and plasticity in the central nervous systems. Recent genetics studies in schizophrenia (SCZ) show that SCZ is susceptible to NMDARs and the NMDAR signaling complex. In autism spectrum disorder (ASD), several studies report dysregulation of NMDARs as a risk factor for ASD. To further examine the association between NMDARs and SCZ/ASD development, we conducted a mutation screening study of GRIN2B which encodes NR2B subunit of NMDARs, to identify rare mutations that potentially cause diseases, in SCZ and ASD patients (n = 574 and 152, respectively). This was followed by an association study in a large sample set of SCZ, ASD, and normal healthy controls (n = 4145, 381, and 4432, respectively). We identified five rare missense mutations through the mutation screening of GRIN2B. Although no statistically significant association between any single mutation and SCZ or ASD was found, one of its variant, K1292R, is found only in the patient group. To further examine the association between mutations in GRIN2B and SCZ/ASD development, a larger sample size and functional experiments are needed.
DOI： 10.1038/srep33311
-
乳幼児精神医学という視点 招待あり
石塚佳奈子, 本城秀次
精神科治療学 31 ( 7 ) 839-843 2016年07月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
-
Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders. 査読あり 国際誌
Jingrui Xing, Hiroki Kimura, Chenyao Wang, Kanako Ishizuka, Itaru Kushima, Yuko Arioka, Akira Yoshimi, Yukako Nakamura, Tomoko Shiino, Tomoko Oya-Ito, Yuto Takasaki, Yota Uno, Takashi Okada, Tetsuya Iidaka, Branko Aleksic, Daisuke Mori, Norio Ozaki
Scientific reports 6 27491 - 27491 2016年06月
記述言語：英語 掲載種別：研究論文（学術雑誌）
PSD-95 associated PSD proteins play a critical role in regulating the density and activity of glutamate receptors. Numerous previous studies have shown an association between the genes that encode these proteins and schizophrenia (SZ) and autism spectrum disorders (ASD), which share a substantial portion of genetic risks. We sequenced the protein-encoding regions of DLG1, DLG2, DLG4, DLGAP1, DLGAP2, and SynGAP in 562 cases (370 SZ and 192 ASD patients) on the Ion PGM platform. We detected 26 rare (minor allele frequency <1%), non-synonymous mutations, and conducted silico functional analysis and pedigree analysis when possible. Three variants, G344R in DLG1, G241S in DLG4, and R604C in DLGAP2, were selected for association analysis in an independent sample set of 1315 SZ patients, 382 ASD patients, and 1793 healthy controls. Neither DLG4-G241S nor DLGAP2-R604C was detected in any samples in case or control sets, whereas one additional SZ patient was found that carried DLG1-G344R. Our results suggest that rare missense mutations in the candidate PSD genes may increase susceptibility to SZ and/or ASD. These findings may strengthen the theory that rare, non-synonymous variants confer substantial genetic risks for these disorders.
DOI： 10.1038/srep27491
-
PM338. Investigation of the association of rare single nucleotide variants in methyl-CpG-binding domain protein 5 (MBD5) with phenotypes of autism spectrum disorders and schizophrenia. 査読あり
Ishizuka K, Aleksic B, Chenyao W, Kimura H, Kushima I, Okada T, Ozaki N, Uno Y
The international journal of neuropsychopharmacology 2016年05月
掲載種別：研究論文（学術雑誌）
-
Investigation of Rare Single-Nucleotide PCDH15 Variants in Schizophrenia and Autism Spectrum Disorders 査読あり
Kanako Ishizuka, Hiroki Kimura, Chenyao Wang, Jingrui Xing, Itaru Kushima, Yuko Arioka, Tomoko Oya-Ito, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki
PLOS ONE 11 ( 4 ) e0153224 2016年04月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：PUBLIC LIBRARY SCIENCE
Both schizophrenia (SCZ) and autism spectrum disorders (ASD) are neuropsychiatric disorders with overlapping genetic etiology. Protocadherin 15 (PCDH15), which encodes a member of the cadherin super family that contributes to neural development and function, has been cited as a risk gene for neuropsychiatric disorders. Recently, rare variants of large effect have been paid attention to understand the etiopathology of these complex disorders. Thus, we evaluated the impacts of rare, single-nucleotide variants (SNVs) in PCDH15 on SCZ or ASD. First, we conducted coding exon-targeted resequencing of PCDH15 with next-generation sequencing technology in 562 Japanese patients (370 SCZ and 192 ASD) and detected 16 heterozygous SNVs. We then performed association analyses on 2,096 cases (1,714 SCZ and 382 ASD) and 1,917 controls with six novel variants of these 16 SNVs. Of these six variants, four (p. R219K, p. T281A, p. D642N, c. 3010-1G> C) were ultra-rare variants (minor allele frequency < 0.0005) that may increase disease susceptibility. Finally, no statistically significant association between any of these rare, heterozygous PCDH15 point variants and SCZ or ASD was found. Our results suggest that a larger sample size of resequencing subjects is necessary to detect associations between rare PCDH15 variants and neuropsychiatric disorders.
