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

Authors

Emma Sprooten
Cota Navin Gupta
Emma Knowles
D. Reese McKay
Samuel R. Mathias
Joanne E. Curran, The University of Texas Rio Grande Valley
Jack W. Kent Jr.
Melanie A. Carless
Marcio Almeida, The University of Texas Rio Grande Valley
Thomas D. Dyer, The University of Texas Rio Grande Valley
Harald H. H. Goring, The University of Texas Rio Grande Valley
Rene L. Olvera, The University of Texas Rio Grande Valley
Peter T. Fox
Ravi Duggirala, The University of Texas Rio Grande Valley
Laura Almasy, The University of Texas Rio Grande Valley
John Blangero, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

12-2015

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 (h2 = 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.

Comments

Original published version available at https://onlinelibrary.wiley.com/doi/10.1002/ajmg.b.32360

Recommended Citation

Sprooten, E., Gupta, C. N., Knowles, E. E., McKay, D. R., Mathias, S. R., Curran, J. E., Kent, J. W., Jr, Carless, M. A., Almeida, M. A., Dyer, T. D., Göring, H. H., Olvera, R. L., Kochunov, P., Fox, P. T., Duggirala, R., Almasy, L., Calhoun, V. D., Blangero, J., Turner, J. A., & Glahn, D. C. (2015). Genome-wide significant linkage of schizophrenia-related neuroanatomical trait to 12q24. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 168(8), 678–686. https://doi.org/10.1002/ajmg.b.32360

Publication Title

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

DOI

10.1002/ajmg.b.32360

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics