title: Genome-wide significant linkage of schizophrenia-related neuroanatomical trait to 12q24.
abstract: The insula and medial prefrontal cortex (mPFC) share functional, histological, transcriptional, and developmental characteristics, and they serve higher cognitive functions of theoretical relevance to schizophrenia and related disorders. Meta-analyses and multivariate analysis of structural magnetic resonance imaging (MRI) scans indicate that gray matter density and volume reductions in schizophrenia are the most consistent and pronounced in a network primarily composed of the insula and mPFC. We used source-based morphometry, a multivariate technique optimized for structural MRI, in a large sample of randomly ascertained pedigrees (N = 887) to derive an insula-mPFC component and to investigate its genetic determinants. Firstly, we replicated the insula-mPFC gray matter component as an independent source of gray matter variation in the general population, and verified its relevance to schizophrenia in an independent case-control sample. Secondly, we showed that the neuroanatomical variation defined by this component is largely determined by additive genetic variation (h(2)  = 0.59), and genome-wide linkage analysis resulted in a significant linkage peak at 12q24 (LOD = 3.76). This region has been of significant interest to psychiatric genetics as it contains the Darier's disease locus and other proposed susceptibility genes (e.g., DAO, NOS1), and it has been linked to affective disorders and schizophrenia in multiple populations. Thus, in conjunction with previous clinical studies, our data imply that one or more psychiatric risk variants at 12q24 are co-inherited with reductions in mPFC and insula gray matter concentration. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.|Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Connecticut.
authors.forename: Emma
authors.initials: E
authors.lastname: Sprooten
authors.affiliation: The Mind Research Network, Albuquerque, New Mexico.
authors.forename: Cota Navin
authors.initials: CN
authors.lastname: Gupta
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.|Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Connecticut.
authors.forename: Emma E M
authors.initials: EE
authors.lastname: Knowles
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.|Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Connecticut.
authors.forename: D Reese
authors.initials: DR
authors.lastname: McKay
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.|Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Connecticut.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Mathias
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.|South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.|South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Kent
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.|South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Carless
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.|South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas.
authors.forename: Marcio A
authors.initials: MA
authors.lastname: Almeida
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.|South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.|South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas.
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.affiliation: Department of Psychiatry, University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Rene L
authors.initials: RL
authors.lastname: Olvera
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Maryland Psychiatric Research Center, Baltimore, Maryland.
authors.forename: Peter
authors.initials: P
authors.lastname: Kochunov
authors.affiliation: Research Imaging Institute, University of Texas Health Science Center San Antonio, San Antonio, Texas.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Fox
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.|South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas.
authors.forename: Ravi
authors.initials: R
authors.lastname: Duggirala
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.|South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas.
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.|The Mind Research Network, Albuquerque, New Mexico.|Department of Psychiatry, University of New Mexico, Albuquerque, New Mexico.|Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.|South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: The Mind Research Network, Albuquerque, New Mexico.|Department of Psychology and Neuroscience Institute, Georgia State University, Atlanta, Georgia.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Turner
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.|Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Connecticut.
authors.forename: David C
authors.initials: DC
authors.lastname: Glahn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002540:Cerebral Cortex / Q000473:pathology; D002881:Chromosomes, Human, Pair 12; D003071:Cognition; D005260:Female; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D066128:Gray Matter / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D017058:Mexican Americans; D008875:Middle Aged; D015999:Multivariate Analysis; D017397:Prefrontal Cortex / Q000473:pathology; D012559:Schizophrenia / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D055815:Young Adult
keywords: extended pedigrees; insula; magnetic resonance imaging; medial prefrontal cortex; quantitative trait locus