Limited evidence for association of genome-wide schizophrenia risk variants on cortical neuroimaging phenotypes

Aristotle N. Voineskos, Daniel Felsky, Anne L. Wheeler, David J. Rotenberg, Melissa Levesque, Sejal Patel, Philip R. Szeszko, James L. Kennedy, Todd Lencz, Anil K. Malhotra

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Background: 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. Methods: 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). Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)1027-1036
Number of pages10
JournalSchizophrenia Bulletin
Issue number4
StatePublished - Jul 2016
Externally publishedYes


  • Asymmetry
  • Cortical thickness
  • DTI
  • Imaging genetics
  • Polygenic risk


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