Whole-exome sequencing identifies variants associated with structural MRI markers in patients with bipolar disorders

Mi Ryung Han, Kyu Man Han, Aram Kim, Wooyoung Kang, Youbin Kang, June Kang, Eunsoo Won, Woo Suk Tae, Yunjung Cho, Byung-Joo Ham

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Bipolar disorder (BD) is one of the most heritable psychiatric disorders. A growing number of whole-exome sequencing (WES) studies for BD has been performed, however, no research has examined the association between single nucleotide variants (SNVs) from WES and structural magnetic resonance imaging (MRI) data. Methods: We sequenced whole-exomes in 53 patients with BD and 82 healthy control participants at an initial discovery stage and investigated the impacts of SNVs in risk genes from WES analysis on the cortical gray-matter thickness and integrity of white matter tracts and in the following stage. Cortical thickness and white matter integrity were investigated using the FreeSurfer and TRACULA (Tracts Constrained by UnderLying Anatomy). Results: We identified 122 BD-related genes including KMT2C, AHNAK, CDH23, DCHS1, FRAS1, MACF1 and RYR3 and observed 27 recurrent copy number alteration regions including gain on 8p23.1 and loss on 15q11.1 - q11.2. Among them, single nucleotide polymorphism (SNP) rs4639425 in KMT2C gene, which regulates histone H3 lysine 4 (H3K4) methylation involved in chromatin remodeling, was associated with widespread alterations of white matter integrity including the cingulum, uncinate fasciculus, cortico-spinal tract, and superior longitudinal fasciculus. Limitation: The small sample size of patients with BD in the genome data may cause our study to be underpowered when searching for putative rare mutations. Conclusion: This study first combined a WES approach and neuroimaging findings in psychiatric disorders. We postulate the rs4639425 may be associated with BD-related microstructural changes of white matter tracts.

Original languageEnglish
Pages (from-to)159-168
Number of pages10
JournalJournal of Affective Disorders
Volume249
DOIs
Publication statusPublished - 2019 Apr 15

Fingerprint

Exome
Bipolar Disorder
Magnetic Resonance Imaging
Psychiatry
Nucleotides
Genes
Chromatin Assembly and Disassembly
Neuroimaging
Sample Size
Histones
Methylation
Lysine
Single Nucleotide Polymorphism
Anatomy
Healthy Volunteers
Genome
Mutation
White Matter
Research

Keywords

  • Bipolar disorder
  • Cortical thickness
  • Diffusion tensor image
  • KMT2C
  • Magnetic resonance imaging
  • Whole-exome sequencing

ASJC Scopus subject areas

  • Clinical Psychology
  • Psychiatry and Mental health

Cite this

Whole-exome sequencing identifies variants associated with structural MRI markers in patients with bipolar disorders. / Han, Mi Ryung; Han, Kyu Man; Kim, Aram; Kang, Wooyoung; Kang, Youbin; Kang, June; Won, Eunsoo; Tae, Woo Suk; Cho, Yunjung; Ham, Byung-Joo.

In: Journal of Affective Disorders, Vol. 249, 15.04.2019, p. 159-168.

Research output: Contribution to journalArticle

Han, Mi Ryung ; Han, Kyu Man ; Kim, Aram ; Kang, Wooyoung ; Kang, Youbin ; Kang, June ; Won, Eunsoo ; Tae, Woo Suk ; Cho, Yunjung ; Ham, Byung-Joo. / Whole-exome sequencing identifies variants associated with structural MRI markers in patients with bipolar disorders. In: Journal of Affective Disorders. 2019 ; Vol. 249. pp. 159-168.
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abstract = "Background: Bipolar disorder (BD) is one of the most heritable psychiatric disorders. A growing number of whole-exome sequencing (WES) studies for BD has been performed, however, no research has examined the association between single nucleotide variants (SNVs) from WES and structural magnetic resonance imaging (MRI) data. Methods: We sequenced whole-exomes in 53 patients with BD and 82 healthy control participants at an initial discovery stage and investigated the impacts of SNVs in risk genes from WES analysis on the cortical gray-matter thickness and integrity of white matter tracts and in the following stage. Cortical thickness and white matter integrity were investigated using the FreeSurfer and TRACULA (Tracts Constrained by UnderLying Anatomy). Results: We identified 122 BD-related genes including KMT2C, AHNAK, CDH23, DCHS1, FRAS1, MACF1 and RYR3 and observed 27 recurrent copy number alteration regions including gain on 8p23.1 and loss on 15q11.1 - q11.2. Among them, single nucleotide polymorphism (SNP) rs4639425 in KMT2C gene, which regulates histone H3 lysine 4 (H3K4) methylation involved in chromatin remodeling, was associated with widespread alterations of white matter integrity including the cingulum, uncinate fasciculus, cortico-spinal tract, and superior longitudinal fasciculus. Limitation: The small sample size of patients with BD in the genome data may cause our study to be underpowered when searching for putative rare mutations. Conclusion: This study first combined a WES approach and neuroimaging findings in psychiatric disorders. We postulate the rs4639425 may be associated with BD-related microstructural changes of white matter tracts.",
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AU - Han, Mi Ryung

AU - Han, Kyu Man

AU - Kim, Aram

AU - Kang, Wooyoung

AU - Kang, Youbin

AU - Kang, June

AU - Won, Eunsoo

AU - Tae, Woo Suk

AU - Cho, Yunjung

AU - Ham, Byung-Joo

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AB - Background: Bipolar disorder (BD) is one of the most heritable psychiatric disorders. A growing number of whole-exome sequencing (WES) studies for BD has been performed, however, no research has examined the association between single nucleotide variants (SNVs) from WES and structural magnetic resonance imaging (MRI) data. Methods: We sequenced whole-exomes in 53 patients with BD and 82 healthy control participants at an initial discovery stage and investigated the impacts of SNVs in risk genes from WES analysis on the cortical gray-matter thickness and integrity of white matter tracts and in the following stage. Cortical thickness and white matter integrity were investigated using the FreeSurfer and TRACULA (Tracts Constrained by UnderLying Anatomy). Results: We identified 122 BD-related genes including KMT2C, AHNAK, CDH23, DCHS1, FRAS1, MACF1 and RYR3 and observed 27 recurrent copy number alteration regions including gain on 8p23.1 and loss on 15q11.1 - q11.2. Among them, single nucleotide polymorphism (SNP) rs4639425 in KMT2C gene, which regulates histone H3 lysine 4 (H3K4) methylation involved in chromatin remodeling, was associated with widespread alterations of white matter integrity including the cingulum, uncinate fasciculus, cortico-spinal tract, and superior longitudinal fasciculus. Limitation: The small sample size of patients with BD in the genome data may cause our study to be underpowered when searching for putative rare mutations. Conclusion: This study first combined a WES approach and neuroimaging findings in psychiatric disorders. We postulate the rs4639425 may be associated with BD-related microstructural changes of white matter tracts.

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