Genome-wide Significant Linkage of Schizophrenia-Related Neuroanatomical Trait to 12q24

Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):678-86. doi: 10.1002/ajmg.b.32360. Epub 2015 Oct 5.


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.

Keywords: extended pedigrees; insula; magnetic resonance imaging; medial prefrontal cortex; quantitative trait locus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Cerebral Cortex / pathology
  • Chromosomes, Human, Pair 12*
  • Cognition
  • Female
  • Genetic Linkage
  • Genome-Wide Association Study
  • Gray Matter / pathology
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mexican Americans*
  • Middle Aged
  • Multivariate Analysis
  • Prefrontal Cortex / pathology
  • Schizophrenia / ethnology
  • Schizophrenia / genetics*
  • Schizophrenia / pathology*
  • Young Adult