title: Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia.
abstract: Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate=10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder.
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: P H
authors.initials: PH
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, USA.|Schizophrenia and Bipolar Disorder Program, Psychotic Disorders Division, McLean Hospital, Belmont, MA, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Baker
authors.affiliation: Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, USA.|Department of Psychology, Yale University, New Haven, CT, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Holmes
authors.affiliation: Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Jahanshad
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.|Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ge
authors.affiliation: Department of Pediatrics, Division of Systems Medicine, Stanford University, Stanford, CA, USA.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Jung
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Harvard Graduate School of Education, Cambridge, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Cruz
authors.affiliation: Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Manoach
authors.affiliation: Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Hibar
authors.affiliation: Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Faskowitz
authors.affiliation: Centre for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia.
authors.forename: K L
authors.initials: KL
authors.lastname: McMahon
authors.affiliation: Faculty of Health and Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, QLD, Australia.
authors.forename: G I
authors.initials: GI
authors.lastname: de Zubicaray
authors.affiliation: Queensland Institute of Medical Research (QIMR) Berghofer, Brisbane, QLD, Australia.
authors.forename: N G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Centre for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia.|Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Wright
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, USA.|Schizophrenia and Bipolar Disorder Program, Psychotic Disorders Division, McLean Hospital, Belmont, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Öngür
authors.affiliation: Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, USA.|Department of Psychology and Center for Brain Science, Harvard University, Cambridge, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Buckner
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, USA.|Schizophrenia Clinical and Research Program, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Roffman
authors.affiliation: Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Thompson
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Smoller
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000033:anatomy & histology / Q000503:physiopathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D066128:Gray Matter / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*