Mi-Ryung Han1, Kyu-Man Han2, Aram Kim3, Wooyoung Kang3, Youbin Kang3, June Kang4, Eunsoo Won2, Woo-Suk Tae5, Yunjung Cho1, Byung-Joo Ham6. 1. Department of Laboratory Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea. 2. Department of Psychiatry, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea. 3. Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea. 4. Department of Brain and Cognitive Engineering, Korea University, Seoul, Republic of Korea. 5. Brain Convergence Research Center, Korea University Anam Hospital, Seoul, Republic of Korea. 6. Department of Psychiatry, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea; Brain Convergence Research Center, Korea University Anam Hospital, Seoul, Republic of Korea. Electronic address: hambj@korea.ac.kr.
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.
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.
Authors: Kelsey S Moore; Reece Moore; Diana B Fulmer; Lilong Guo; Cortney Gensemer; Rebecca Stairley; Janiece Glover; Tyler C Beck; Jordan E Morningstar; Rachel Biggs; Rupak Muhkerjee; Alexander Awgulewitsch; Russell A Norris Journal: J Cardiovasc Dev Dis Date: 2022-02-17
Authors: Jonathan A Hollander; Deborah A Cory-Slechta; Felice N Jacka; Steven T Szabo; Tomás R Guilarte; Staci D Bilbo; Carolyn J Mattingly; Sheryl S Moy; Ebrahim Haroon; Mady Hornig; Edward D Levin; Mikhail V Pletnikov; Julia L Zehr; Kimberly A McAllister; Anika L Dzierlenga; Amanda E Garton; Cindy P Lawler; Christine Ladd-Acosta Journal: Neuropsychopharmacology Date: 2020-02-28 Impact factor: 8.294
Authors: Timothy A McCaffrey; Georges St Laurent; Dmitry Shtokalo; Denis Antonets; Yuri Vyatkin; Daniel Jones; Eleanor Battison; Joel T Nigg Journal: BMC Med Genomics Date: 2020-10-28 Impact factor: 3.063