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

Genome-wide significant linkage of schizophrenia-related neuroanatomical trait to 12q24.

Author information

1
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
2
Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Connecticut.
3
The Mind Research Network, Albuquerque, New Mexico.
4
Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.
5
South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, Texas.
6
Department of Psychiatry, University of Texas Health Science Center San Antonio, San Antonio, Texas.
7
Department of Psychiatry, University of Maryland School of Medicine, Maryland Psychiatric Research Center, Baltimore, Maryland.
8
Research Imaging Institute, University of Texas Health Science Center San Antonio, San Antonio, Texas.
9
Department of Psychiatry, University of New Mexico, Albuquerque, New Mexico.
10
Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, New Mexico.
11
Department of Psychology and Neuroscience Institute, Georgia State University, Atlanta, Georgia.

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.

KEYWORDS:

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

PMID:
26440917
PMCID:
PMC4639444
DOI:
10.1002/ajmg.b.32360
[Indexed for MEDLINE]
Free PMC Article

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