Analysis of t(9;17)(q33.2;q25.3) chromosomal breakpoint regions and genetic association reveals novel candidate genes for bipolar disorder

TY - JOUR

T1 - Analysis of t(9;17)(q33.2;q25.3) chromosomal breakpoint regions and genetic association reveals novel candidate genes for bipolar disorder

AU - Rajkumar, Anto

AU - Christensen, Jane H

AU - Mattheisen, Manuel

AU - Jacobsen, Iben

AU - Bache, Iben

AU - Pallesen, Jonatan

AU - Grove, Jakob

AU - Qvist, Per

AU - McQuillin, Andrew

AU - Gurling, Hugh M

AU - Tümer, Zeynep

AU - Mors, Ole

AU - Børglum, Anders D

N1 - © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PY - 2015/3

Y1 - 2015/3

N2 - OBJECTIVES: Breakpoints of chromosomal abnormalities facilitate identification of novel candidate genes for psychiatric disorders. Genome-wide significant evidence supports the linkage between chromosome 17q25.3 and bipolar disorder (BD). Co-segregation of translocation t(9;17)(q33.2;q25.3) with psychiatric disorders has been reported. We aimed to narrow down these chromosomal breakpoint regions and to investigate the associations between single nucleotide polymorphisms within these regions and BD as well as schizophrenia (SZ) in large genome-wide association study samples.METHODS: We cross-linked Danish psychiatric and cytogenetic case registers to identify an individual with both t(9;17)(q33.2;q25.3) and BD. Fluorescent in situ hybridization was employed to map the chromosomal breakpoint regions of this proband. We accessed the Psychiatric Genomics Consortium BD (n = 16,731) and SZ (n = 21,856) data. Genetic associations between these disorders and single nucleotide polymorphisms within these breakpoint regions were analysed by BioQ, FORGE, and RegulomeDB programmes.RESULTS: Four protein-coding genes [coding for (endonuclease V (ENDOV), neuronal pentraxin I (NPTX1), ring finger protein 213 (RNF213), and regulatory-associated protein of mammalian target of rapamycin (mTOR) (RPTOR)] were found to be located within the 17q25.3 breakpoint region. NPTX1 was significantly associated with BD (p = 0.004), while ENDOV was significantly associated with SZ (p = 0.0075) after Bonferroni correction.CONCLUSIONS: Prior linkage evidence and our findings suggest NPTX1 as a novel candidate gene for BD.

AB - OBJECTIVES: Breakpoints of chromosomal abnormalities facilitate identification of novel candidate genes for psychiatric disorders. Genome-wide significant evidence supports the linkage between chromosome 17q25.3 and bipolar disorder (BD). Co-segregation of translocation t(9;17)(q33.2;q25.3) with psychiatric disorders has been reported. We aimed to narrow down these chromosomal breakpoint regions and to investigate the associations between single nucleotide polymorphisms within these regions and BD as well as schizophrenia (SZ) in large genome-wide association study samples.METHODS: We cross-linked Danish psychiatric and cytogenetic case registers to identify an individual with both t(9;17)(q33.2;q25.3) and BD. Fluorescent in situ hybridization was employed to map the chromosomal breakpoint regions of this proband. We accessed the Psychiatric Genomics Consortium BD (n = 16,731) and SZ (n = 21,856) data. Genetic associations between these disorders and single nucleotide polymorphisms within these breakpoint regions were analysed by BioQ, FORGE, and RegulomeDB programmes.RESULTS: Four protein-coding genes [coding for (endonuclease V (ENDOV), neuronal pentraxin I (NPTX1), ring finger protein 213 (RNF213), and regulatory-associated protein of mammalian target of rapamycin (mTOR) (RPTOR)] were found to be located within the 17q25.3 breakpoint region. NPTX1 was significantly associated with BD (p = 0.004), while ENDOV was significantly associated with SZ (p = 0.0075) after Bonferroni correction.CONCLUSIONS: Prior linkage evidence and our findings suggest NPTX1 as a novel candidate gene for BD.

KW - Adaptor Proteins, Signal Transducing

KW - Bipolar Disorder

KW - C-Reactive Protein

KW - Chromosomes, Human, Pair 17

KW - Chromosomes, Human, Pair 9

KW - Deoxyribonuclease (Pyrimidine Dimer)

KW - Family

KW - Genetic Linkage

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - In Situ Hybridization, Fluorescence

KW - Nerve Tissue Proteins

KW - Polymorphism, Single Nucleotide

KW - Schizophrenia

KW - Translocation, Genetic

KW - Ubiquitin-Protein Ligases

U2 - 10.1111/bdi.12239

DO - 10.1111/bdi.12239

M3 - Article

C2 - 25053281

SN - 1398-5647

VL - 17

SP - 205

EP - 211

JO - Bipolar Disorders

JF - Bipolar Disorders

IS - 2

ER -