title: A targeted sequencing study of glutamatergic candidate genes in suicide attempters with bipolar disorder.
abstract: Suicidal behavior has been shown to have a heritable component that is partly driven by psychiatric disorders [Brent and Mann, 2005]. However, there is also an independent factor contributing to the heritability of suicidal behavior. We previously conducted a genome-wide association study (GWAS) of bipolar suicide attempters and bipolar non-attempters to assess this independent factor [Willour et al., 2012]. This GWAS implicated glutamatergic neurotransmission in attempted suicide. In the current study, we have conducted a targeted next-generation sequencing study of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, neurexin, and neuroligin gene families in 476 bipolar suicide attempters and 473 bipolar non-attempters. The goal of this study was to gather sequence information from coding and regulatory regions of these glutamatergic genes to identify variants associated with attempted suicide. We identified 186 coding variants and 4,298 regulatory variants predicted to be functional in these genes. No individual variants were overrepresented in cases or controls to a degree that was statistically significant after correction for multiple testing. Additionally, none of the gene-level results were statistically significant following correction. While this study provides no direct support for a role of the examined glutamatergic candidate genes, further sequencing in expanded gene sets and datasets will be required to ultimately determine whether genetic variation in glutamatergic signaling influences suicidal behavior. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Sophia C
authors.initials: SC
authors.lastname: Gaynor
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Marie E
authors.initials: ME
authors.lastname: Breen
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Monson
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Kelly
authors.initials: K
authors.lastname: de Klerk
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Meredith
authors.initials: M
authors.lastname: Parsons
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Adam P
authors.initials: AP
authors.lastname: DeLuca
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa.|Department of Biomedical Engineering, University of Iowa College of Engineering, Iowa City, Iowa.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Scheetz
authors.affiliation: Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Zandi
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Willour
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001714:Bipolar Disorder / Q000235:genetics* / Q000523:psychology; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D018846:Excitatory Amino Acids; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D019006:Neural Cell Adhesion Molecules; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D059020:Suicidal Ideation; D013405:Suicide / Q000523:psychology; D013406:Suicide, Attempted / Q000523:psychology*
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D018846:Excitatory Amino Acids; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D016194:Receptors, N-Methyl-D-Aspartate; C093438:neuroligin 1; D018698:Glutamic Acid
keywords: GRIN3A; NLGN1; bipolar disorder; candidate gene sequencing; suicidal behavior