A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Johanna Hass - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Esther Walton - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Holger Kirsten - , Universität Leipzig (Autor:in)
  • Jingyu Liu - , University of New Mexico, The Mind Research Network (Autor:in)
  • Lutz Priebe - , Universität Bonn (Autor:in)
  • Christiane Wolf - , Max Planck Institute of Psychiatry (Autor:in)
  • Nazanin Karbalai - , Max Planck Institute of Psychiatry (Autor:in)
  • Randy Gollub - , Harvard University, Massachusetts General Hospital (Autor:in)
  • Tonya White - , University of Minnesota System (Autor:in)
  • Veit Roessner - , Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Kathrin U. Müller - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Tomas Paus - , University of Toronto, University of Nottingham, Centre Universitaire de Sante McGill (Autor:in)
  • Michael N. Smolka - , Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Gunter Schumann - , King's College London (KCL) (Autor:in)
  • Markus Scholz - , Universität Leipzig (Autor:in)
  • Sven Cichon - , Universität Bonn, Max Planck Institute of Psychiatry, Forschungszentrum Jülich (Autor:in)
  • Vince Calhoun - , University of New Mexico, The Mind Research Network (Autor:in)
  • Stefan Ehrlich - , Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Universitätsklinikum Carl Gustav Carus Dresden, Massachusetts General Hospital, University of Minnesota System (Autor:in)

Abstract

Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75×10-6 and 8.3×10-7. Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders.

Details

OriginalspracheEnglisch
Aufsatznummere64872
FachzeitschriftPloS one
Jahrgang8
Ausgabenummer6
PublikationsstatusVeröffentlicht - 21 Juni 2013
Peer-Review-StatusJa

Externe IDs

PubMed 23805179
ORCID /0000-0003-2132-4445/work/160950929
ORCID /0000-0001-5398-5569/work/160953125

Schlagworte

ASJC Scopus Sachgebiete