Polygenic risk scores in schizophrenia with clinically significant copy number variants

Satoru Taniguchi, Kohei Ninomiya, Itaru Kushima, Takeo Saito, Ayu Shimasaki, Takaya Sakusabe, Yukihide Momozawa, Michiaki Kubo, Yoichiro Kamatani, Norio Ozaki, Masashi Ikeda, Nakao Iwata

Research output: Contribution to journalArticle

Abstract

Aims: Recent studies have revealed that the interplay between polygenic risk scores (PRS) and large copy number variants (CNV; >500kb) is essential for the etiology of schizophrenia (SCZ). To replicate previous findings, including those for smaller CNV (>10kb), the PRS between SCZ patients with and without CNV were compared. Methods: The PRS were calculated for 724 patients with SCZ and 1178 healthy controls (HC), genotyped using array-based comparative genomic hybridization and single nucleotide polymorphisms chips, and comparisons were made between cases and HC, or between subjects with and without ‘clinically significant’ CNV. Results: First, we replicated the higher PRS in patients with SCZ compared to that in HC (without taking into account the CNV). For clinically significant CNV, as defined by the American College of Medical Genetics (‘pathogenic’ and ‘uncertain clinical significance, likely pathogenic’ CNV), 66 patients with SCZ carried clinically significant CNV, whereas 658 SCZ patients had no such CNV. In the comparison of PRS between cases with/without the CNV, despite no significant difference in PRS, significant enrichment of the well-established risk CNV (22q11.2 deletion and 47,XXY/47,XXX) was observed in the lowest decile of PRS in SCZ patients with the CNV. Conclusion: Although the present study failed to replicate the significant difference in PRS between SCZ patients with and without clinically significant CNV, SCZ patients with well-established risk CNV tended to have a lower PRS. Therefore, we speculate that the CNV in SCZ patients with lower PRS may contain ‘genuine’ risk; PRS is a possible tool for prioritizing clinically significant CNV because the power of the CNV association analysis is limited due to their rarity.

Original languageEnglish
JournalPsychiatry and clinical neurosciences
DOIs
Publication statusAccepted/In press - 01-01-2019

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Schizophrenia
Comparative Genomic Hybridization
Single Nucleotide Polymorphism

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health

Cite this

Taniguchi, Satoru ; Ninomiya, Kohei ; Kushima, Itaru ; Saito, Takeo ; Shimasaki, Ayu ; Sakusabe, Takaya ; Momozawa, Yukihide ; Kubo, Michiaki ; Kamatani, Yoichiro ; Ozaki, Norio ; Ikeda, Masashi ; Iwata, Nakao. / Polygenic risk scores in schizophrenia with clinically significant copy number variants. In: Psychiatry and clinical neurosciences. 2019.
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abstract = "Aims: Recent studies have revealed that the interplay between polygenic risk scores (PRS) and large copy number variants (CNV; >500kb) is essential for the etiology of schizophrenia (SCZ). To replicate previous findings, including those for smaller CNV (>10kb), the PRS between SCZ patients with and without CNV were compared. Methods: The PRS were calculated for 724 patients with SCZ and 1178 healthy controls (HC), genotyped using array-based comparative genomic hybridization and single nucleotide polymorphisms chips, and comparisons were made between cases and HC, or between subjects with and without ‘clinically significant’ CNV. Results: First, we replicated the higher PRS in patients with SCZ compared to that in HC (without taking into account the CNV). For clinically significant CNV, as defined by the American College of Medical Genetics (‘pathogenic’ and ‘uncertain clinical significance, likely pathogenic’ CNV), 66 patients with SCZ carried clinically significant CNV, whereas 658 SCZ patients had no such CNV. In the comparison of PRS between cases with/without the CNV, despite no significant difference in PRS, significant enrichment of the well-established risk CNV (22q11.2 deletion and 47,XXY/47,XXX) was observed in the lowest decile of PRS in SCZ patients with the CNV. Conclusion: Although the present study failed to replicate the significant difference in PRS between SCZ patients with and without clinically significant CNV, SCZ patients with well-established risk CNV tended to have a lower PRS. Therefore, we speculate that the CNV in SCZ patients with lower PRS may contain ‘genuine’ risk; PRS is a possible tool for prioritizing clinically significant CNV because the power of the CNV association analysis is limited due to their rarity.",
author = "Satoru Taniguchi and Kohei Ninomiya and Itaru Kushima and Takeo Saito and Ayu Shimasaki and Takaya Sakusabe and Yukihide Momozawa and Michiaki Kubo and Yoichiro Kamatani and Norio Ozaki and Masashi Ikeda and Nakao Iwata",
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Polygenic risk scores in schizophrenia with clinically significant copy number variants. / Taniguchi, Satoru; Ninomiya, Kohei; Kushima, Itaru; Saito, Takeo; Shimasaki, Ayu; Sakusabe, Takaya; Momozawa, Yukihide; Kubo, Michiaki; Kamatani, Yoichiro; Ozaki, Norio; Ikeda, Masashi; Iwata, Nakao.

In: Psychiatry and clinical neurosciences, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Polygenic risk scores in schizophrenia with clinically significant copy number variants

AU - Taniguchi, Satoru

AU - Ninomiya, Kohei

AU - Kushima, Itaru

AU - Saito, Takeo

AU - Shimasaki, Ayu

AU - Sakusabe, Takaya

AU - Momozawa, Yukihide

AU - Kubo, Michiaki

AU - Kamatani, Yoichiro

AU - Ozaki, Norio

AU - Ikeda, Masashi

AU - Iwata, Nakao

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N2 - Aims: Recent studies have revealed that the interplay between polygenic risk scores (PRS) and large copy number variants (CNV; >500kb) is essential for the etiology of schizophrenia (SCZ). To replicate previous findings, including those for smaller CNV (>10kb), the PRS between SCZ patients with and without CNV were compared. Methods: The PRS were calculated for 724 patients with SCZ and 1178 healthy controls (HC), genotyped using array-based comparative genomic hybridization and single nucleotide polymorphisms chips, and comparisons were made between cases and HC, or between subjects with and without ‘clinically significant’ CNV. Results: First, we replicated the higher PRS in patients with SCZ compared to that in HC (without taking into account the CNV). For clinically significant CNV, as defined by the American College of Medical Genetics (‘pathogenic’ and ‘uncertain clinical significance, likely pathogenic’ CNV), 66 patients with SCZ carried clinically significant CNV, whereas 658 SCZ patients had no such CNV. In the comparison of PRS between cases with/without the CNV, despite no significant difference in PRS, significant enrichment of the well-established risk CNV (22q11.2 deletion and 47,XXY/47,XXX) was observed in the lowest decile of PRS in SCZ patients with the CNV. Conclusion: Although the present study failed to replicate the significant difference in PRS between SCZ patients with and without clinically significant CNV, SCZ patients with well-established risk CNV tended to have a lower PRS. Therefore, we speculate that the CNV in SCZ patients with lower PRS may contain ‘genuine’ risk; PRS is a possible tool for prioritizing clinically significant CNV because the power of the CNV association analysis is limited due to their rarity.

AB - Aims: Recent studies have revealed that the interplay between polygenic risk scores (PRS) and large copy number variants (CNV; >500kb) is essential for the etiology of schizophrenia (SCZ). To replicate previous findings, including those for smaller CNV (>10kb), the PRS between SCZ patients with and without CNV were compared. Methods: The PRS were calculated for 724 patients with SCZ and 1178 healthy controls (HC), genotyped using array-based comparative genomic hybridization and single nucleotide polymorphisms chips, and comparisons were made between cases and HC, or between subjects with and without ‘clinically significant’ CNV. Results: First, we replicated the higher PRS in patients with SCZ compared to that in HC (without taking into account the CNV). For clinically significant CNV, as defined by the American College of Medical Genetics (‘pathogenic’ and ‘uncertain clinical significance, likely pathogenic’ CNV), 66 patients with SCZ carried clinically significant CNV, whereas 658 SCZ patients had no such CNV. In the comparison of PRS between cases with/without the CNV, despite no significant difference in PRS, significant enrichment of the well-established risk CNV (22q11.2 deletion and 47,XXY/47,XXX) was observed in the lowest decile of PRS in SCZ patients with the CNV. Conclusion: Although the present study failed to replicate the significant difference in PRS between SCZ patients with and without clinically significant CNV, SCZ patients with well-established risk CNV tended to have a lower PRS. Therefore, we speculate that the CNV in SCZ patients with lower PRS may contain ‘genuine’ risk; PRS is a possible tool for prioritizing clinically significant CNV because the power of the CNV association analysis is limited due to their rarity.

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