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Schizophr Bull. 2014 Nov;40(6):1263-71. doi: 10.1093/schbul/sbt174. Epub 2013 Dec 10.

Prefrontal inefficiency is associated with polygenic risk for schizophrenia.

Author information

1
Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany;
2
The Mind Research Network, Albuquerque, NM;
3
Minneapolis Veterans Affairs Health Care System, Minneapolis, MN; Department of Psychiatry, University of Minnesota, Minneapolis, MN;
4
Department of Child and Adolescent Psychiatry, Erasmus University, Rotterdam, Netherlands;
5
Department of Psychiatry, University of Iowa, Iowa City, IA;
6
Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA; MGH/MIT/HMS Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA;
7
The Mind Research Network, Albuquerque, NM; Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM.
8
Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany; Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA; MGH/MIT/HMS Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA; stefan@nmr.mgh.harvard.edu.

Abstract

Considering the diverse clinical presentation and likely polygenic etiology of schizophrenia, this investigation examined the effect of polygenic risk on a well-established intermediate phenotype for schizophrenia. We hypothesized that a measure of cumulative genetic risk based on additive effects of many genetic susceptibility loci for schizophrenia would predict prefrontal cortical inefficiency during working memory, a brain-based biomarker for the disorder. The present study combined imaging, genetic and behavioral data obtained by the Mind Clinical Imaging Consortium study of schizophrenia (n = 255). For each participant, we derived a polygenic risk score (PGRS), which was based on over 600 nominally significant single nucleotide polymorphisms, associated with schizophrenia in a separate discovery sample comprising 3322 schizophrenia patients and 3587 control participants. Increased polygenic risk for schizophrenia was associated with neural inefficiency in the left dorsolateral prefrontal cortex after covarying for the effects of acquisition site, diagnosis, and population stratification. We also provide additional supporting evidence for our original findings using scores based on results from the Psychiatric Genomics Consortium study. Gene ontology analysis of the PGRS highlighted genetic loci involved in brain development and several other processes possibly contributing to disease etiology. Our study permits new insights into the additive effect of hundreds of genetic susceptibility loci on a brain-based intermediate phenotype for schizophrenia. The combined impact of many common genetic variants of small effect are likely to better reveal etiologic mechanisms of the disorder than the study of single common genetic variants.

KEYWORDS:

DLPFC; fMRI; genetic risk score; intermediate phenotype; schizophrenia; working memory

PMID:
24327754
PMCID:
PMC4193692
DOI:
10.1093/schbul/sbt174
[Indexed for MEDLINE]
Free PMC Article

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