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Title: Polymorphisms in MIR137HG and microRNA-137-regulated genes influence gray matter structure in schizophrenia

Evidence suggests that microRNA-137 (miR-137) is involved in the genetic basis of schizophrenia. Risk variants within the miR-137 host gene (MIR137HG) influence structural and functional brain-imaging measures, and miR-137 itself is predicted to regulate hundreds of genes. We evaluated the influence of a MIR137HG risk variant (rs1625579) in combination with variants in miR-137- regulated genes TCF4, PTGS2, MAPK1 and MAPK3 on gray matter concentration (GMC). These genes were selected based on our previous work assessing schizophrenia risk within possible miR-137-regulated gene sets using the same cohort of subjects. A genetic risk score (GRS) was determined based on genotypes of these four schizophrenia risk-associated genes in 221 Caucasian subjects (89 schizophrenia patients and 132 controls). The effects of the rs1625579 genotype with the GRS of miR-137-regulated genes in a three-way interaction with diagnosis on GMC patterns were assessed using a multivariate analysis. We found that schizophrenia subjects homozygous for the MIR137HG risk allele show significant decreases in occipital, parietal and temporal lobe GMC with increasing miR-137-regulated GRS, whereas those carrying the protective minor allele show significant increases in GMC with GRS. No correlations of GMC and GRS were found in control subjects. Variants within or upstream of genes regulated by miR-137more » in combination with the MIR137HG risk variant may influence GMC in schizophrenia-related regions in patients. Furthermore, given that the genes evaluated here are involved in protein kinase A signaling, dysregulation of this pathway through alterations in miR-137 biogenesis may underlie the gray matter loss seen in the disease.« less
Authors:
 [1] ;  [2] ;  [2] ;  [2] ;  [1] ;  [3] ;  [4] ;  [5] ;  [5] ;  [6]
  1. The Mind Research Network, Albuquerque, NM (United States); Univ. of New Mexico, Albuquerque, NM (United States)
  2. The Mind Research Network, Albuquerque, NM (United States)
  3. Technische Univ., Dresden (Germany); Harvard Medical School, Massachusetts General Hospital, Boston, MA (United States); Massachusetts General Hospital, Charlestown, MA (United States)
  4. Northwestern Univ. Feinberg School of Medicine, Chicago, IL (United States)
  5. Univ. of New Mexico, Albuquerque, NM (United States)
  6. The Mind Research Network, Albuquerque, NM (United States); Georgia State Univ., Atlanta, GA (United States)
Publication Date:
OSTI Identifier:
1258018
Grant/Contract Number:
FG02-99ER62764
Type:
Accepted Manuscript
Journal Name:
Translational Psychiatry
Additional Journal Information:
Journal Volume: 6; Journal Issue: 2; Journal ID: ISSN 2158-3188
Publisher:
Nature Publishing Group
Research Org:
Minds Institute, Sacramento, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES