title: Limited Evidence for Association of Genome-Wide Schizophrenia Risk Variants on Cortical Neuroimaging Phenotypes.
abstract: There are now over 100 established genetic risk variants for schizophrenia; however, their influence on brain structure and circuitry across the human lifespan are not known.
  
  
  
  We examined healthy individuals 8-86 years of age, from the Centre for Addiction and Mental Health, the Zucker Hillside Hospital, and the Philadelphia Neurodevelopmental Cohort. Following thorough quality control procedures, we investigated associations of established genetic risk variants with heritable neuroimaging phenotypes relevant to schizophrenia, namely thickness of frontal and temporal cortical regions (n = 565) and frontotemporal and interhemispheric white matter tract fractional anisotropy (FA) (n = 530).
  
  
  
  There was little evidence for association of risk variants with imaging phenotypes. No association with cortical thickness of any region was present. Only rs12148337, near a long noncoding RNA region, was associated with white matter FA (splenium of corpus callosum) following multiple comparison correction (corrected p = .012); this single nucleotide polymorphism was also associated with genu FA and superior longitudinal fasciculus FA at p <.005 (uncorrected). There was no association of polygenic risk score with white matter FA or cortical thickness.
  
  
  
  In sum, our findings provide limited evidence for association of schizophrenia risk variants with cortical thickness or diffusion imaging white matter phenotypes. When taken with recent lack of association of these variants with subcortical brain volumes, our results either suggest that structural neuroimaging approaches at current resolution are not sufficiently sensitive to detect effects of these risk variants or that multiple comparison correction in correlated phenotypes is too stringent, potentially "eliminating" biologically important signals.
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; These authors contributed equally to the article. Aristotle.Voineskos@camh.ca.
authors.forename: Aristotle N
authors.initials: AN
authors.lastname: Voineskos
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; These authors contributed equally to the article.
authors.forename: Daniel
authors.initials: D
authors.lastname: Felsky
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Anne L
authors.initials: AL
authors.lastname: Wheeler
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada;
authors.forename: David J
authors.initials: DJ
authors.lastname: Rotenberg
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada;
authors.forename: Melissa
authors.initials: M
authors.lastname: Levesque
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada;
authors.forename: Sejal
authors.initials: S
authors.lastname: Patel
authors.affiliation: Zucker Hillside Hospital, Glen Oaks, NY; Center for Psychiatric Neuroscience, Feinstein Institute, Manhasset, NY.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Szeszko
authors.affiliation: Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada;
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.affiliation: Zucker Hillside Hospital, Glen Oaks, NY; Center for Psychiatric Neuroscience, Feinstein Institute, Manhasset, NY.
authors.forename: Todd
authors.initials: T
authors.lastname: Lencz
authors.affiliation: Zucker Hillside Hospital, Glen Oaks, NY; Center for Psychiatric Neuroscience, Feinstein Institute, Manhasset, NY.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Malhotra
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002540:Cerebral Cortex / Q000000981:diagnostic imaging*; D002648:Child; D015331:Cohort Studies; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000706:statistics & numerical data*; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012559:Schizophrenia / Q000000981:diagnostic imaging* / Q000235:genetics*; D066127:White Matter / Q000000981:diagnostic imaging*; D055815:Young Adult
keywords: DTI; asymmetry; cortical thickness; imaging genetics; polygenic risk